Nadia I. Awad, PharmD, MS, BCPS
Emergency Medicine Pharmacist
Robert Wood Johnson University Hospital
New Brunswick, New Jersey
Twitter: @Nadia_EMPharmD

Introduction

Given the burden of opioid harms realized in recent years, acute care providers must develop an arsenal of alternatives for the management of both acute and chronic pain. Many of the agents reviewed in this chapter–central alpha agonists, gabapentinoids, and sodium channel antagonists– are utilized in an off-label fashion and via non-conventional routes of administration. Healthcare providers may therefore consider developing local guidelines and criteria for appropriate use in patients who present with various pain conditions.

Central Alpha Agonists

Central alpha agonists have been utilized for decades as adjunctive agents for the management of acute pain. Much of the evidence surrounding the use clonidine and dexmedetomidine originates from their clinical application in the perioperative period and ICU. 

Clonidine and dexmedetomidine are alpha-2 receptor agonists; dexmedetomidine is more selective for the alpha-2 receptor than clonidine and also stimulates the alpha-1 receptor. (Giovannitti 2015, Habib AS 2005)

Alpha-2 receptors are present throughout both the peripheral and central nervous systems; their target organs include the brainstem and vascular smooth muscle. Presynaptic alpha-2 receptor activation results in sympatholysis, sedation, hypotension, bradycardia and analgesia. It is thought that analgesic effects arise from alpha-2A targets in the spinal cord and midbrain and agonism of imidazoline receptors (Smith H 2001) In addition, clonidine inhibits the release of substance P in animal models, which may contribute to its analgesic effects. (Pal 1997) The analgesic effects induced by alpha-2 agonists has been noted to occur along the supraspinal pathways and, more notably, in the dorsal horn of the spinal column. (Viratanen R 1988,Jaakola ML 1991, Zhu QM 1999)

In addition to its traditional use as an antihypertensive agent, clonidine has been used in the perioperative setting, particularly for anxiolysis and sedation. It has been used in both adults and children at doses between 2 and 5 mcg/kg orally. When used in this setting, in addition to providing adequate sedation and anxiolysis, clonidine is associated with a decrease in both intraoperative anesthetic requirements as well as the need for postoperative opioid analgesics. (Hall DL 2006) (Cao J 2009) (Yanagidate F 2001) (Marinangeli F 2002) (Bergendahl HT 2004) (Blaudszun G 2012) Intravenous clonidine, given as a bolus  between 2 and 5 mcg/kg, has been used for the management of post-operative pain in both adult and pediatric patients. (Giovannoni MP 2009) (Sung CS 2000) (Lyons B 1996) 

Clonidine has been used as an analgesic adjunct in peripheral nerve blocks in conjunction with local anesthetics, but has not demonstrated superiority to intermediate-acting and long-acting local anesthetics alone. (McCartney CJ 2007) (Popping DM 2009) (Axelsson K 2009)

Though topical clonidine has been extensively studied for neuropathic pain, one recent Cochrane Review concluded that the evidence surrounding its clinical application in this setting is low to moderate at best for peripheral diabetic neuropathy, with inconclusive evidence for its use in the management of pain associated with other neuropathic conditions. (Wrzosek A 2015)

The use of dexmedetomidine has traditionally been confined to sedation and analgesia in patients requiring mechanical ventilation in the intensive care unit setting. The standard regimen includes a loading dose of 1 mcg/kg intravenous bolus over ten minutes followed by a continuous intravenous infusion of 0.2 to 1 mcg/kg/hr. (Venn RM 2002) Dexmedetomidine has been used as an adjunct to benzodiazepines in the management of patients with alcohol withdrawal syndrome, but most studies have not evaluated clinical outcomes beyond its potential benzodiazepine-sparing effects. (Wong A 2015) (Bielka K 2015) (Vanderweide LA 2016) (Beg M 2016) (Hayes BD 2016) Relative to other common agents used in this setting, such as benzodiazepines, one of the advantages that dexmedetomidine poses is the lack of respiratory compromise and/or depression. A disadvantage is the inability of central alpha agonists to treat the underlying  pathophysiology of withdrawal, allowing them to serve only as an adjunct agent to a GABA-ergic agent.

With its effective distribution half-life of six minutes, highly lipophilic nature, and elimination half-life of two hours, dexmedetomidine has an evolving role as a sedo-analgesic agent in both adult and pediatric patients, demonstrating a decrease in benzodiazepine requirements by 80% and decrease in opioids by 50 to 75%. (Venn RM 2002) (Nichols DP 2005) (Berkenbosch JW 2005) (Koroglu A 2005) (Mason KP 2008) (Jewett J 2010) (Godwin SA 2014) 

Dexmedetomidine is well-studied in pediatric patients and in patients undergoing non-invasive procedures, and there is limited literature describing its use in combination with ketamine as a means to mitigate the adverse effects of each agent. (Tobias JD 2012) (Goyal R 2013) (Kako H 2014) (Goyal R 2016) (Hadi SM 2015) (Ibacache ME 2015)

The manufacturer of dexmedetomidine has put forth recommendations for its use as an adjunctive sedative agent in procedural sedation to augment sedation and minimize respiratory depression when used in conjunction with benzodiazepines, opioid analgesics, and propofol. Below is a table with guiding doses for dexmedetomidine for initiation and maintenance when used for procedural sedation:

Similar to clonidine, dexmedetomidine has been demonstrated to induce analgesia and decrease opioid requirements for analgesia in both the intraoperative and perioperative periods, but further evaluation of the use of dexmedetomidine for this purpose is needed. (Bhana N 2000) (Alhashemi JA 2004) (Arain SR 2004) (Aho MS 1991) (Schnabel A 2013) Vaso-occlusive pain crisis associated with sickle cell disease is another potential area for further investigation of the analgesic role of dexmedetomidine. (Sheehy KA 2015) (Phillips WJ 2007)

Dexmedetomidine has also been evaluated for administration via the buccal, intranasal, and oral routes in pediatric patients to induce sedation and anxiolysis. Recommended buccal and oral doses of dexmedetomidine range between 3 and 4 mcg/kg and doses that have been evaluated for administration via the intranasal route are 1 to 1.5 mcg/kg. (Cimen ZS 2013) (Mountain BW 2011) (Sakurai Y 2010) (Fallah R 2015) (Karaaslan D 2006) Intramuscular dexmedetomidine has been evaluated as a surgical premedication for induction of sedation and maintenance of analgesia, as well as a sedative to facilitate painless procedures (CT, MRI, EEG) with doses generally ranging between 1 and 4.5 mcg/kg. (Mason KP 2012) (Ravipati P 2014) (Sun Y 2014) (Mason KP 2011) (Karaaslan D 2006)

Alpha-2 agonists cause dose-dependent hypotension and bradycardia, and should be used cautiously or avoided in hemodynamically marginal patients or those with a history of bradyarrhythmia.

Compared to opioids, clonidine and dexmedetomidine may be of particular value for analgesia, anxiolysis, and sedation of patients with obstructive sleep apnea, as alpha-2 agonists cause comparatively little respiratory depression. (Pawlik MT 2005) (Sollazzi L 2009) Dexmedetomidine should be dosed according to ideal body weight. (Cortinez LI 2015) (Ingrande J 2010, Tu 2015) 

There is a paucity of evidence for the use of dexmedetomidine in the emergency department, with the bulk of the literature surrounding the use of dexmedetomidine for procedural sedation and analgesia coming from its use in anesthesiology and critical care. The conventional ten-minute bolus dose followed by continuous infusion is suboptimal for use in a chaotic emergency department, and the traditional dosing is prone to errors relative to other agents that have been more commonly and safely used for procedural sedation, analgesia, and anxiolysis. (Calver L 2012) Though dexmedetomidine has a number of limitations for use in the ED, especially in patients prone to hypotension or bradycardia, its unique sympatholytic, hypnotic, and analgesic properties absent respiratory depression make it appealing for a variety of emergency indications, particularly if more favorable dosing strategies are developed. 

Gabapentinoids

Gabapentin and pregabalin have a long history of use in the management of neuropathic pain, and may play a role as an alternative to opioid analgesics for certain acute and chronic pain conditions in the emergency department. 

Although gabapentin and pregabalin are structurally similar to gamma-amino-butyric acid (GABA), the major inhibitory transmitter within the central nervous system, they do not interact with this system at therapeutic doses. Their hypothesized mechanism of action is binding to the alpha-2-delta subunit of voltage-gated calcium channels, which increase in expression after nerve injury. (Field MJ 2006) (Gee NS 1996) (Taylor CP 2009) (Kremer M 2016) (Patel R 2016)

Gabapentin has a favorable record of efficacy for various peripheral neuropathies such as post-herpetic neuralgia, mixed neuropathic pain, diabetic neuropathy, Guillain-Barre syndrome, amputation phantom limb pain, complex regional pain syndrome, pain associated with multiple sclerosis, carpal tunnel syndrome, sciatica, fibromyalgia, cancer-induced neuropathy, and pain induced by human immunodeficiency virus. (Canadian Agency for Drugs and Technologies in Health 2014) (Moore RA 2014) Doses of gabapentin evaluated in these studies generally ranged between 900 mg to 3600 mg daily divided in three to four oral doses.

Few studies have evaluated the safety and efficacy of pregabalin for peripheral neuropathic pain. However, as reviewed in the latest Cochrane analysis, doses of pregabalin ranging between 300 mg and 600 mg are generally effective for most patients with few adverse effects associated with use for chronic neuropathic pain; there is minimal evidence to suggest its utility in the management of acute pain. (Moore RA 2009)

Both gabapentin and, less so pregabalin, have been evaluated for reduction of perioperative and postoperative pain, which may be extrapolated to acute pain syndromes encountered in the emergency department. However, use of gabapentinoids in these clinical scenarios has demonstrated at best mixed results in their analgesic effects as well as in reduced use of opioid analgesics.  The advantage of a reduced incidence of nausea and vomiting induced by the surgical procedure with is balanced by the risk for gabapentinoid-induced adverse effects, which are predominantly somnolence, respiratory depression, and dizziness. (Yan PZ 2014) (Fabritius ML 2016) (Dahl JB 2014) (Mishriky BM 2015) (Clarke H 2012)(FDA 2019)

In the perioperative literature, gabapentin is initiated for analgesia with a loading dose of 1200 mg, then 600 mg TID.  (Schmidt PC 2013) Dosing in acute care settings is typically lower; starting with a loading dose of 300 mg followed by 100 mg TID, increasing each dose by 100 mg QOD as needed. (Cisewski 2019)

Gabapentinoids are generally well tolerated, with somnolence and dizziness as their most common adverse effects. Other adverse effects that have been reported with gabapentinoids include lethargy, respiratory depression, impaired memory, blurred vision, ataxia, diplopia, nausea, peripheral edema, constipation, impaired sexual function, and weight gain. Upon dose reduction or gradual downward tapering of the dose leading to discontinuation of the agent, these adverse effects are generally reversible. 

Gabapentin is commercially available as an oral solution (250 mg/5 mL), in addition to orally formulated capsules and tablets. In pediatric patients, gabapentin can be used for the treatment of neuropathic pain at an initial dose of 2 mg/kg/dose (up to 100 mg) by mouth daily. This may be titrated upward over a two-week period to 6 mg/kg/dose (up to 300 mg) TID. 

In efforts to thwart the ramifications of the prescription opioid abuse epidemic, gabapentinoids may pose some advantages in the provision of analgesia within specific patient populations – namely neuropathic pain syndromes. However, there is now emerging evidence to demonstrate that gabapentinoids are not without the consequences, of  misuse and abuse, which is fast becoming a global phenomenon. (Schifano F 2014) (Kapil V 2014) (Stannard C 2014) (Chiappini S 2016) The pharmacologic mechanism surrounding this effect may be explained their GABA-mimetic properties; their ability to induce a “high” may be related to their effects within the dopaminergic reward system, particularly with supratherapeutic doses. (Badgaiyan RD 2013) (Cai K 2012) (Mersfelder TL 2016) 

This potential for abuse did not go unrecognized in the approval process of pregabalin in the United States, as it is currently a schedule V substance under the Controlled Substance Act; however, gabapentin is still available as a non-controlled prescription medication. In the United Kingdom, with more reports of abuse of gabapentinoids, the Advisory Council on the Misuse of Drugs has taken action to recommend both gabapentin and pregabalin as category C substances. (Stannard C 2014)

In one cohort of patients with established opioid abuse, over 20% had misused gabapentin, and among these patients, 65% had been prescribed gabapentin for off-label use. (Smith RV 2016) Similarly, post-marketing evaluations of pregabalin have also demonstrated similar effects, particularly in those patients with a history of benzodiazepine abuse. (Gahr M 2013) (Schifano F 2011) (Schjerning O 2016) There are reports of the potentiation by gabapentinoids of effects induced by recreational opioids, including sedation and respiratory depression, and gabapentin co-prescribed with opioids has been associated with an increase in opioid-related death. (Baird CR 2014) (Reeves RR 2014) (Gomes 2017)

Gabapentinoids also have the potential to induce dependence leading to withdrawal, which may occur up to one week after abrupt cessation of therapy. Common signs and symptoms associated with withdrawal are similar to those observed during withdrawal from opioid analgesics. These findings include agitation, diaphoresis, hypertension, and insomnia, and may also cause confusion. (Mersfelder TL 2016)

In summary, gabapentin and pregabalin have a role in acute care in the management of neuropathic pain such as post-herpetic neuralgia and diabetic neuropathy. Gabapentinoids should not be routinely used to treat other types of acute and chronic pain, and should be avoided in patients who use daily opioids or are at risk for abuse and long term use harms.

Lidocaine and Sodium Channel Antagonists

Sodium channel antagonists are a therapeutic class of agents that have become increasingly popular in recent years for use in the emergency department due to their analgesic effects. Cocaine was the first local anesthetic discovered in this class of agents, and it was introduced as a topical anesthetic for ophthalmic surgery in 1884. Lidocaine was introduced nearly 70 years later as the search for local anesthetic agents with a shorter onset and longer duration of action ensued and shortly thereafter, by 1950, it was routinely being used in clinical practice with administration via several different routes for a variety of indications that continue along its trajectory of traditional uses today as a local anesthetic. Lidocaine is ubiquitous in the emergency department for its properties as a local anesthetic and anti-arrhythmic, and in recent years, it has emerged as the prototypical sodium channel antagonist that may be used to manage a variety of conditions associated with both acute and chronic pain. 

Local anesthetics generally fall within one of two categories based on their chemical structure – esters or amides. Lidocaine is an amide local anesthetic; other anesthetics that fall within this category include prilocaine, bupivacaine, and ropivicaine; ester local anesthetics include cocaine and procaine. (Whiteside JB 2001)

Lidocaine is widely used to induce local and regional anesthesia. The safe maximum dose when used for this indication is 4.5 mg/kg; however, if epinephrine is used as an adjunct, the safe maximum dose increases to 7 mg/kg. (McLure 2005) (Grabinsky A 2009) (Rosenberg PH 2004)

Topical formulations of lidocaine exist in the form of a gel, oral solution, and ointment. Viscous lidocaine available as a 2% oral solution has been used in clinical practice for topical application to minimize pain associated with inflammation in mucous membranes and dyspepsia. (Welling LR 1990) (Vilke GM 2004) (Hopper SM 2014) Topical ointments and gel formulations of lidocaine have also been used to facilitate minor procedures such as insertion of Foley catheters and nasogastric tubes. Some topical formulations of lidocaine are commercially available in combination with fixed ratios of other agents such as epinephrine and tetracaine (L.E.T. [4%:0.05 to 0.1%:0.5%] solution) and prilocaine (eutectic mixtures of local anesthetics, or EMLA cream [2.5% lidocaine:2.5% prilocaine] cream), which may be used as pre-treatment local anesthetic for wound lacerations. This may be beneficial in pediatric patients due to lack of pain associated with administration, no requirement for injection, and retention of wound edges. L.E.T. solution and EMLA cream should be applied to the site at least 20 and 45 minutes, respectively, prior to subsequent wound management. (Ali S 2016) L.E.T. can be used in the management of lacerations, however EMLA should not be applied to broken skin.

Lidocaine is available as a transdermal patch for topical application, and is approved by the FDA for use in the setting of post-herpetic neuralgia. This patch, containing 5% lidocaine in prescription form, should be applied for twelve hours of the day, and removed to provide a drug-free interval for 12 hours. It has gained some use in clinical practice for pain associated with rib fractures, but a recent review demonstrated that there was not sufficient evidence to support its use in improvement in control of pain nor in mitigation of requirements for opioid analgesics (Williams H 2015) Each patch contains 700 mg of lidocaine and no more than three patches should be applied topically to an adult within a 24-hour period. (PI Lidocaine) For patients who may be limited by the cost of the 5% lidocaine patch as a prescription, an over-the-counter patch formulation containing 4% lidocaine exists, which may be equally effective. (Castro 2017)

Other common uses for lidocaine include digital and hematoma blocks since little volume of the local anesthetic is required to achieve sufficient results, particularly when the 2% solution of lidocaine is used at the site. There is insufficient evidence to suggest that addition of vasoconstrictors such as epinephrine is associated with any risk or benefit  in digital nerve block. (Prabhakar H 2015) 

Intravenous regional anesthesia via the Bier block technique can also incorporate the use of lidocaine injected into the veins of the affected extremity with a dose of up to 3 mg/kg. This techniques has been described in the literature for the reduction of fractures in the ankle, elbow, forearm, and hand. (Mohr B 2006) (Grabinsky A 2009) (Blasier RD 1996)

Ultrasound-guided peripheral nerve block has gained popularity in recent years, and this technique has become part of institutional standards for both adult and pediatric patients in emergency departments across the country. There is much literature describing ultrasound-guided nerve block for femoral nerves in the setting of hip fractures, femur fractures, and patellar injuries; sciatic nerve block for distal tibia and fibula fractures; and interscalene brachial plexus nerve block for elbow dislocations and humeral and forearm injuries. (Liebmann O 2006) (Blaivas M 2011) (Beaudoin FL 2010) (Reid N 2009) (Stone MB 2008) (Herring AA 2012) (Beaudoin FL 2013) (Haines L 2012) (Guay J 2016) {See the Pain&PSA Regional Nerve Block Chapter}

Intra-articular lidocaine has been increasingly utilized in recent decades for manual reduction of anterior shoulder dislocations and may be a sedation-sparing alternative to intravenous sedation and analgesia. (Fitch RW 2008) (Wakai A 2011) (Jiang N 2014) (White BJ 2008) The typical dose of intra-articular lidocaine is 4 mg/kg up to a maximum of 200 mg (or 20 mL of 1% lidocaine solution). 

The systemic route of administration for lidocaine may be used for the management of pain in the ED. Doses of lidocaine ranging between 1 and 2 mg/kg administered as an intravenous infusion over 20 to 30 minutes have been evaluated for pain associated with conditions such as critical limb ischemia, (Vahidi E 2015) radiculopathy, (Tanen DA 2014) acute migraine (Reutens DC 1991) (Bell R 1990) and renal colic that is refractory to or as an alternative to traditional analgesics such as nonsteroidal anti-inflammatory drugs and opioids. (Soleimanpour H 2011) (Soleimanpour H 2012) (Sin B 2016) (Firouzian A 2016) Enthusiasm for IV lidocaine in this context has dampened with more recent negative studies, however. (Motov 2019)(Firouzian 2016) Following parenteral administration of lidocaine, its onset of action is within 10 minutes with a duration of action ranges between 30 and 60 minutes.

Toxicity may occur with sodium channel antagonists due to their systemic absorption in the general circulation. This phenomenon is known as local anesthetic systemic toxicity (LAST). (Tanawuttiwat T 2014)

Neurotoxicity may first manifest as a seizure through antagonism of the inhibitory neurons in the brain. This  unopposed excitability leads to altered mental status and decreases the seizure threshold. Seizures should be treated with benzodiazepines, immediate-acting barbiturates, or propofol. Other adverse effects associated with the central nervous system secondary to the systemic absorption of local anesthetics include headache, slurred speech, confusion, tremor, xerostomia, and perioral paresthesia. (Dorf 2006) (Drasner 2002)

Cardiotoxicity secondary to lidocaine can occur because of its action on the myocardium, where it reduces electrical excitability, which can slow down both the conduction rate and force of contraction within the ventricles. (Covino BG 1987) Other cardiotoxic effects include hypotension, prolongation of the PR interval, widening of the QRS complex (conduction abnormality), bradycardia, atrioventricular block, and cardiovascular collapse. (Alfano SN 1984)

Beyond implementation of standard measures of resuscitation, should serious manifestations of LAST occur, treatment of the patient with intravenous lipid emulsion therapy should be prioritized. Based on consensus guidelines, it may be reasonable to initiate treatment with a 20% solution of intravenous lipid emulsion; (Gosselin S 2016) one of the most commonly suggested regimens involves a bolus dose of 1.5 mL/kg (approximately 100 mL in a normal sized adult) followed by a continuous infusion of 0.25 to 0.5 mL/kg/min until there is resolution of toxicity or for up to 2 hours, whichever comes first.  (Neal JM 2010)

Another systemic adverse effect of certain local anesthetics is methemoglobinemia, where iron in hemoglobin is oxidized from the ferrous state to the ferric state, which decreases its oxygen-carrying capacity. Signs and symptoms associated with this condition may include altered mental status, cyanosis, fatigue, anxiety, lightheadedness, seizures, coma, and death. This condition is rarely induced by lidocaine compared to other local anesthetics, such as benzocaine. (Guay J 2009) With prompt recognition of local anesthetic-induced methemoglobinemia based on clinical signs and symptoms as well as a formal laboratory diagnosis, which entails evaluation of blood via co-oximetry and/or calculation of the oxygen saturation gap, antidotal treatment with methylene blue at a dose of 1 to 2 mg/kg administered intravenously over ten minutes should be initiated. (Barash M 2015) 

Tricyclic antidepressants (TCAs) such as amitriptyline are  sodium channel antagonists that are sometimes used off-label for analgesia. They are most often used in patients with chronic neuropathy associated with diabetes and postherpetic neuralgia as well as fibromyalgia, facial pain syndrome, arthritis, post-surgical pain, irritable bowel syndrome, headache, and non-freezing cold injury. (Verdu 2008) (Jackson 2010) (Wong 2014) (Joslin 2014) These agents antagonize both serotonin and norepinephrine transporters, which thereby inhibits the reuptake of these neurotransmitters. However, some of their analgesic properties may occur through modulation of the peripheral inflammatory cascade as well as due by antagonism of central sodium and calcium channels as well as N-methyl-D-aspartate receptors. (Verdu 2008) (Sawynok 2001) (Kremer 2016) It is generally recommended that when used for analgesia, initial doses of TCAs should be one-half of those doses typically used for their antidepressant effects with upward titration as necessary. Common adverse effects notable with TCAs surround their anticholinergic effects, which include dry mouth, dizziness, somnolence, urinary retention and constipation, postural hypotension, and cognitive dysfunction. (Verdu 2008)  The analgesic effects of TCAs may not be apparent for several days to weeks, limiting their utility in acute pain; ensuring outpatient follow up is essential should these agents be initiated for patients in the emergency department (Dowell 2016). 

This chapter was significantly truncated from a more comprehensive manuscript, to better apply to acute care practitioners. The complete list of references for the original chapter is available here.

Alexis LaPietra, DO
Medical Director of Pain Management
Department of Emergency Medicine
St. Joseph’s University Hospital
Paterson, NJ
@DrAlexisLa

Introduction

Nitrous oxide (N2O) is a colorless, non-flammable gas administered in combination with oxygen via inhalation as an analgesic, anxiolytic and sedative agent. Nitrous oxide is a volatile anesthetic with an incompletely understood and complex mechanism of action that involves activation of endogenous opioid and GABA pathways. (Emmanouil 2007) The maximum N2O delivery concentration is 70%, with a corresponding 30% concentration of oxygen. Nitrous oxide is non-irritating and rapidly absorbed via the pulmonary vasculature into the systemic circulation.  It does not combine with hemoglobin or other body tissues, (Becker 2008) and reaches the central nervous system within seconds of inhalation. Nitrous oxide can achieve analgesia comparable to opioids, with the benefits of noninvasive administration, easy titration, and rapid onset and resolution. (Becker 2008, Stenqvist 1994) As anticipatory anxiety surrounding a painful event or medical illness is linked to higher levels of pain, (Craven 2013) the ability of N2O to decrease pain may be due in part to its anxiolytic properties. (Gross 1981) Nitrous oxide has a long and robust record of safety with few side effects and requires minimal monitoring when used as a sole agent.

Pediatrics

Because fear and anxiety drives so much distress in pediatric emergency patients, N2O’s potent anxiolytic effect is of particular value in children. An extensive base of literature demonstrates the benefits of N2O in safely reducing stress, anxiety, and pain in children. Nitrous oxide can be safely administered to children as young as 1 year of age (Babl 2008) and in 50-70% concentration is used to reduce pain and anxiety associated with venipuncture, dental care, bronchoscopy, lumbar puncture, joint aspiration, and laceration repair. (Furuya 2009, Annequin 2000, Cleary 2002) It can be administered in combination with agents such as intranasal ketamine, midazolam, or fentanyl for procedural sedation or combined with a hematoma block to facilitate forearm fracture reduction. (Seith 2012, Luhmann 2001, Lee 2012, Luhmann 2006) The most frequent adverse effect, nausea and vomiting, is typically seen with concentrations at or near 70% or with concomitant opioid administration. The most common serious adverse event associated with N2O, hypoventilation, occurs in fewer than 1 in 500 patients in most series, and almost always when N2O is used in combination with other sedatives. (Babl 2015, Zier 2011, Tsze 2015)

Adults

Nitrous oxide provides analgesia and anxiolysis without deep sedation and has been used in a variety of care environments for the management of acute pain in adults. (Table 1) (Parlow 2005, Klomp 2012, Aboumarzouk 2011) N2O is often effective as a sole agent when used for mild and moderate pain, an there are emerging data regarding its utility as the primary analgesic for acute pain management in the ED when used in 50-70% concentration. (Herres 2015) For more severe pain, N2O is valuable as an analgesic adjunct and especially as a pre-procedural anxiolytic. Nitrous oxide provides effective analgesia for pain associated with long bone fracture, joint dislocation, abscess, musculoskeletal pain, abdominal pain, headache, constipation, and burn care. (Herres 2015)  The most common side effects when N2O is used in adults are dizziness, euphoria, and laughter with no significant effects on heart rate, respiratory rate, or oxygen saturation. (Kariman 2011) Nitrous oxide is gaining popularity as a pre-hospital analgesic due to its excellent safety profile, ease of administration, minimal monitoring requirements, and rapid onset of action. (Ducasse 2013) Additionally, N2O in combination with other analgesics can relieve exacerbations of cancer pain in terminal illness. (Parlow 2005) Evidence demonstrates N2O is a well-tolerated, safe, and effective analgesic for acute pain management in the pre-hospital and adult emergency department setting.

Table 1: Typical indications for use of nitrous oxide in the emergency department

Contraindications

Nitrous oxide is overall very safe, but there are important contraindications to its use. (Table 2) It is easily able to diffuse out of the bloodstream and into air filled cavities, increasing cavity size or pressure, depending on tissue distensibility. Therefore, in patients with pneumothorax, recent vitreoretinal surgery, otitis media, bowel obstruction or chronic obstructive pulmonary disease with blebs, N2O is contraindicated. (Duncan 1984, Seaberg 1995, Becker 2008, Hart 2002, Brodsky 1986) Chronic daily exposure, common in dental hygienists, may contribute to infertility or spontaneous abortion, therefore its use is contraindicated in patients during the first and second trimester of pregnancy. (Rowland 1995) Nitrous oxide may interfere with vitamin B12 function and should be avoided in patients with pernicious anemia or other vitamin B12 deficiencies. (Myles 2004) Nitrous oxide is considered safe for the majority of patients, and a routine history and physical exam will identify most at-risk patients.

Table 2: Contraindications to use of nitrous oxide

Monitoring and Fasting

There are no fasting requirements for N2O. (Gozal 2010)

When used without co-sedatives, N2O in concentrations at or below 50% is considered minimal sedation and hemodynamic monitoring can be limited to clinical observation of the patient’s responsiveness, with continued verbal interaction demonstrating adequate airway patency and breathing. (Cote 2016, AAPD 2013, ADA 2016, Gross 2002) If N2O is used in >50% concentration, especially for longer procedures, we recommend continuous pulse oximetry. When N2O is combined with other sedatives (including opioids), full procedural sedation setup and monitoring is recommended.

Equipment

Nitrous oxide can be delivered via nasal hood or full face mask, which may be disposable or reusable depending on the vendor. For most clinical environments outside of a dental or maxillofacial surgery office, N2O is not available through a wall hook-up. However, self-contained mobile units are available for rapid, portable administration. These units generally have an area for N2O tanks and either space for oxygen tanks or a connection for wall oxygen. A scavenging system is a mandatory component of the unit as it decreases ambient N2O exposure to clinicians, and some units require a hose to be plugged into wall suction as part of the scavenging mechanism.  Nitrous oxide units are made with either a demand flow or a continuous flow mechanism. A demand flow system is triggered by negative inspiratory force as a safety precaution against over-sedation. Both systems are safe and require the patient or assistant to hold the mask in place. If a patient becomes over-sedated, either it will be recognized by the assistant or the patient will allow the mask to fall off their face. The maximum percentage of N2O provided on any unit is 70%; however some units have a maximum of 50%. Although 50% is effective, higher concentrations may provide better analgesia. (Babl 2008)

Administration

Prior to or during initiation of N2O, local or regional anesthetic and other analgesic adjuncts should be used for appropriate procedures (I&D and wound management), especially if significant post-procedural pain is expected.

Nitrous oxide works rapidly and should be administered to patients immediately before a painful procedure. The mask or nasal hood should be placed on the patient with oxygen flowing to avoid breathing against dead space in the breathing circuit. Nitrous oxide can be titrated by 10-20% every 30-60 seconds to desired effect. The flow of oxygen may have to be adjusted depending on the tidal volume requirements of each patient, but the percentage of N2O will not change with adjustments in oxygen. The patient should be visually monitored for signs of oversedation such as inability to communicate. Once the procedure is completed, N2O should be discontinued and the patient allowed to breathe nitrous-free oxygen for several minutes during recovery. (American Dental Association 2017) The breathing circuit can then be removed and the patient should remain seated for 1-2 minutes before mobilizing.  Once the patient has a normal mental status and stable gait, the patient can be discharged without any restrictions.

Abuse potential

Nitrous oxide is a euphoriant and prone to abuse. There have been case reports of medical professionals and hospital staff that have abused, and in rare cases died, as a result of inhaling 100% N2O. (Winek 1995) Portable delivery systems must be stored in a secure or easily monitored area, and many departments require that practitioners “sign out” the device using an ID badge to track usage. Contemporary delivery systems commonly employed in emergency departments only function when used with disposable breathing circuits which can be kept in a separate locked area, providing an additional deterrent to abuse. Lastly, many devices require attachment into wall suction and wall oxygen for delivery of the gas, confining use to clinical areas.

Chronic use of N2O is associated with signs and symptoms of vitamin B12 (cyanocobalamin) deficiency, including megaloblastic anemia, peripheral neuropathy, and a myelopathy that particularly affects the dorsal columns. The latter is akin to subacute combined degeneration seen with B12 deficiency, and is due to the ability of N2O to oxidize the cobalt ion within the vitamin. Treatment includes the administration of high doses of parenteral vitamin B12. (Long 2018)

Conclusion

The use of nitrous oxide as a single agent analgesic and anxiolytic in the management of moderate, severe, and procedural pain in the ED is a rising but still underutilized therapy. The ability to rapidly titrate N2O makes it attractive for use in emergency care, allowing clinicians to tailor effect to the analgesic needs of each patient with minimal monitoring no post-administration restrictions. The longstanding, routine use of N2O in dental practice demonstrates a compelling record of safety and efficacy. (American Dental Association 2017) Although adequate evidence supports its use in both pediatric and adult emergency department patients, the limited experience of most emergency clinicians, as well as concerns around abuse, pregnancy risks, and equipment costs present barriers for implementation. There is potential to improve the management of pain and alleviate anxiety in acute care with expanded use of N2O, especially in departments that see a significant number of children. Continued research and efforts to improve awareness in the EM community regarding nitrous oxide’s versatility and efficacy will support N2O as another important analgesic tool in the emergency clinician’s therapeutic armamentarium.

An example emergency department protocol is available here.

References

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Annequin D, Carbajal R, Chauvin P, Gall O, Tourniaire B, Murat I. Fixed 50% nitrous oxide oxygen mixture for painful procedures: A French survey. Pediatrics. 2000 Apr;105(4):E47.

Babl FE, Grindlay J, Barrett MJ. Laryngospasm With Apparent Aspiration During Sedation With Nitrous Oxide. Ann Emerg Med. 2015 Nov;66(5):475-8.

Babl FE, Oakley E, Seaman C, Barnett P, Sharwood LN. High-concentration nitrous oxide for procedural sedation in children: adverse events and depth of sedation. Pediatrics. 2008 Mar;121(3):e528-32.

Becker DE, Rosenberg M. Nitrous oxide and the inhalation anesthetics. Anesth Prog. 2008 Winter;55(4):124-30.

Brodsky JB, Cohen EN. Adverse effects of nitrous oxide. Med Toxicol. 1986 Sep-Oct;1(5):362-74.

Cleary AG, Ramanan AV, Baildam E, Birch A, Sills JA, Davidson JE. Nitrous oxide analgesia during intra-articular injection for juvenile idiopathic arthritis. Arch Dis Child. 2002 Jun;86(6):416-8.

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Duncan GH, Moore P. Nitrous oxide and the dental patient: a review of adverse reactions. J Am Dent Assoc. 1984 Feb;108(2):213-9.

Emmanouil DE, Quock RM. Advances in understanding the actions of nitrous oxide. Anesth Prog. 2007 Spring;54(1):9-18.

Furuya A, Ito M, Fukao T, Suwa M, Nishi M, Horimoto Y, Sato H, Okuyama K, Ishiyama T, Matsukawa T. The effective time and concentration of nitrous oxide to reduce venipuncture pain in children. J Clin Anesth. 2009 May;21(3):190-3.

Gozal D, Mason KP. Pediatric sedation: a global challenge. Int J Pediatr. 2010;2010:701257.

Gross RT, Collins FL. On the relationship between anxiety and pain: A methodological confounding. Clinical Psychology Review. 1981.

Hart RH, Vote BJ, Borthwick JH, McGeorge AJ, Worsley DR. Loss of vision caused by expansion of intraocular perfluoropropane (C(3)F(8)) gas during nitrous oxide anesthesia. Am J Ophthalmol. 2002 Nov;134(5):761-3.

Herres J, Chudnofsky CR, Manur R, Damiron K, Deitch K. The use of inhaled nitrous oxide for analgesia in adult ED patients: a pilot study. Am J Emerg Med. 2016 Feb;34(2):269-73.

Kariman H, Majidi A, Amini A, Dolatabadi AA, Derakhshanfar H, Hatamabadi H, Shahrami A, Yaseri M, Sheibani K. Nitrous oxide/oxygen compared with fentanyl in reducing pain among adults with isolated extremity trauma: a randomized trial. Emerg Med Australas. 2011 Dec;23(6):761-8.

Klomp T, van Poppel M, Jones L, Lazet J, Di Nisio M, Lagro-Janssen AL. Inhaled analgesia for pain management in labour. Cochrane Database Syst Rev. 2012 Sep12;(9):CD009351.

Lee JH, Kim K, Kim TY, Jo YH, Kim SH, Rhee JE, Heo CY, Eun SC. A randomized comparison of nitrous oxide versus intravenous ketamine for laceration repair in children. Pediatr Emerg Care. 2012 Dec;28(12):1297-301.

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Luhmann JD, Kennedy RM, Porter FL, Miller JP, Jaffe DM. A randomized clinical trial of continuous-flow nitrous oxide and midazolam for sedation of young children during laceration repair. Ann Emerg Med. 2001 Jan;37(1):20-7.

Luhmann JD, Schootman M, Luhmann SJ, Kennedy RM. A randomized comparison of nitrous oxide plus hematoma block versus ketamine plus midazolam for emergency department forearm fracture reduction in children. Pediatrics. 2006 Oct;118(4):e1078-86.

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Rowland AS, Baird DD, Shore DL, Weinberg CR, Savitz DA, Wilcox AJ. Nitrous oxide and spontaneous abortion in female dental assistants. Am J Epidemiol. 1995 Mar 15;141(6):531-8.

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pdf format

Equivalence to 5 mg IV Morphine column was originally included in this table, however, equipotency estimates are widely variant and often based on scant, methodologically poor data. We find equivalence estimates may confuse initial dosing strategies and therefore have pulled out the column but it can be viewed separately here. Bonus: Topical NSAIDs table

The authors thank Maryann Mazer-Amirshahi and Bryan Hayes for their review and erudite commentary. 

Paul L. DeSandre, DO
Chief, Palliative and Supportive Care, Grady Memorial Hospital
Fellowship Director, Hospice and Palliative Medicine
Assistant Professor, Emergency Medicine
Emory University School of Medicine
Atlanta, GA

Eashwar B. Chandrasekaran, MD MSc
Assistant Professor of Clinical Emergency Medicine
Palliative Care Services
Department of Emergency Medicine
Indiana University School of Medicine
Indianapolis, IN

Introduction

For patients with serious illness nearing the end of life, uncontrolled suffering is among their greatest fears. The cause of suffering can be complex and is often due not just to pain and other physiologic changes that reduce function and capacity, but also psychosocial distress and spiritual distress. As symptoms escalate, patients and their caregivers may feel they have little choice other than to seek help in a hospital setting; even patients receiving home hospice services may come or be brought to the hospital in search of relief. While acute care clinicians recognize the need for effective and efficient interventions for these patients, they may feel ill-equipped to provide appropriately aggressive treatment to alleviate pain at the end of life. (Smith 2009, Grudzen 2012) A widely held fear limiting appropriate titration of medications–particularly opioids–near the end of life is that they may hasten death. These concerns are generally unfounded if proper dose selection and clinical assessment are appropriate. (Thorns 2000, Morita 2001) Of far greater concern to the individual is inadequate analgesia leading to persistent pain and suffering near the end of life, particularly in cancer patients. (Portenoy 2006, Steindal 2011) The Institute of Medicine has reinforced the need to improve primary pain management skills for all clinicians caring for patients nearing the end of life. (IOM 2014)

The emergency department is the most accessible point of entry for many individuals with chronic, life-threatening diseases. Emergency clinicians are therefore often confronted with the need to manage symptoms and other concerns that arise at the end of life. Furthermore, patients, and their caregivers, may benefit from initiating goals-of-care discussions in the ED, and these discussions may have a significant impact on both the in-hospital trajectory and prognosis. As in many other clinical domains, emergency physicians have expanded their scope of practice to better serve this growing patient population by augmenting their palliative care skills, seeking specialized training through fellowships and other focused programs, and by partnering with local palliative care specialists. The patient- and family-oriented palliative care priorities apply to patients at every stage of life; implementation of ED-based palliative care initiatives therefore broadly improves the quality of emergency care. (Lamba 2014)

There is much room to improve the care of patients approaching death. Family reports suggest that half of patients who die in the hospital have moderate to severe pain more than 50% of the time, (SUPPORT 1995) and cancer patient caregivers report 61% prevalence of “very distressing” pain. (Constantini 2009) Risk factors for the undertreatment of pain at the end of life include a history of substance abuse, older age, minority status, and physician discordance in the perception of pain. (Cleeland 1994, Higginson 2012)

Assessment

The first and most important consideration for successful pain management is an adequate assessment, including an understanding of the cause of pain, prior to selecting interventions. There are two broad classes of pain that are readily distinguished and have markedly different treatment requirements: Nociceptive pain is caused by immediate tissue threat or injury, such as in cancer progression into previously healthy tissue. Somatic nociceptive fibers are highly myelinated, causing rapid transmission of pain impulses with discrete localization of pain. Visceral nociceptive fibers are less myelinated and transmit more diffuse, poorly localized symptoms such as cramping. In visceral abdominal cancers, both systems may be activated–visceral pain from, for example, bowel involvement, and somatic pain from invasion of the parietal pleura. Neuropathic pain, on the other hand, may develop from neurotoxic effects of chemotherapeutics, metabolic microvascular conditions such as diabetes, infectious diseases such as HIV, or direct neoplastic invasion of neural tissue. It may be felt as a numb or tingling sensation, hypersensitivity, or abnormally severe and altered response to minor stimulation known as allodynia.  

Once the likely cause of pain is determined, its severity should be repeatedly assessed to gauge the adequacy of analgesia and facilitate safe titration to the relief of pain or the development of intolerable adverse effects that limit further dose escalation. A patient’s ability to quantify their distress determines the most appropriate method of assessment; no pain scale has been shown to be superior to others, so the tool most acceptable or applicable to the patient should be used. For some patients able to communicate, a subjective response to adequate or inadequate control may be sufficient. For others, an objective assessment may be more helpful. Commonly used and equally valid pain scales for communicative patients include the Visual Analogue Scale (VAS), the Numerical Rating Scale (NRS), the Wong-Baker FACES scale, and the Verbal Rating Scale (VRS).  All of these use the anchors of “no pain” to “worst pain” to help quantify changes. (Jensen 2003) Patients may differ in their response to one scale or another, some being more comfortable with the 0 to 10 NRS, whereas others may only be able to point to one of the FACES expressions, and still others may be limited to only “mild, moderate, or severe.”  Whichever is most useful should continue to be used to optimize longitudinal assessment of a patient’s pain trajectory. For patients with severe dementia, non-verbal pain scales may be more useful, such as PAINAD. (Warden 2003) For patients in critical condition, either conscious or unconscious, the Critical Care Pain Observation Tool (CPOT) is well-validated and widely used. (Gelinas 2006) At the end of life, CPOT can be particularly helpful in looking for signs of distress related to pain, and for determining adequacy of response to interventions.

Once an appropriate assessment tool is chosen for the patient, whether numeric or descriptive, the same scale should be used among clinicians to assess analgesic effect based on the patient’s response to treatment and the pharmacokinetics of the agent(s) used. Reassessments focus on both analgesic efficacy and adverse effects. The goal is the patient’s report that they are comfortable and do not wish to have more pain medication. For patients only able to use a verbal scale, “better” or “enough” may be sufficient to communicate their level of response. For critical patients, alleviation of non-verbal signs of distress, for example, a CPOT score less than 3, suggests an adequate response.

Management

Environmental influences such as excessive light, noise, strong smells, or direct physical manipulation may undermine efforts to provide comfort to the patient and should be controlled to the degree possible. Placing the patient in a quiet room with familiar caregivers and family, turning off or adjusting device alarm settings, and turning monitors to “comfort mode” allow attention to be focused on the patient rather than their evolving physiological decline.

Goals specific to palliation should be established and regularly reassessed. For example, if maintaining consciousness is an equal priority to adequate pain control, this requires a different approach than when maximal pain control is paramount.

A pain crisis occurs when the patient develops severe, uncontrolled pain that causes the patient or family severe distress. A pain crisis requires immediate and rapid medication titration, generally using multimodal analgesia, to alleviate symptoms. (Moryl 2008)

Route of administration

For patients in the hospital with severe pain, The oral or rectal routes are not optimal, as delayed onset limits effective titration. (DeSandre 2009) For patients in an acute care setting, intravenous (IV) administration is most effective. If IV access is unavailable, the subcutaneous (SQ) route is a reasonable alternative, and intramuscular administration is discouraged as it is more painful  and provides no analgesic or pharmacokinetic advantage over SQ delivery. If IV or SQ administration is not desired, orally administered liquid morphine is commonly used and effective; peak effect is reached in approximately 60 minutes. The rectal route is feasible and has similar absorption characteristics to oral administration, but is often impractical and uncomfortable. Fentanyl is available in various formulations, including a transmucosal lozenge (lollipop) and dissolving buccal tablets, which are indicated for breakthrough pain in opioid tolerant individuals. All formulations are associated with a specific risk evaluation and mitigation strategy (https://www.tirfremsaccess.com) that outlines specific criteria for use. Transdermal fentanyl patches are commonly used for long term management of chronic pain, but due to their delayed onset of action they are not appropriate for the treatment of breakthrough pain. Fentanyl and ketamine can be delivered via atomizer to the nares, and fentanyl can be inhaled via conventional or breath-actuated nebulizer for both pain and air hunger at the end of life. If fentanyl is not available, lesser evidence supports the use of nebulized morphine in this context. (Pavis 2002, Fitzgibbon 2003, Zeppetella 2000)

Evidence supports direct opioid placement into exposed ulcers such as decubiti, which are known to have mu receptors and may respond fairly rapidly. One approach to topical application of opioids for malignant ulcers or painful decubiti is to create a gel dressing of 10 mg IV morphine solution in 8 grams of hydrogel, and apply to the ulcer in a thin layer one to three times per day. (Graham 2013)

Opioids

Opioids are considered first line therapy for patients with acute severe pain.  The most commonly used parenteral opioids in the acute care setting include morphine, hydromorphone, and fentanyl. The analgesic efficacy of all three drugs is similar when administered in equianalgesic doses; efficacy correlates more with dose and interval than drug choice. For terminally ill patients in pain, analgesic selection is based on palliative goals, altered physiology at the end of life, and, most importantly, the patient’s prior experience with efficacy and adverse effects of the individual agents.

Morphine and hydromorphone are often used parenterally at the end of life. Both achieve peak effect in 5-10 minutes when given IV, or 20-30 minutes when given SQ. (Table 1) We recommend reassessment of efficacy and adverse effects every 15 minutes when morphine or hydromorphone is given as an intravenous bolus. For patients with renal or hepatic impairment, lower initial dosing is recommended with extended titration intervals. Morphine is particularly prone to accumulating toxic metabolites in patients with severe renal failure, and alternative agents are favored in this group.

For acute care providers, fentanyl has several advantages for managing pain at the end of life. Intravenous fentanyl reaches peak effect in less than five minutes, allowing rapid titration; has minimal renal clearance, making it well suited for patients with kidney failure; and is less likely than commonly used alternatives to cause or worsen hypotension. However, IV fentanyl has a duration of action of only 30-60 minutes, and so is best suited to rapid titration followed by a continuous infusion. As mentioned, fentanyl may also be administered transdermally, intranasally, and by inhalation, as appropriate.

Patients may be considered opioid tolerant if in the week prior to presentation they have consistently been exposed to at least 60 mg oral morphine per day (equivalent to 25 mcg transdermal fentanyl/hour, 40 mg oral oxycodone/day, or 8 mg oral hydromorphone/day). All other patients should be considered opioid naïve.  For patients near the end of life in a pain crisis who are opioid naive, doses as low as 4 mg IV morphine or 0.5 mg IV hydromorphone with reassessment every 15 minutes may be sufficient. Using rapidly-titrated small doses is more likely to limit side effects, to which the dying patient may be more susceptible, while optimizing efficacy. If, after repeating the dose, pain is still severe (>7/10 NRS) and the patient remains alert and without distressing side effects, the dose may be doubled once and then repeated at this dose, and this rapid-titration process is continued until adequate analgesia is achieved, the patient is no longer alert, or adverse effects such as nausea or delirium supervene. In the majority of patients, adequate analgesia without severe side effects should be achievable within 60 mins. (Harris 2003) If an acceptable effect cannot be achieved with the chosen opioid, switching to an alternative opioid or adding a non-opioid such as ketamine may produce better results.  

Once the acute pain crisis has been managed and the patient is comfortable, a continuous analgesic infusion may initiated using a 4-hour reassessment of the total dose required to achieve adequate analgesia without significant adverse effects, and dividing that dose into an hourly rate. For example, if 20 mg morphine is required over 4 hours, then the hourly rate would be 5 mg/hour. If the patient is able to use a patient-controlled analgesic (PCA) device, it may be programmed to start the demand dose at 1-3 mg morphine with a lockout of 10-15 minutes and no continuous rate initially if opioid naive. In most patients, self-administering an opioid using these parameters would cause somnolence (and therefore an inability to push the demand button) before overdose complications occur. Patients with sleep apnea or significant lung disease should be started at lower doses with longer lockout intervals, and all patients recently started on continuous or PCA opioid infusions require continued close monitoring for efficacy and adverse effects. (Caraceni 2012) PCAs should only be initiated and titrated by those trained in their use.

Patients with end-of-life pain who are on high dose opioids at home and present with severe pain present a particular challenge. For these opioid-tolerant patients, a four-step fentanyl titration can provide rapid control based on prior opioid dosing. (Table 2 and Figure 1) Such assessments and calculations are complicated, and may require the assistance of a physician or pharmacist with expertise in pain management.

Step 1: Initial bolus of fentanyl IV, based on 10% of prior 24 hour IV morphine equivalent use. For example, if the patient has taken a total equivalent of 180 mg of oral morphine in the past 24 hours, the IV equivalent would be 1/3 the oral amount or 60 mg IV morphine. 10% of this amount is 6 mg IV morphine, which is equivalent to 60 mcg IV fentanyl. If daily morphine equivalence for an opioid tolerant patient cannot be calculated, fentanyl titration may reasonably be initiated at 25-50 mcg.

Step 2: Reassess in 5 minutes. If no severe side effects or excessive somnolence, and patient is still distressed or requesting further analgesia (pain > 4/10), repeat initial dose.

Step 3: Reassess in 5 minutes. If no severe side effects or excessive somnolence, and patient is still distressed or requesting further analgesia (pain > 4/10), double the original fentanyl dose.

Step 4: Reassess in 5 minutes. If no severe side effects or excessive somnolence, and patient is still distressed or requesting further analgesia (pain > 4/10), repeat step 3 dose.

Many patients will achieve adequate analgesia using this 4-step protocol in 30 minutes. (Soares 2003) If ineffective, consider adding a non-opioid adjuvant such as ketamine to augment analgesia. It is recommended to discuss the use of ketamine as an effective analgesic with the patient or family prior to administration, as it may contribute to terminal delirium, and may require combined dosing with benzodiazepines.

see online calculators for more conversion information:
NYC Health MME Calculator
AMDG Calculator
Practical Pain Management Calculator

Overdose

When rapidly titrating opioids to treat pain at the end of life, ideally symptoms are relieved with a single opioid or opioid alternative. Co-titration of other sedating medications, such as benzodiazepines, complicates reassessment and increases the risk of serious adverse effects. A cautious approach centered on small, frequent doses and frequent reassessment minimizes the likelihood of dangerous adverse effects, but individual response characteristics may be unpredictable. If the patient is not in the final stages of dying or if the goals for critical intervention remain unclear and a dangerous opioid overdose has been determined, then intervention may be necessary. Hypoventilation causing decreased level of consciousness, agitation, or distress from hypoxia that is thought to be caused by overmedication requires prompt but judicious intervention, especially in opioid-tolerant patients. The opioid antagonist naloxone reliably reverses dangerous hypoventilation but can precipitate withdrawal and associated pain and distress, which may be difficult to overcome. Unless hypoventilation is thought to be causing immediately dangerous consequences (bradycardia or malignant arrhythmia), a gentle approach to reversal, starting with aliquots of 0.04 mg IV, will avert overdose harms without precipitating a distressing (and sometimes dangerous) withdrawal syndrome. (Figure 2)

The goal is not a fully awake and alert patient, rather a patient who is breathing adequately, maintaining their airway, and at least partially responsive to voice or gentle painful stimuli. Once an adequate reversal response is achieved, the patient should be carefully observed for at least 90 minutes, to verify that dangerous overdose effects do not recur as the naloxone is metabolized. If repeat dosing of naloxone is required, the patient should be moved to a clinical setting capable of continuous cardiorespiratory monitoring; a continuous infusion of very-low-dose naloxone may be required in these patients. (Boyer 2012)

Adjuvant analgesics

A variety of non-opioid analgesics may augment (or replace) the efficacy of opioids. Non-steroidal antiinflammatory drugs (NSAIDs) and acetaminophen are useful supplemental analgesics. NSAIDs are particularly effective in visceral inflammatory pain, but require a careful harm:benefit consideration in patients with renal failure or gastrointestinal bleeding. Patients who are suffering from chronic life-threatening illness may also benefit from the use of adjuvant analgesics such as gabapentin or a tricyclic antidepressant for the treatment of neuropathic pain; these agents are poorly studied as therapies for acute pain because of their limited parenteral availability.

Subdissociative-dose ketamine can provide remarkably effective analgesia in palliative care patients, especially opioid tolerant patients whose pain may be difficult to control with additional opioids. The dose is 0.1-0.3 mg/kg IV as a loading dose given over 15-30 minutes, followed by an intravenous infusion at 0.1-0.3  mg/kg/hour. The goal is a calm and comfortable patient who doesn’t have bothersome or distressing psychoperceptual effects due to the ketamine; this can usually be achieved with frequent reassessments and titration. Subdissociative-dose ketamine does not require cardiorespiratory monitoring, though effective ketamine analgesia may lead to important adverse effects from co-delivered opioids. (Shlamovitz 2013, Winegarden 2016, Prommer 2012)

There are a variety of palliative procedures that may offer significant relief for certain types of terminal pain; for example, bony pain may be best addressed through palliative radiation and visceral pain of cholangiocarcinoma and pancreatic cancer may be very effectively treated by a celiac plexus block. The efficacy of these specialized procedures underscores the benefit of early involvement of pain medicine and palliative care in the management of patients with refractory pain at the end of life.

Palliative Sedation

Refractory pain is pain that cannot be controlled, usually because therapeutic efforts are associated with intolerable side effects. Refractory pain presumes that other symptoms which could be labeled as pain, such as dyspnea, agitation, delirium, and anxiety are properly addressed. (Cherny 1994) If it is determined that all appropriate efforts to alleviate the patient’s pain have failed and future efforts would be ineffective, it is appropriate to consider using sedating medications to alleviate suffering; this is known as palliative sedation. Following an informed consent process including the patient or appropriate proxy, sedating medications such as benzodiazepines are administered to achieve a condition where conscious suffering is no longer evident. The level of sedation is proportionate to the level of distress, and this approach is often a planned temporary intervention to determine if the patient’s suffering can be improved through the procedure. The intent of palliative sedation must always be solely to alleviate suffering. Given that patients being considered for palliative sedation have refractory symptoms in the late stages of a terminal illness, the use of palliative sedation would not be expected to alter the timing or mechanism of dying. (AAHPM 2014)

Summary

Patients entering an acute care setting in pain at the end of life often are experiencing suffering that may be multifactorial, including physiologic/nociceptive distress, psychosocial distress, and spiritual distress. A careful evaluation of the etiology and characteristics of pain using frequent reassessments of symptoms is the foundation for rapid control. Opioids should be considered first-line therapy for severe pain at the end of life. With careful consideration of the patient’s physiological challenges and the characteristics of available drugs, successful pain control can usually be achieved rapidly and safely. Optimal pain control often requires a multimodal approach with non-opioid adjuvants. When appropriately dosed and targeted therapies have failed to alleviate suffering from refractory pain in the dying patient, palliative sedation may be considered.

The editors thank Ashley Shreves, MD and Michael Turchiano, MD for their thoughtful reviews of the manuscript.

The authors report no relevant conflicts of interest.

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Kay Odashima, MD
Director, Medical Student Education in Emergency Ultrasound
Department of Emergency Medicine
Maimonides Medical Center

Stephen Strasberg, MD
Assistant Professor of Emergency Medicine
Zucker School of Medicine
Northshore University Hospital

Eitan Dickman, MD, FACEP, FAIUM
Executive Vice Chairman and Medical Director
Department of Emergency Medicine
Maimonides Medical Center

QUICK LINKS TO NERVE BLOCK FIGURES
Superficial Cervical Plexus Nerve Block
Interscalene Brachial Plexus Nerve Block
Supraclavicular Brachial Plexus Nerve Block
Infraclavicular Brachial Plexus Nerve Block
Axillary Brachial Plexus Nerve Block
Median Nerve Block
Radial Nerve Block
Ulnar Nerve Block
Femoral Nerve Block
Fascia Iliaca Compartment Block
Popliteal Sciatic Nerve Block Position
Popliteal Sciatic Nerve Block Screen
Posterior Tibial Nerve Block
Intercostal Nerve Block
Serratus Anterior Plane Block

INTRODUCTION

Painful conditions are the most common reason patients seek care in an Emergency Department, and ultrasound guided regional anesthesia is an important analgesic modality available to emergency clinicians. Ultrasound guidance has demonstrated similar success rates compared to traditional peripheral nerve block techniques and provides the advantages of real-time needle visualization, demonstration of anesthetic spread, shorter procedure time, and fewer needle attempts. (Chin 2008) With the addition of color Doppler, ultrasound guidance can also prevent inadvertent intravascular injection. (Hahn 2014) Sonographic guidance of nerve blocks is therefore preferred over landmark based techniques, when feasible. Nerve stimulators are commonly employed by anesthesiologists when performing regional anesthesia; however, ultrasound guidance of these procedures has equivalent or better success rates. (Duncan 2013, Schnabel 2013) Numerous studies demonstrate that ultrasound-guided regional anesthesia performed by emergency clinicians is safe and effective. (Akhtar 2013, Aydin 2016, Beaudoin 2013, Baker 2015, Dickman 2015, Fletcher 2003, Flores 2015a, Flores 2015b, Hahn 2014, Haslam 2013, Heflin 2015, Johnson 2014a, Johnson 2014b)

PREPARATION AND EQUIPMENT

A high-frequency linear ultrasound transducer is recommended for most ultrasound-guided nerve blocks. Additionally, the operator will need a long needle such as a commercially available nerve block needle or, if these are not available, a spinal needle. Some specialized needles consist of an echogenic tip that provides improved visualization. The operator may administer the injection on her own using a syringe and needle; alternatively, IV catheter extension tubing may be attached between the needle and the syringe to allow for better manual control of the needle during the procedure, with an assistant performing the aspiration and injection. (Figure 1) Recommended setup for ultrasound-guided regional nerve blocks is demonstrated in Figure 2. The clinician should position herself in a comfortable seated or standing upright position, with the ultrasound machine placed on the opposite side of the patient in the direct line of sight of the location of planned needle insertion.

IN-PLANE VS. OUT-OF-PLANE TECHNIQUE

Two techniques can be employed when performing real-time ultrasound-guided regional anesthesia: in-plane and out-of-plane. For both approaches, the nerve is visualized in its transverse (short) axis. When utilizing the in-plane technique, the needle is passed under the long axis of the ultrasound probe and remains visualized for the entirety of the procedure. This is generally the preferred technique, (Akhtar 2013, Fingerman 2009) as visualization of the needle throughout its trajectory decreases the likelihood of lacerating critical soft tissue structures or impaling the nerve. In the out-of-plane technique, the needle is inserted perpendicular to the probe and only a cross-section of the needle directly under the ultrasound beam is visualized. It is possible to follow the trajectory of the needle tip by sliding the probe forward as the needle is advanced through the tissues. However, this can be technically challenging especially when performing blocks on nerves located in deep tissues. There are instances where an out-of-plane technique can be successfully utilized, but this is usually only for superficial nerves without surrounding vasculature or other structures that could be inadvertently punctured.

ANISOTROPY

While performing ultrasound guided nerve blocks, it is important to understand the concept of anisotropy. Anisotropy is a sonographic quality exhibited by musculoskeletal structures such as tendons and nerves, in which the nerve appears maximally hyperechoic when the angle of the insonating beam runs perpendicular to the nerve fibers. At oblique angles, the echogenicity of the nerve bundle will appear significantly reduced. If a nerve is difficult to visualize, instead of moving the probe, try to rock, tilt or “heel toe” the probe to change the angle at which the ultrasound beams reflect off of the nerve. (Suk 2013)

COMPLICATIONS OF REGIONAL ANESTHESIA

Sensitivity to Local Anesthetic

Local anesthetics (LA) are classified as esters or amides by the type of bond that connects the lipophilic aromatic ring to the hydrophilic amine group. Commonly used esters include cocaine, chloroprocaine, procaine, tetracaine and benzocaine while commonly used amides include lidocaine, bupivacaine, levobupivacaine, ropivacaine, prilocaine and etidocaine.

LA’s often contain preservatives such as methylparaben, propylparaben, or sulphites, which likely contribute to some sensitivity reactions. (Boren 2007) However, true allergic reactions to LA’s are rare, and estimated to constitute less that 1% of all reactions to LA. (Schatz 1984)

Nerve Damage

Peripheral nerve damage secondary to regional anesthesia is rare and its effects are usually transient, mild, or subclinical. In a study of 158,083 regional blocks performed without ultrasound guidance, only 12 (0.0024%) peripheral neuropathies were reported, of which 7 had persistent symptoms after 6 months. (Liguori 2004) In a later study of 6,069 patients who received ultrasound-guided regional nerve blocks, only 30 had a block-related nerve injury (0.04%). (Barrington 2009)

Several factors are linked to an increased risk of nerve damage, including high-pressure injections, needle type, and underlying medical conditions. Several animal studies found that while low-pressure (<12 psi) intraneural injections did not result in functional nerve damage, high-pressure injections (>20-38 psi) were more likely to result in the development of functional neurologic injury. It is postulated that the high-pressure injections were indicative of accidental intrafascicular injections, i.e. the tip of the needle was within the nerve itself. (Jeng 2011) Another study demonstrated that an opening injection pressure of ≥15 psi indicated needle contact with the nerve. Disposable manometers that attach in between the syringe and needle to monitor injection pressures are commercially available and may help to prevent inadvertent intraneural injection. Though some experts recommend using an injection pressure monitor while performing nerve blocks, (Gadsen 2010) there is no evidence to suggest that routine monitoring of opening injection pressures reduces the risk of neural injury, (Gadsen 2014) and manometry during PNB is currently not standard care. Feeling resistance against the injection of anesthetic may be an indication of intraneural needle placement; anesthetic ought to be injected slowly and in small aliquots, and the injection should be halted if the patient reports painful paresthesias.

The type of needle used may also play a role in the likelihood of nerve injury. Because the perineural sheath surrounding the fascicle is composed of tough tissue, it is less likely to be penetrated with a blunt, short-bevel needle. (Jeng 2011) A study of rabbit sciatic nerves found that short bevel needles were less likely to pierce the perineurium than long bevel needles. The study also found that a needle that penetrated the fascicle perpendicularly to the nerve fibers was associated with greater nerve injury than when the bevel was oriented parallel to the nerve fibers. (Selander 1997) However, when a short bevel needle does penetrate the fascicle, it is associated with more severe and longer duration nerve injury than with long bevel needles. (Rice 1992) Yet another study compared beveled needles to tapered needles and found that tapered needles transected fewer axons when inserted intrafascicularly. (Maruyama 1997) Echogenic needles have demonstrated improved needle tip visualization over standard needles, (Hebard 2001, Hocking 2012, Fuzier 2015) however, further studies are needed to determine whether echogenic needles improve clinical outcomes of ultrasound-guided regional anesthesia procedures. (Sviggum 2013) There is presently insufficient evidence to favor one needle tip design over another, and current consensus leaves this choice to provider preference. Finally, though the reason is unclear, patients with preexisting nerve pathology (e.g. chemotherapy related neurotoxicity or diabetic neuropathy) are more likely to develop nerve injury after a regional nerve block. (Borgeat 2001, Neal 2002)

It is important to document the following elements in the patient’s chart: the type of block, the anesthetic used and its amount, a complete pre-block neurovascular exam (sensory and motor), and the time that the nerve block was performed. In cases where compartment syndrome is of concern (i.e. crush injuries), this procedure ought to be communicated with the appropriate consulting service. A skin marker should also be used to label the anatomic site of injection as well as write the time of the procedure.

Local Anesthetic Systemic Toxicity (LAST)

Epidemiologic data on LAST is limited to a few studies reporting incidence within a specific patient population, case series, and case reports. One study found that 79 out of 10,000 patients from a single institution that had a brachial plexus block performed developed a seizure, possibly from unintentional intravascular injection. (Brown 1995) Another study found that the frequency of seizures with various regional blocks ranged between 0-25 in 10,000. There were no cardiac arrests secondary to LAST reported in this study. (Auroy 2002)

Symptoms and signs of LAST are classically described as starting with perioral numbness, tinnitus, and a metallic taste in the mouth. This progresses to seizure, altered mental state, and coma, which may shortly thereafter be followed by arrhythmias and cardiovascular collapse. Onset of LAST can be immediate (<60 secs) if inadvertent intravascular injection occurs, or can be more delayed (up to 30 mins) in situations that require tissue absorption such as subcutaneous infiltration. Because the timing of the onset of LAST is variable, it is recommended that a patient be closely monitored for at least 30 minutes after injection. (Neal 2010) Severe lidocaine toxicity generally manifests as seizure progressing to cardiac arrest and lasts 10-20 minutes; therefore patients can often be managed through the duration of toxicity with supportive cardiac arrest care (chest compressions, rescue oxygenation) even if lipid emulsion is not available. In contrast, severe bupivacaine toxicity causes cardiac arrest without antecedent seizure activity, and toxicity may last hours–all efforts should be made to treat these patients with lipid emulsion therapy. (Schwartz 2015)

Techniques recommended to reduce the incidence of LAST include careful attention to maximum recommended doses and using the lowest effective dose of local anesthetic, injecting local anesthetic in small increments (3-5 mL aliquots and pausing 15-30 seconds between each injection), and aspirating before each injection to ensure no vascular entry. Sonographic guidance has the potential to reduce intravascular injections; however, its overall effectiveness in reducing LAST has yet to be determined. (Neal 2010)

Table 1: Recommended doses, onset and duration of action of commonly used local anesthetics for peripheral nerve blocks.

Life threatening LAST is generally due to IA or IV injection, whereas milder toxicity is more typical from overdoses administered into the SQ tissue. For cardiac arrest thought to be due to LAST, after initiating basic and advanced life support, 20% lipid emulsion should be administered as a 1.5 mL/kg bolus followed by a 0.25 mL/kg/min infusion. The bolus can be repeated and the infusion rate can be increased to 0.5 mL/kg/min as needed for persistent cardiovascular collapse and should be continued for at least 10 minutes after cardiovascular stability has been achieved, or up to one hour. One key deviation from ACLS guidelines in managing patients with LAST is to use significantly smaller doses of epinephrine (<1 mcg/kg), as some animal studies have demonstrated poorer outcomes with epinephrine compared to lipid therapy in the treatment of bupivacaine induced-asystole. (Neal 2010)

NERVE BLOCK PROCEDURES

There are many locations throughout the body that are amenable to ultrasound-guided regional anesthesia. Below we will highlight some of the more common and high yield nerve blocks relevant to emergency care.

UPPER EXTREMITY NERVE BLOCKS

Superficial Cervical Plexus Nerve Block (Figure 3)

Block Distribution: Skin of anterolateral neck from the inferior ⅓ of ear down to skin overlying clavicle.

Block Volume: 10-15 mL

Uses in the Emergency Department: Lower ear laceration, clavicle fracture, central venous catheter placement

Probe Placement: Transversely over the middle portion of the sternocleidomastoid muscle (SCM).

Sonographic landmarks: The cervical plexus lies immediately posterior to the lateral border of the sternocleidomastoid (SCM) muscle and below the prevertebral fascia. Identify the lateral border of the SCM and inject just below the prevertebral fascia which appears as a hyperechoic line immediately below the SCM. (Photo)

Approach and Needle Trajectory: In-plane, from lateral to medial until the needle tip is located just deep to the lateral edge of the SCM and prevertebral fascia.

Special Considerations: There is considerable variability in the distribution of analgesia at the level of the ear.

Lit Bit: Use of the superficial cervical plexus block for analgesia in an acute clavicle fracture:. The patient’s pain score went from a 9/10 to a 1-2/10 immediately post-procedure with a return to moderate pain controlled with oral analgesics at hour 20. (Herring 2012)

Interscalene Brachial Plexus Nerve Block (Figure 4)

Block Distribution: Clavicle, shoulder, lateral arm above elbow.

Block Volume: 10-20 mL

Uses in the Emergency Department: Clavicle fracture, proximal and mid-humerus fracture, reduction of shoulder dislocation, drainage of deltoid abscess, laceration repair at the lateral arm.

Probe Placement: Transversely over the lateral neck at the level of the thyroid

Sonographic landmarks: Start at the clavicle and scan cephalad. First, identify the subclavian artery and the supraclavicular brachial plexus and then trace the brachial plexus to the interscalene groove located between the anterior and middle scalene muscles, which are located deep to the lateral edge of the sternocleidomastoid. The nerve roots appear as stacked hypoechoic circles surrounded by hyperechoic tissue and have been described as having a “traffic light” appearance.

Approach and Needle Trajectory: In-plane, from lateral to medial until the needle tip is in the interscalene groove between the C5 and C6 nerve roots.

Special Considerations: This block will likely cause transient ipsilateral diaphragmatic paralysis due to the close proximity of the phrenic nerve to the interscalene groove. Be cautious if patient has underlying pulmonary disease or known contralateral diaphragmatic paralysis; patients receiving this nerve block should have cardiopulmonary monitoring including pulse oximetry during and after the procedure.

High volumes of local anesthetic may also cause an ipsilateral Horner’s syndrome due to the proximity of the sympathetic chain; this will resolve as the local anesthetic wears off.

Lit Bit: Randomized study demonstrating successful use of an interscalene brachial plexus block for acute shoulder dislocation as an alternative to procedural sedation with reduced ED length of stay and less one-on-one provider time with similar pain scores. (Blaivas 2011)

Supraclavicular Brachial Plexus Nerve Block (Figure 5)

Block Distribution: Arm below the level of the shoulder excluding the medial proximal arm

Block Volume: 20-25 mL

Uses in the Emergency Department: reduction of distal humerus fractures and elbow dislocations, complex laceration repair, drainage of large abscess, and other procedures/analgesia distal to the shoulder.

Probe Placement: Transversely just superior to the clavicle.

Sonographic landmarks: Identify the subclavian artery and the supraclavicular brachial plexus which appears as a cluster of anechoic circular structures surrounded by hyperechoic tissue often described as a cluster of grapes or honeycomb. This cluster rests on the first rib and lies above the apex of the lung.

Approach and Needle Trajectory: In-plane, from lateral to medial until the needle tip is located near the brachial plexus. The area is hydrodissected until local anesthetic is seen surrounding all the nerve roots.

Special Considerations: Ipsilateral diaphragmatic paralysis and Horner’s syndrome are potential complications of this block (see Interscalene Brachial Plexus Nerve Block). Pneumothorax is another potential complication given the close proximity of the pleura to the needle insertion site, making visualization of the needle tip throughout the procedure critical to performing a safe block. There is sometimes an arterial branch overlying the nerve plexus, preventing use of this block.

Lit Bit: A case series of 5 patients demonstrating the use of ultrasound-guided supraclavicular brachial plexus block for the treatment of various acute painful conditions (I&D of forearm abscess, closed reduction of metacarpal fracture, analgesia for midshaft humerus fracture, reduction of posterior elbow dislocation). The blocks were performed successfully without complications, and excellent analgesia was achieved in all cases, obviating the need for procedural sedation. (Stone 2007)

Infraclavicular Brachial Plexus Nerve Block (Figure 6)

Block Distribution: Arm distal to the the shoulder excluding the medial proximal arm.

Block Volume: 20-30 mL

Uses in the Emergency Department: reduction of distal humerus fractures and elbow dislocations, complex laceration repair, drainage of large abscess, and other procedures/analgesia distal to the shoulder.

Probe Placement: Parasagittally along lateral clavicle.

Sonographic landmarks: Identify the axillary artery. The lateral, posterior, and medial cords of the plexus are located in a “U” shape around the axillary artery.

Approach and Needle Trajectory: In-plane, with the needle inserted below the clavicle, from cephalad to caudad, until the needle is posterior to the axillary artery and the local anesthetic spreads in a “U” shape around the artery.

Special Considerations: The pleura should be visualized and avoided in order to decrease the incidence of pneumothorax.

Lit Bit: Case report describing the successful use of an ultrasound-guided infraclavicular block instead of procedural sedation for the reduction of an acute posterior elbow dislocation (Heflin 2015)

Axillary Brachial Plexus Nerve Block (Figure 7)

Block Distribution: Mid arm down to and including hand, excluding skin overlying the deltoid and lateral arm.

Block Volume: 20-25 mL

Uses in the Emergency Department: reduction of distal radius fractures/dislocations, complex laceration repairs and abscess drainage of the hand, forearm and medial arm.

Probe Placement: With the shoulder abducted and elbow flexed, perpendicular to the humerus in the axillary crease.

Sonographic landmarks: Identify the axillary artery. The radial, median, and ulnar nerves are located around the axillary artery. The musculocutaneous nerve is located between the biceps and coracobrachialis muscle.

Approach and Needle Trajectory: In-plane, from superior to inferior, aiming posterior to the axillary artery and injecting to surround all the nerves (radial, median, ulnar and musculocutaneous nerves). Often a single approach is inadequate, and this technique may require multiple redirections toward each nerve.

Special Considerations: To perform multiple injections, first withdraw the needle until it is just below the skin, before redirecting it toward the new target. Avoid compressing the axillary vein which is usually superficial to the artery.

Lit Bit: Case reports demonstrate that upper extremity fractures can be safely and effectively reduced in the emergency department using landmark technique axillary nerve block, (Alimohammadi 2014) as well as successful ultrasound-guided axillary nerve block for the reduction of a first metacarpal fracture and a mid-shaft ulnar and radial fracture. (Bhoi 2010)

Median Nerve Block (Figure 8)

Block Distribution: Distribution of median nerve in the hand and wrist.

Block Volume: 5-10 mL

Uses in the Emergency Department: Complex laceration repairs, abscess drainage, burns, foreign body removal

Probe Placement: Transversely over the volar aspect of the mid forearm.

Sonographic landmarks: Identify the median nerve, which runs between the flexor digitorum profundus and the flexor digitorum superficialis, scanning both proximally and distally to ensure the nerve is correctly identified.

Approach and Needle Trajectory: In-plane or out-of-plane technique may be used depending on how superficial the nerve is and the presence of vasculature. Either a medial or lateral approach may be utilized. It is unnecessary to completely surround the nerve with anesthetic.

Special Considerations: Unlike the radial and ulnar nerves which run alongside their corresponding arteries within the forearm, the median nerve has no corresponding artery. As the median nerve approaches the wrist or elbow, the surrounding tendons can make identifying the nerve more challenging. To reduce patient discomfort, use a small (25 or 27 gauge) needle for this block.

Lit Bit: Ultrasound-guided forearm nerve blocks are more effective than landmark based wrist blocks in the emergency department in a prospective, randomized study. (Sohoni 2016)

Radial Nerve Block (Figure 9)

Block Distribution: Distribution of the radial nerve in the hand and wrist.

Block Volume: 5-10 mL

Uses in the Emergency Department: Complex laceration repairs, abscess drainage, burns, foreign body removal

Probe Placement: Transversely over the lateral aspect of the distal arm with the elbow flexed and placed across the patient’s chest.

Sonographic landmarks: Identify the hyperechoic triangular or oval-shaped radial nerve in the fascial plane between the brachialis and brachioradialis muscles. Scan both proximally and distally to ensure the nerve is correctly identified.

Approach and Needle Trajectory: In-plane or out-of-plane technique may be used depending on how superficial the nerve is and the presence of vasculature. Either a medial or lateral approach may be utilized. It is unnecessary to completely surround the nerve with anesthetic.

Special Considerations: If the radial nerve is not readily identified, locate the radial nerve in the forearm using the radial artery as a landmark and trace the nerve proximally to the distal lateral arm. To reduce patient discomfort, use a small (25 or 27 gauge) needle for this block.

Ulnar Nerve Block (Figure 10)

Block Distribution: Distribution of ulnar nerve in the hand and wrist.

Block Volume: 5-10 mL

Uses in the Emergency Department: Complex laceration repairs, abscess drainage, burns, foreign body removal, Boxer’s fracture reduction

Probe Placement: Transversely over the mid forearm.

Sonographic landmarks: Identify the ulnar nerve immediately medial to the ulnar artery. Scan both proximally and distally to ensure the nerve is correctly identified.

Approach and Needle Trajectory: In-plane or out-of-plane technique may be used depending on how superficial the nerve is and the presence of vasculature. Either a medial or lateral approach may be utilized. It is unnecessary to completely surround the nerve with anesthetic.

Special Considerations: Color doppler can be helpful in identifying the ulnar artery. To reduce patient discomfort, use a small (25 or 27 gauge) needle for this block.

LOWER EXTREMITY NERVE BLOCKS

Femoral Nerve Block (Figure 11)

Block Distribution: Anterior and medial thigh down to the knee, component of the hip joint, and a variable portion of the medial leg and foot.

Block Volume: 10-20 mL

Uses in the Emergency Department: Hip fracture, femur fracture, knee injury including patellar fracture, incision and drainage of abscess or laceration repair over anterior or medial thigh.

Probe Placement: Transversely over the inguinal crease.

Sonographic landmarks: At the level of the inguinal crease, find the femoral artery medially. The femoral nerve lies immediately lateral to the femoral artery and often appears as a hyperechoic triangular structure shaped like a “pennant.” The nerve sits superficial to the iliacus muscle and is covered by the fascia iliaca.

Approach and Needle Trajectory: In-plane, from lateral to medial through both the fascia lata and fascia iliaca until the needle tip is immediately above, lateral or below the nerve. It is beneficial to first inject anesthesia deep to the nerve, so that the anesthesia will lift the nerve superficially and make any subsequent injection above the nerve easier.

Special Considerations: In order to achieve an adequate block, the needle must penetrate both the fascia lata and fascia iliaca. Correct needle placement will be demonstrated by the local anesthetic spreading below the femoral nerve, lifting it off the iliacus muscle.

Lit Bit: Ultrasound-guided femoral nerve block is equally effective in reducing pain for both patients with intracapsular and extracapsular hip fractures in the emergency department has been demonstrated in a multicenter, randomized clinical trial. (Dickman 2015)

Fascia Iliaca Compartment Block (Figure 12)

Block Distribution: Lateral thigh (lateral femoral cutaneous nerve), anterior and medial thigh down to the knee, and a variable portion of the medial leg and foot (femoral and obturator nerves).

Block Volume: 30-40 mL

Uses in the Emergency Department: Hip fracture, femur fracture, knee injury, incision and drainage of abscess or laceration repair over lateral, anterior or medial thigh.

Probe Placement: Transversely over the inguinal crease.

Sonographic landmarks: The relevant landmarks for the fascia iliaca compartment block are the same as for the femoral nerve block. At the level of the inguinal crease, find the femoral artery medially. The femoral nerve lies immediately lateral to the femoral artery and often appears as a hyperechoic triangular structure shaped like a “pennant.” The nerve sits superficial to the iliacus muscle and is covered by the fascia iliaca.

Approach and Needle Trajectory: In-plane, from lateral to medial. The needle tip should be 1-2 cm lateral to the femoral nerve and just deep to the fascia iliaca. The local anesthetic will hydrodissect the fascia away from the iliacus muscle, spreading both medially toward the femoral nerve and laterally toward the lateral femoral cutaneous nerve.

Special Considerations: The fascia iliaca compartment block differs from the femoral nerve block in that instead of injecting directly adjacent to the nerve, the local anesthetic is deposited in the potential space between the fascia iliaca and iliacus muscle 1-2 cm lateral to the femoral nerve itself. Because the injection is performed away from the femoral nerve and artery, there is less risk of intraneural or intravascular local anesthetic injection. Because the fascia iliaca compartment block is a high-volume block, it is especially important to be aware of the maximum recommended dosage in order to prevent local anesthetic systemic toxicity (LAST).

Lit Bit: Ultrasound-guided fascia iliaca compartment block has been demonstrated to provide safe and effective pain control in patients with hip fractures in the emergency department. (Haines 2012)

Popliteal Sciatic Nerve Block (Figure 13 and Figure 14)

Block Distribution: The entire lower leg below the knee except for a variable portion of the medial leg and foot which is innervated by the saphenous nerve.

Block Volume: 20-30 mL

Uses in the Emergency Department: Fractures, lacerations and abscesses involving the lower leg, ankle and foot.

Probe Placement: With the patient in a prone,lateral decubitus, or supine (bending the knee, with pillows/blankets placed underneath the elevated foot) position, place the transducer transversely over the popliteal crease and scan proximally until the appropriate sonographic landmarks are identified, usually between 5-10 cm proximal to the popliteal crease.

Sonographic Landmarks: Identify the popliteal artery and vein at the level of the popliteal crease. By applying gentle pressure with the ultrasound transducer, the popliteal vein will compress and the tibial nerve will be visible as a hyperechoic circular or ovoid structure immediately superficial and lateral to the popliteal artery. The common peroneal nerve may also be visualized lateral to the tibial nerve. Slide the transducer proximally until the tibial and common peroneal nerves fuse to form the sciatic nerve.

Approach and Needle Trajectory: The needle is inserted in-plane from lateral to medial until the needle tip is adjacent to the sciatic nerve. Inject a small volume of local anesthetic to confirm needle position within the epineural sheath that surrounds the sciatic nerve. With the needle in correct position, the local anesthetic will be seen surrounding the sciatic nerve and tracking proximally and distally along the nerve sheath, and may cause a separation of the tibial and common peroneal nerves.

Special Considerations: Though controversial, it is thought that regional anesthesia can potentially delay the diagnosis of compartment syndrome by masking pain especially in high-risk injuries such as tibial plateau fractures or crush injuries. (Mutty 2008) Femoral neck fractures and ankle fractures are less frequently associated with this complication of orthopedic injuries. (Wu 2011)

Lit Bit: Emergency physician-performed ultrasound-guided popliteal nerve blocks were successfully used for pain control without need for procedural sedation for wound irrigation and reduction of bilateral open calcaneal fractures, plantar foot foreign body removal and laceration repair, calf abscess incision and drainage, and closed reduction and splinting of a tri-malleolar and posterior ankle dislocation. (Herring 2011)

Posterior Tibial Nerve Block (Figure 15)

Block Distribution: Heel and plantar surface of foot.

Block Volume: 3-5 mL

Uses in the Emergency Department: laceration repair, foreign body removal.

Probe Placement: Transversely, immediately posterior or just proximal to the medial malleolus.

Sonographic Landmarks: Find the tibial artery and vein just posterior to the medial malleolus. By applying gentle pressure with the transducer, the vein will collapse. The tibial nerve appears as a hyperechoic oval or circle immediately adjacent and posterior to the tibial artery.

Approach and Needle Trajectory: Position the patient’s leg in eversion. Either in-plane or out-of-plane technique can be used and the approach will be dependent on patient positioning and ergonomics.

Special Considerations: Color Doppler can be helpful in identifying the tibial artery. Tendons in the medial ankle (tibialis anterior, flexor digitorum longus, and flexor hallucis longus) can be mistaken for the tibial nerve, but noting that the tibial nerve is directly posterior and adjacent to the tibial artery will help to minimize misidentification. To reduce patient discomfort, use a small (25 or 27 gauge) needle for this block.

Lit Bit: A 49 year-old man with bilateral comminuted calcaneal fractures received bilateral ultrasound-guided posterior tibial nerve blocks with almost complete resolution of pain and tolerated splint placement without pain. (Clattenburg 2016)

TRUNCAL BLOCKS

Intercostal Nerve Block (Figure 16)

Block Distribution: Sensory blockade of the targeted anterolateral dermatome and the underlying parietal pleura. This block can be performed at the T1-T12 levels.

Block Volume: 3-5 mL per intercostal level

Uses in the Emergency Department: Pain control for rib fractures, analgesia prior to chest tube placement.

Probe Placement: Parallel to the posterior-axillary line at the level of the target intercostal nerve. Probe placement medial to the scapula with the patient in prone position has also been described. The advantage of this is that the intercostal nerve can be blocked prior to its division into the deep and lateral cutaneous branches (Stone 2011)

Sonographic landmarks: Identify the external, internal and innermost intercostal nerves between two ribs. The intercostal nerve, artery and vein are located at the caudal border of the rib between the internal and innermost intercostal muscle planes.

Approach and Needle Trajectory: In-plane, from caudal to cephalic, with the needle tip caudal to the inferior margin of the rib between the internal and innermost intercostal muscles.

Special Considerations: The parietal pleura lies immediately below the innermost intercostal muscle. To avoid causing a pneumothorax, extra care must be taken to avoid advancing the needle without clear needle tip visualization.

Lit Bit: A case report describes the case of a 39 year-old female with a traumatic right pneumothorax who received ultrasound-guided intercostal nerve blocks performed by an emergency physician for analgesia prior to placement of a tube thoracostomy. (Stone 2011)

Serratus Anterior Plane Block (Figure 17)

Block Distribution: This block targets the lateral cutaneous branches of the T3-T9 thoracic intercostal nerves.

Block Volume: 30-40 mL

Uses in the Emergency Department: Pain control for rib fractures, analgesia prior to chest tube placement.

Probe Placement: Transversely over the mid-axillary line at the level of the nipple (approximate location of the 5th rib) with the probe marker facing the nipple with the patient lying supine or in the lateral decubitus position with the injured side up. The probe may be rotated slightly in a clockwise fashion so that a better view of the ribs and pleura in cross-section can be obtained.

Sonographic landmarks: The serratus anterior is located between the pectoralis muscle anteriorly and the latissimus dorsi muscle posteriorly. The distal branches of the thoracic intercostal nerves are located in the fascial plane immediately superficial to the serratus anterior.

Approach and Needle Trajectory: In-plane, from anterior to posterior in the supine patient and from posterior to anterior in the lateral decubitus patient with the needle tip ending immediately superficial to the serratus anterior muscle.

Special Considerations: Because the long thoracic nerve and the thoracodorsal nerve are located in the fascial plane between the latissiumus dorsi and the serratus anterior, winging of the ipsilateral scapula is an expected effect of the block. Because the serratus anterior plane block is a high-volume block, it is especially important to be aware of the maximum recommended dosage in order to prevent local anesthetic systemic toxicity (LAST).

Lit Bit: Durant et al. describe the cases of a 82 year-old male and a 65 year-old female with multiple rib fractures in whom ultrasound-guided serratus plane blocks were successfully performed in the ED for pain control. Both patients had significant pain despite receiving IV opioids. After the block, the first patient’s pain score decreased from 8/10 to 0/10 and she did not request additional analgesics for >12 hours post-block. The second patient had 9/10 and reported “minimal pain” post-block and did not require additional analgesia for 10 hours. (Durant 2017)

Table 2: Summary of upper extremity, truncal, and lower extremity nerve blocks

The editors thank Stephen Alerhand, MD, for his thoughtful review of the manuscript.

The authors report no relevant conflicts of interest.

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Timothy Horeczko, MD, MSCR, FACEP, FAAP
Associate Professor of Emergency Medicine
David Geffen School of Medicine at UCLA
Harbor-UCLA Medical Center Torrance, CA USA
thoreczko@emedharbor.edu
@EMtogether

INTRODUCTION

Pain is multifactorial: it is comprised of physical, psychological, emotional, cultural, and contextual features. Determining which among these features is the dominant contributor to pain and distress may be difficult, especially in children. Although clinicians may focus on the physical component of pain, much time, energy, and suffering can be saved through a holistic approach. What is the age and developmental stage of the child?  How is the child reacting to his condition? What are the circumstances?  What is the family or caregiver dynamic?

Assessing and managing a child’s pain can be challenging, because children may not exhibit typical signs and symptoms of pain. (Srouji 2010)  Further, children participate in and absorb their family’s culture and specific personality from a very young age, (Finley 2009) and we rely on how patients and families interact with us to gauge pain.  For example, a very anxious caregiver can easily transmit his or her anxiety to the child, which may either inhibit or amplify the presentation of symptoms. (Bearden 2012)

The guiding principles in pediatric pain assessment and management are: know the child; know the family; and know the physiology. Children have long suffered from under-treatment of pain, due both to our incomplete recognition and acknowledgement of their pain as well as our fear of treatment. (Howard 2003) Though pain management paradigms have shifted in recent years, the central approach remains and well serves the emergency clinician caring for a child in pain: know the signs and symptoms, treat promptly, and frequently reassess for effectiveness.

ASSESSMENT

Each stage of development offers a unique framework to the child’s signs and symptoms of pain.  In pre-verbal children, use observational skills in addition to the parent’s report of behavior. Verbal children can self-report; younger children require pictorial descriptions, while older children and adolescents may use standard adult scales. In all ages, ask open-ended questions and allow the child to report and speak for himself whenever possible.

Neonates

Neonates are a unique group in pain assessment.  The neonate (birth to one month of age) has not yet acquired social expression of pain, and their nascent nervous system is only now learning to process it.  Do not expect typical pain behaviors in neonates.  Facial grimacing is a weak indicator of pain in this age group. (Liebelt 2000)  Look for a furrowed brow, eyes squeezed shut, and an expressionless vertically open mouth.  Tachycardia, tachypnea, and a change in behavior can be indicators not only of the presence of pain, but possibly suggestive of its etiology as well.

Neonatal observational scales have been validated in the intensive care and post-operative settings; ED-specific quantitative scales are lacking.  CRIES is a 10-point scale, using a physiologic basis similar to APGAR: Crying; Requires increased oxygen administration (distress and breath-holding); Increased vital signs; Expression; and Sleeplessness. (Krechel 1995)  CRIES (Table 1) was validated for post-operative patients; to adapt its use for the ED, substitute “preoperative baseline” with normal range for age. Although the numerical values of CRIES have not been validated to date in the ED, the clinician may find the domains included in CRIES to be a useful construct in assessing neonatal pain.  

Neonatal pain pathways are particularly plastic; prompt assessment of and alertness to neonatal pain may help mitigate long-lived pain sensitivity and hyperalgesia. (Taddio 2002)  

Infants and Toddlers

This group will begin to exhibit more reproducible, reliable signs and symptoms of pain.  

For infants less than one year of age, the Neonatal Infant Pain Scale (NIPS) uses observational and physiologic parameters to detect pain (Table 2).  A score of 0-2 indicates no pain present.  A score of 3-4 indicates mild to moderate pain; non-pharmacologic techniques may be tried first in this group.  A score of 5 or greater indicates severe pain; pharmacologic intervention is indicated (Lawrence 1993).

For children greater than one year who are preverbal, a well performing scale is the FLACC score: Face, Legs, Activity, Cry, Consolability (Table 3).

Contextual and caregiver features predominate in this group.  Frequent reassessments are helpful, as the initial trepidation and fright in triage may not accurately reflect the child’s overall pain status.

Preschool and School-age children

Increasing language development offers the hope of more information to the clinician, but be careful not to ask leading questions.  Do not jump directly to “does this hurt?” Preschoolers will say yes to anything, in an attempt to please you.  School-age children may passively affirm your “statement,” if only to validate their need for care or attention.  Start with some ice-breaking banter, lay down the foundations for rapport, and then ask open-ended questions. Be careful not to allow the caregiver to “instruct” the child to tell you where it hurts, how much, how often, etc.  Rather, engage the parents by asking them what behavior they have noticed. Eliciting history from both the child and the parent will go a long way in constructing a richer picture of the etiology and severity of the pain, and will help to build rapport and trust.

The Baker-Wong FACES Pain Rating scale (Figure 1) was developed with feedback from children and has been validated for use in those 3 years of age and older. (Keck 1996, Tomlinson 2010)

Adolescents

Adolescents vary in their development, maturity, and coping mechanisms.  You may see a mixture of childhood and adult behaviors in the same patient; e.g. he may be initially stoic or evasive of questioning, then later exhibiting pseudo-inconsolability.  Do what you can to see the visit from the adolescent’s perspective, and actively transmit your concern and intention to help–many will respond to a warm, open, non-judgemental, and helpful attitude.  The overly “tough” adolescent is likely secretly fearful, and the “dramatic” adolescent may simply be very anxious. Take a moment to gauge the background behind the presentation.

Adolescents can often engage directly on analgesia decision-making, but if a scale is needed, the typical adult scale of 0 (no pain) to 10 (worst pain), or the Faces Pain Scale–Revised (FPS-R) can be used.  The FPS-R uses more neutral and realistic faces and, unlike the Wong Baker scale, does not use smiling or crying faces to anchor the extremes of pain (Tsze 2013).

PAIN PHYSIOLOGY

Pain includes two major components: generation and perception. Generation of pain involves the actual propagation of painful stimuli, either through nociceptive pain or neuropathic pain.  

Nociceptive pain arises from free nerve endings responding to tissue damage or inflammation and follows a specific sequence: transduction (an action potential triggered by chemical mediators in the tissue, such as prostaglandins, histamine, bradykinin, and substance P); transmission (the movement of the action potential signal along the nerve fibers to the spinal cord); perception (the impulse travels up the spinothalamic tract to the thalamus and midbrain, where input is splayed out to the limbic system, somatosensory cortex, and parietal and frontal lobes); and modulation (the midbrain enlists endorphins, enkephalins, dynorphin, and serotonin to mitigate pain). (Pasero 2011)  As clinicians, we can target specific “stations” along the pain route to act on the signal more effectively.

Simple actions such as ice, elevation, local anesthetics, or splinting help in pain transduction.  Various standard oral, intranasal, or IV analgesics may help with pain transmission. Non-pharmacologic techniques such as distraction and re-framing can help with pain perception. The sum of these efforts encourages pain modulation.

A phenomenon separate from nociceptive pain is neuropathic pain, the abnormal processing of pain stimuli.  It is a dysregulated, chaotic process that is difficult to manage in any setting. Separating nociceptive from neuropathic symptoms may help to select specific pain treatments and to clarify treatment goals and expectations.

Neonates

Neonates are exquisitely sensitive to many analgesics.  Hepatic enzymes are immature and exhibit decreased clearance and prolonged circulating levels of the drug administered.  Once the pain is controlled, less frequent administration of medications, with frequent reassessments, is indicated.

The neonate’s vital organs make up a larger proportion of their body mass than do muscle and fat.  Therefore, the volume of distribution is unique in a neonate.  Water-soluble drugs (e.g., morphine) reach these highly perfused vital organs quickly; relatively small excess in dosing will have rapid and exaggerated central nervous system and cardiorespiratory effects.  The neonate’s small fat stores and muscle mass limit the volume of distribution of lipophilic medications (e.g., fentanyl), also making them more available to the central nervous system, and therefore more clinically potent.  Other factors that predispose neonates to accidental analgesic overdose are their decreased concentrations of albumin and other plasma proteins, causing a higher proportion of unbound drug.  Renal clearance is also decreased in the first few months of life.

In the ED, neonates often require analgesia for procedures, and non-pharmacologic techniques predominate (see below).  Make liberal use of local anesthetics such as eutectic mixture of local anesthetics (EMLA; for intact skin, e.g. IV access, lumbar puncture) and lidocaine-epinephrine-tetracaine gel (LET; for superficial open skin and soft tissue application).  Oral sucrose (30%) solutions, administered either with a small-volume syringe or pacifier frequently dipped in solution, are effective for minor procedures, (Harrison 2010, Stevens 2013) as is distraction by mechanical means.  Neonates with severe pain may be managed with parenteral analgesics, while on a monitor, and with caution.

Infants and Toddlers

With increasing body mass comprised of fat stores in conjunction with an increase in metabolism, this group will require a different approach than the neonate.  For many medications, these children will have a greater weight-normalized clearance than adults (Berde 2002) and  will often require more frequent dosing. Infants and toddlers have a larger functioning liver mass per kilogram of body weight, with implications for medications cleared by this organ.

Some drugs, such as benzodiazepines, will have both a per-kilogram dosing as well as an age-specific modification. When giving analgesics or anxiolytics to young children, always consult a reference for proper dosing and frequency.

School-age children and Adolescents

This group retains some hyper-metabolic features of younger children, but the dose-effect relationship is more linear.  Pharmacologic clearance is improved, and from a physiologic standpoint, these children are at lower risk for adverse drug events. From a psychological standpoint, this group may need more non-pharmacologic interventions and emotional support to modulate pain optimally.

NON-PHARMACOLOGIC TREATMENT

The first line of treatment in all pain management is non-pharmacologic. (Horeczko 2016) Not only are these the safest of all techniques, but often the most effective. Some are simple comfort measures such as splinting (fracture or sprain) or applying cold (acute soft tissue injury) or heat (non-traumatic, non-specific pain).  Many pain control regimens are sabotaged by the failure to consider non-pharmacologic techniques, which may augment, or at times replace, analgesics.

A tailored approach based on age will allow the practitioner to employ a child’s developmental strengths and avoid the frustration that results from asking the child to do what she is not capable of doing.  A brief review of Piaget’s stages of development will help to meet the child at her developmental stage for best effect (Piaget 1928, Sheppard 1977) when managing painful conditions and performing minor procedures.

Sensorimotor stage (from birth to age 2): Children use the five senses and movement to explore the world.  They are egocentric: they cannot see the world from another’s viewpoint.   At 6 to 9 months, object permanence is established: understanding that objects (or people) exist even without seeing them.

Preoperational stage (from ages 2 to 7):  Children learn to use language.  Magical thinking predominates. They do not understand rational or logical thinking.

Concrete operational stage (from age 7 to early adolescence): Children can use logic, but in a very straightforward, concrete manner (they do well with simple examples).  By this stage, they move from egocentrism to understanding another point of view.  

Formal operational stage (early adolescence to adult): children are capable of abstract thinking, rationalizing, and logical thinking.

It is important to assess the child’s general level of development when preparing and guiding her through the minor procedure or utilizing distraction until pain is controlled.  It is not uncommon for an acutely ill or injured child to regress temporarily in their behavior as a coping mechanism.

Neonate and Infant (0-12 months)

Involve the parent, and have the parent visible to the child at all times if possible. Make advances slowly, in a non-threatening manner; limit the number of staff in the room.  Use soothing sensory measures: speak softly, offer a pacifier, and stroke the skin softly. Swaddle the infant and encourage the parent to comfort her during and after the procedure.  Engage their developing sensorimotor skills to distract them.

Toddler to Preschooler (1-5 years)

Use the same techniques as for the infant, and add descriptions of what she will see, hear, and feel; you can use a doll or toy to demonstrate the procedure.  Use simple, direct language, and give calm, firm directions, one at a time. Explain what you are doing just before doing it (do not allow too much time for fear or anxiety to take root).  Offer choices when appropriate; ignore temper tantrums. Distraction techniques include storytelling, bright and flashy toys, blowing bubbles, pinwheels, or having another staff member play peek-a-boo across the room.  The ubiquitous smart phone with videos or games can be mesmerizing at this age.

School age (6-12 years)

Explain procedures using simple language and (briefly) the reason for the procedure (understanding of bodily functions is vague in this age group). Allow the child to ask questions, and involve them when possible or appropriate. Distraction techniques may include electronic games, videos, guided imagery, and participation in the minor procedure as appropriate.

Adolescent (13 and up)

Use the same techniques for the school age child, but can add detail. Encourage questioning. Impose as few restrictions as possible – be flexible. Expect more regression to childish coping mechanisms in this age group. Distraction techniques include electronic games, video, guided imagery, muscle relaxation-meditation, and music (especially the adolescent’s own music, if available).

APPLIED PHARMACOLOGY

No amount of knowledge of physiology, pharmacology, or developmental theory will help your pediatric patient in pain without a well constructed and executed plan. Identify and reverse the source of the pain, if possible. Frequent reassessments are paramount to ensure that breakthrough pain is recognized and medication re-administration is indicated, or when a change of plan is necessary.  This is the time to involve parents or caregivers: deputize them to notify you when the patient needs additional analgesia, and let them know what the next steps are, and what to expect.

Start with the least invasive modality and progress as needed.  After non-pharmacologic treatments such as splinting, ice, elevation, distraction, and guided imagery, have an escalation of care in mind (Figure 2).

From a pharmacological perspective, many options are available. The pain management plan will differ depending on whether a painful procedure is performed in the ED (Table 4; see also Procedural Sedation in Children). Once pain is addressed, create a plan to keep it managed. Consider the trajectory of illness and the expected time frame of the painful episode. Include practicalities such as how well the pain may be controlled as an outpatient. Poorly controlled pediatric pain is more often managed as an inpatient than the same condition in an adult. Speak frankly with the parents about what drug is indicated for what type of pain and that treatment goals typically do not include absence of all pain, but increased function and comfort, in anticipation of clinical improvement.

A special note on codeine: Codeine (often prescribed as acetaminophen with codeine – “T3”) is a comparatively ineffective analgesic, and up to 10% of patients lack enzymatic activity to metabolize it into morphine, its active form. (Crews 2014)  More importantly, recent evidence demonstrates that some children are ultra-rapid-metabolizers of codeine to morphine, which causes in effect a “bolus” of the available drug, with respiratory depression and death reported. (Ciszkowski 2009, Racoosin 2013)  Codeine, including codeine combination preparations such as acetaminophen/codeine, should not be used for children and we recommend that codeine be removed from the formulary in pediatric hospitals or pediatric units.

COMMON CONDITIONS

Head and neck pain

Most common non-traumatic head and neck complaints can be managed non-pharmacologically (e.g. headache: improved hydration, sleep, stress management, nutrition) or with PO medications, such as NSAIDs.  The anti-inflammatory properties of ibuprofen (10 mg/kg PO q 6 h prn, up to adult dose), for example, will often treat the cause as well as the symptoms of ear pain, sore throat, and muscular pain.  Ibuprofen is more effective than acetaminophen for odontogenic pain, (Bailey 2013) and other painful conditions (MSK pain, migraine headache (Pierce 2010, Clark 2007, Hamalainen 1997) but evidence suggests equivalency or near-equivalency of ibuprofen and acetaminophen for most applications. The combination of both NSAIDs and acetaminophen is likely to be more effective than either agent individually. (Smith 2012, Ong 2010, Kraglund 2014, Pickering 2002)

Migraine headache may be treated with all of the above, and rescue therapy may include prochlorperazine (0.15 mg/kg IV, up to 10 mg) (Brousseau 2004), often given with diphenhydramine (1 mg/kg PO or IV, up to 50 mg) and IV fluids. Ketorolac (0.5 mg/kg IV, up to 15 mg) may be substituted for ibuprofen (Paniyot 2016).   

Chest pain

After ruling out important pulmonary (e.g. pneumothorax) and cardiac (e.g. pericarditis, myocarditis) etiologies, many chest complaints are amenable to NSAIDs. There is often a component of anxiety in children with chest pain and in their parents as well; no amount of medication will assuage them without addressing these concerns.

Abdominal pain

Abdominal pain in children is common and generally benign, but the evaluation can be challenging. For patients with mild pain, consider acetaminophen as indicated (15 mg/kg/dose, up to 650 mg, q 4-6 h prn).  The oral route is preferred, but intravenous acetaminophen is an option for patients unable to tolerate PO, or for those in whom the per rectum (PR) route is contraindicated (e.g. neutropenia). (Babl 2011, Dokko 2014)  For children with moderate to severe acute abdominal pain who are unable to tolerate oral intake, consider intravenous rehydration/volume repletion, and small, titrated aliquots of an opioid. Surgical pain is not masked by opioids (Thomas 2003, Poonai 2014); in fact treating pain improves diagnostic specificity to certain surgical emergencies. (Manterola 2007) If there is inter-departmental concern about prolonged effects, sedation, limitation in the physical exam, or there is a need to “see if the pain will come back,” fentanyl is an option due to its shorter half-life, and more frequent re-assessments may help the surgical team in its deliberations.

Long-bone injuries

Fracture pain should be addressed immediately with splinting, ice, and analgesia. Oral, intranasal, and intravenous routes are all acceptable, depending on the severity of the injury and pain.  

Intranasal (IN) medications offer the advantage of a fast onset for patients with moderate-to-severe pain, (Graudins 2015) either as monotherapy or as a bridge to intravenous treatment (Table 4).  The ideal volume of IN medication is 0.25 mL/naris, with a maximum of 1 mL/naris.  Common concentrations of fentanyl limit its use to the school-aged child; intranasal ketamine may be used for pain (i.e. in sub-dissociative dose) up to adult weight.

Patients with long-bone injuries are amenable to analgesia with nebulized fentanyl, which can be administered quickly and simply.  Clinically significant improvement in pain is achieved with 3 mcg/kg/dose of fentanyl administered via standard nebulizer. (Miner 2007, Furyk 2009) Early data suggests that nebulized fentanyl is a rapid, non-invasive alternative to the IN route for older children, adolescents, or adults, in whom the volume of IN medication would exceed the recommended per naris volume (Deaton 2015).

Consider an aggressive, multi-modal approach to control pain up front.  For example, in a simple forearm fracture, consider an oral opioid, perform a hematoma block, and offer inhaled nitrous oxide for fracture reduction, rather than a formal intravenous procedural sedation (Luhmann 2006).

Ultrasound-guided peripheral nerve blocks are an effective pain control adjunct, after initial treatment, and in communication with downstream consultants (Ganesh 2009, Suresh 2014) who may rely on serial exams of the region.

Skin and Soft tissue

Skin and soft tissue injuries or abscesses often are best managed with non-pharmacologic analgesia in addition to local anesthetics. For IV cannulation, consider EMLA if the patient is stable and a minor delay is acceptable.  

Topical ethyl chloride vapo-coolant offers transient pain relief due to rapid cooling and may be used just prior to an IV start. (Farion 2008)  Engage a young child’s imagination to distract her and say, “have you ever held a snowball? You are in luck – it’s just like that – here, do you feel it?”  

Vibratory adjuncts such as the “BUZZY” bee can be placed near the IV cannulation site to provide mechanical and cognitive distraction. (Moadad 2016)

Needleless lidocaine injectors may facilitate IV placement without obscuring the target vein (Spanos 2008, Lunoe 2015).  The medication is propelled into the dermis by a CO2 cartridge that makes a loud popping sound. Just before using it, say “your skin looks thirsty – it needs a drink – there you are!”  

As with any minor procedure, when you tell the child what you are doing, be sure to do it right away.  Do not delay or build suspense.

Lidocaine-epinephrine-tetracaine gel (LET) is used for open or mucosal wounds.  Apply as soon as possible in the visit. The goal of LET is to pretreat the wound to allow for a painless administration of injectable anesthetic.  Applying LET two or three times at 15-minute intervals for deeper anesthesia may avoid the need for injection anesthesia altogether.

Pediatric burns should be assessed carefully and treated aggressively. Submersion of the affected extremity in room-temperature water (if possible) or applying room-temperature saline-soaked gauze will reduce ongoing thermal damage, soothe the wound, and provide foundational first-aid.  Minor burns can be treated with topical and/or oral medications. Major burns generally require parenteral analgesia with opioids, ketamine, or nitrous oxide. In pediatric patients with severe or extensive burns, it is appropriate to use dissociative-dose ketamine to facilitate wound care. (Gandhi 2010) Post-traumatic psychological disorders are common in burns; effective pain management is ever-more important in these cases.

SPECIFIC SCENARIOS

The child with chronic medical problems

Children with acute exacerbations of their chronic pain or episodic painful crises require special attention.  Some examples of children with recurring pain are those suffering from sickle cell disease, juvenile idiopathic arthritis, and breakthrough cancer pain.  Find out whether these symptoms and circumstances are typical for them, and what regimen has helped in the past. Previous unpleasant experiences may prime these children with amplified anxiety and perception of pain. (Cornelissen 2014)  Target the disease process and do your best to show the patient and family you understand their condition and needs.

An equally challenging scenario is the child with chronic pain.  Treat the entire patient with a multimodal approach and limit opioids as possible.  As an opioid-sparing strategy or as rescue therapy, sub-dissociative ketamine is effective for conditions such as sickle cell crisis, autoimmune disorders, or chronic pain due to sub-acute trauma. (Sheehy 2015) Intranasal ketamine may be used for sub-dissociative pain control at 0.5 – 1 mg/kg. (Andolfatto 2013, Yeaman 2013) Intravenous infusions of ketamine at 0.1 – 0.3 mg/kg/h may be initiated in the ED and continued 4 – 8 h/d, up to a maximum of 16 h total in 3 consecutive days. (Sheehy 2015)  In sickle cell patients with vaso-occlusive pain crises, dexmedetomidine is an effective adjunct for severe pain poorly responsive to opioids and/or ketamine. (Sheehy 2015b)

The child with cognitive impairment

Children with cognitive impairment such as those with genetic or metabolic syndromes, or primary neurologic conditions such as cerebral palsy are challenging to assess and treat.  These children not only cannot explain their symptoms, but they also have atypical expressions of pain.  Pain responses in severely intellectually disabled children include a smile (which may or may not accompany inappropriate laughter), stiffening, and non-cooperation. (Hadden 2002) Other observed behaviors include the freezing phenomenon, in which the child acutely feels the pain, and abruptly pauses without moving their face for several seconds.  Look also for episodes of unexplained pallor, diaphoresis, breath-holding, and shrill vocalizations. The Face, Legs, Activity, Cry, Consolability (FLACC) scale has been revised (r-FLACC) for children with cognitive impairment and appears to be reliable for acute care. (Malviya 2006)

A distressing and perplexing presentation is the parent who brings their child with cognitive impairment for “fussiness,” “irritability,” or “I think he’s in pain.”  This may occur is after significant investigations have been performed, sometimes repeatedly. Poorly controlled spasticity is an often under-appreciated cause of unexplained pain; treat not with opioids, but with GABA-receptor agonists, such as baclofen. Benzodiazepines may be effective in an acute exacerbation of spasticity, though benzodiazepine prescriptions should be used cautiously in children, for the same reasons they should be used cautiously in adults.

Take special precautions in the administration of opioids or benzodiazepines in children with metabolic disorders (e.g. mitochondrial disease) or various syndromes (e.g. Trisomy 21), as they may be disproportionately oversedated by these medications. Start with a low dose and reassess frequently, titrating in small aliquots as needed.

After careful consideration and workup to exclude occult dangerous conditions, the child with cognitive impairment who continues to be symptomatic despite ED treatment may require admission for observation.  The addition of gabapentin to the typical regimen has been shown to manage unexplained irritability in these children, (Hauer 2007) perhaps by treating visceral hyperalgesia.

Multi-trauma

The use of intravenous analgesics and frequent assessments of pain and analgesic response are necessary to gauge the child’s pain trajectory. Unexplained tachycardia may be an early signs of shock, and without controlling the child’s pain, it may be difficult to distinguish whether tachycardia is from pain or blood loss.  

The child under palliative care

Children undergoing palliative care require a multidisciplinary approach.  This includes engaging the patient’s care team and special attention to the patient’s family who are coping with the natural course of devastating chromosomal, neurologic, and other congenital lesions; terminal cancer or other life-limiting conditions (Michelson 2007).  Focus on the productive and beneficial treatments that can be offered.  Treat pain promptly, but speak with the parents about end-of-life goals as early as possible, as any analgesic or sedative may have an untoward effect. You do not want to be in the position of potentially having to resuscitate a child undergoing palliative care, because of a lack of understanding of how increasingly large doses of pain medications can affect breathing and circulation. (AAP 2000)

Children with chronic or terminal pain may present with complications of chronic opioid treatment. Identify, assess and aggressively treat constipation, nausea and vomiting, pruritus, and urinary retention; (Friedrichsdorf 2007) treating side-effects of pain management may be just as important for quality of life as treating the pain itself.

PEARLS AND PITFALLS IN PEDIATRIC PAIN

Allow the child to speak for themselves whenever possible.  After acknowledging the parent’s input, try “I want to make sure I understand how the pain is for you. Tell me more.”

Engage parents and communicate the plan to them.  Elicit their expectations, and give them a preview of what to expect in the ED.

Opioids are meant for pain caused by acute tissue injury, for the briefest period of time required to diminish suffering.  Older school-aged children and adolescents are increasingly at risk for opioid dependence and addiction.

Premature infants present a challenge in pain control.  Their pain is under-recognized, as they often display atypical responses to painful stimuli. Treatment is equally difficult, as they are particularly sensitive to analgesia-sedation, and this high-risk group is more likely to undergo painful procedures than their peers.

Give detailed advice on how to manage pain at home.  Set rational expectations.  Let them know you understand and will develop a strategy that will carry them through this difficult time. Patients and families often just need a plan–map it out clearly.

SUMMARY

• In pediatric acute pain, know the child; know the family; and know the pain trajectory.

• Use your observational skills enhanced with collateral information to assess and reassess for pain in children.

• Treat pediatric pain effectively and with frequent reassessments. Failure to address the child’s pain has long-lasting consequences.

• Non-pharmacologic treatments for all, pharmacologic treatments for many. Opioids for few.  A multi-modal approach is the most effective.

• Neonates, infants and toddlers, and school-aged children and adolescents exhibit specific physiology in expression of pain and in response to treatment. Tailor your regimen to your young patient’s physiologic pitfalls and needs.

The author has no relevant conflicts of interest to disclose.

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Rachel S. Wightman, MD
Assistant Professor of Emergency Medicine
Division of Medical Toxicology
Alpert Medical School of Brown University
University Emergency Medicine Foundation

Jeanmarie Perrone, MD FACMT
Professor, Emergency Medicine
Director, Medical Toxicology
Department of Emergency Medicine
University of Pennsylvania School of Medicine

Introduction

Opioids are effective for treatment of acute pain in the Emergency Department. Opium and its derivatives have been used for millennia both medically for analgesia and non-medically for psychoactive effects, and problems with opioid abuse have coexisted throughout. Today, opioid analgesics are the most commonly prescribed class of medications in the United States and health care provider prescriptions are a major source of diverted opioids. (CDC 2014a) In 2014, almost 2 million Americans abused or were dependent on prescription opioids, 18,893 overdose deaths from prescription opioids occurred, and there were 10,574 deaths from heroin. (CDC 2014b, NIH 2015)

The decision to administer an opioid for acute pain should be thoughtfully considered, and providers need to be cognizant of the risks of opioid dependence, misuse, and addiction, as well as other opioid harms, when initiating opioid analgesia. Unfortunately, once initiated, opioids are often continued, in part because acute pain can transition to chronic pain. When used for the treatment of chronic pain, the risk of tolerance, hyperalgesia, dependence, and addiction should be considered, as these issues may outweigh any potential benefit. Data to support the efficacy and safety of opioids for management of chronic pain are limited and generally indicate that they are more likely to cause harm than benefit.

The range of available opioid medications and formulations is extensive, but only a few are commonly used in acute pain management. Regardless,  all opioids have similar clinical effects and liabilities, and they differ primarily in their pharmacokinetic properties. This chapter will focus on the opioids most commonly used for acute pain management in the ED.

Definitions

Opiate: Alkaloids naturally derived from the poppy plant Papaver somniferum. Examples include morphine and codeine.

Opioid: A broad term that applies to substances that bind to and stimulate (agonize) the mu opioid receptors. Opioids may be naturally occurring, such as opiates, or endogenous opioid peptides, such as endorphin, or they may be semi-synthetic or synthetic. In general, opioids are full agonists, and display a linear dose-response relationship, i.e. greater dose yields greater effect).

Semi-synthetic opioid: Created by chemical modification of an opiate. Examples include heroin (diacetyl morphine) and oxycodone.

Synthetic opioid: A substance  without apparent  structural similarity  to an opiate yet capable of binding the mu opioid receptor and producing opioid-like effects clinically. Examples include methadone and fentanyl.

Narcotic: Originally referred to any drug that causes sleepiness or narcosis. It is now used in legal contexts to refer to a variety of substances with abuse or addictive potential, including cocaine. This term should not be used in clinical medicine.

Agonist-antagonist: A substance that possesses agonist properties at one opioid receptor subtype (usually kappa) and antagonist effects at another (usually mu). Examples: nalbuphine, butorphanol

Partial agonist: A substance that binds to the mu opioid receptor and exerts less than full agonist effects; may appear to be an antagonist if used in a patient receiving a full agonist since its agonist effect is less pronounced. As the dose increases, the effects of a partial agonist plateau. Example: buprenorphine.

Potency: Refers to the amount of drug required to produce an effect.

Pharmacology & Mechanism of Action

Opioids act via binding to and stimulating specific opioid receptors, which are located in the brain, spinal cord, and peripheral nervous system. Many types and subtypes of opioid receptors exist, including mu, kappa, and delta receptors. Most opioids exert their clinical analgesic effects via binding to the mu-opioid receptors, which are densely concentrated in the brain regions that regulate pain perception and pain-induced emotional responses, as well as the regions that underlie the sensation of pleasure and well being. Though some of the  clinical variability of opioid medications is due to differential binding to the various opioid receptors or to other neurotransmitter receptors and transporters, most is due to alterations in pharmacological properties such as lipid solubility, metabolic fate, and duration of action.

Although classic teaching attributes the analgesic effects of opioids to the brain, opioid receptors at the supraspinal, spinal, and peripheral level appear to modulate cortical perception of pain. Most opioid-mediated analgesia arises from enhanced inhibition of nociceptive sensory neurotransmission from the periphery to the spinal cord and brain. Additionally, opioid receptor agonists may inhibit the release of pro-inflammatory compounds. (Stein 2003)

Morphine is considered the prototypical opioid to which all other opioids are compared. A Morphine Milligram Equivalent (MME) is a conversion factor frequently used to assess differences in potency among opioids. This conversion is intended for use when dosing or converting among opioids that are being used chronically, but can be applied conceptually to opioids used for shorter periods.

Clinical Effects

Opioid analgesics are commonly used for the treatment of moderate to severe pain in the hospital, and should be considered for the treatment of acute pain when the likelihood of benefit outweighs harm. When administered at appropriate doses, all full opioid agonist analgesics produce the same analgesic effect. However, available route of administration and pharmacokinetic differences including bioavailability, distribution, metabolism, and excretion may support specific opioid selections in certain circumstances.

In general, providers should start with the lowest effective dose possible of a short-acting opioid and titrate up as needed with frequent reassessment. When used at appropriate doses for medical purposes, opioids are generally safe and effective, but in excess dose or if combined with other sedative agents, clinically significant toxicity can occur. All opioids in excess dose lead to a constellation of clinical effects collectively referred to as the opioid toxidrome, which includes miosis, respiratory depression, sedation, and hypoperistalsis. Respiratory depression is the primary cause of death in patients with opioid overdose.

Extended-release and long-acting opioids should not be used for management of acute pain and will not be discussed.

Routes of Administration for Acute Pain Management

ORAL: The oral route is a convenient and cost-effective way to administer opioids. Opioids are well absorbed after oral administration, but they are subject to first pass metabolism and the onset of action is slower and more variable compared to parenteral administration. Frequently administered or prescribed oral opioids in the acute care setting are oxycodone, hydrocodone, tramadol (an atypical opioid), and hydromorphone.

INTRAVENOUS: Intravenous administration of opioids provides the most rapid onset of analgesia with more reliable absorption. Commonly used intravenous opioids for acute pain management are morphine, hydromorphone, and fentanyl.  When given intravenously for acute pain the ED, opioids should be titrated promptly, whether the initial dosing strategy is weight-based or fixed, until the pain level is acceptable to the patient or adverse effects develop.

INTRAMUSCULAR: Intramuscular administration allows for greater volume of medication than the subcutaneous route, but is painful and also can lead to variable absorption. Intramuscular administration should be reserved for use when intravenous access is difficult or undesired. Examples of appropriate uses of intramuscular opioid medication would be pain management for a patient with a femur fracture in the prehospital setting or a patient with sickle cell disease and difficult IV access who requires opioid medications for breakthrough crisis pain. Repetitive or prolonged use of IM opioids can lead to aseptic necrosis and myofibrosis and should be avoided. (Von Kemp 1989, Yamanaka 1985, Johnson 1976)

INTRANASAL: Intranasal fentanyl can be considered for pain control in adult or pediatric patients with difficult IV access (see chapter on pediatric analgesia). However, the intranasal route can have significant inter-individual bioavailability and requires patent nasal passages.

SUBCUTANEOUS: Subcutaneous administration is faster in onset than oral administration and does not rely on GI function or subject the drug to first pass metabolism. However, absorption can be variable and erratic, and because the subcutaneous space is less vascular than muscle, onset of analgesia is generally slower for subcutaneous versus intramuscular administration. For this reason we recommend intramuscular use over subcutaneous administration of opioids in the acute care setting.

TRANSDERMAL: Due to the requirement for drug to traverse multiple layers of skin, the clinical effects of opioids by this route are unpredictable and generally very slow in onset. Not recommended for acute pain management.

INHALATIONAL: Inhalation provides rapid delivery of a drug across the large surface area of the mucous membranes of the respiratory tract, producing an effect almost as rapid as the intravenous route of administration. In order for medications to be administered via the inhalational route they need to be dispersed in an aerosolized gaseous form. Nebulized morphine and fentanyl are examples of inhalational opioids.

TRANSMUCOSAL/SUBLINGUAL (BUCCAL): Transmucosal administration enables a medication to infuse directly into the capillary network and systemic circulation. Medications delivered via the transmucosal route have rapid onset of action and the added benefit of bypassing first-pass metabolism. Examples of transmucosal opioids currently available are effervescent morphine sulfate tablets and fentanyl sprays, lozenges, buccal tablets, and buccal soluble film. These preparations have traditionally been used for patients with end of life pain.

Individual Opioids Used for Acute Pain Management

All pharmacokinetic information listed is for immediate-release preparations.

Morphine is a naturally occurring opioid obtained directly  from opium which acts as an agonist at the mu and kappa opioid receptors. Morphine is approved for the treatment of moderate to severe pain not responsive to non-opioid analgesics. Multiple routes of administration are available including oral, parenteral (intravenous, subcutaneous, intramuscular) intrathecal, and rectal (suppositories). Ninety percent of morphine is metabolized by the liver and excreted by the kidney. In liver failure it is recommended to initiate therapy at lower doses and titrate slowly with consideration to extend the inter-dose interval. Because morphine’s active hepatic glucuronide metabolite (M6G) accumulates in renal failure, it is generally recommended to avoid morphine in patients with renal failure or, if used, reduce the dose and extend the dosing interval.  (Patwardhan 1981, Soleimanpour 2016, Mazoit 1987, Tegeder 1999, Bosilkovska 2012, Dean 2004) Although morphine and its active metabolite M6G are dialysable from the blood compartment, M6G can cross the blood brain barrier and the CNS effects of M6G, including seizures and respiratory depression, may persist even after or between dialysis sessions as M6G re-equilibrates between the CNS and systemic circulation.

Onset: Oral (IR) 30 min; IV 5 min; IM 10-30 min; SQ 10-30 min
Time to Peak: Oral (IR) 1 hr; IV/IM 10-60 min
Analgesic Duration: Oral: 3-5 hr; IV 3-5 hr; IM 4-5 hr; SQ 4-5 hr
Absorption: Variable, extensive first-pass metabolism
Volume of Distribution: 1-6L/kg
Metabolism: Hepatic via conjugation with glucuronic acid primarily to morphine-6-glucuronide (active analgesic), morphine-3-glucuronide (inactive as analgesic)
Elimination T1/2: Adults 2-4 hr
Excretion: Urine (primarily as morphine-3-glucuronide)

Hydromorphone is a more potent and lipophilic derivative of morphine with similar pharmacokinetic properties. The side effect profile is similar to other opioids, though hydromorphone is associated with higher rates of euphoria and misuse than comparable immediate-release opioids. (Atluri 2014, Dasgupta 2013, Hill 2000) Hydromorphone is available as tablets for oral administration or as a solution for intravenous use. One (1) mg of intravenous hydromorphone produces pain relief and respiratory depression equivalent to 8 mg intravenous morphine and 7.5 mg oral hydromorphone is approximately equal to 30 mg oral morphine or 15-20 mg oxycodone. The main active liver metabolite of hydromorphone is hydromorphone-3-glucuronide (H3G), which is renally excreted along with small amounts of additional liver metabolites and free hydromorphone. H3G is neuroexcitatory and can potentially cause seizures, especially with accumulation in patients with renal failure. Although hydromorphone and its active metabolite H3G are dialyzable, the dose should be reduced 50-75% in patients with a CrCl <30. For patients with mild to moderate liver impairment, initiate hydromorphone at 25-50% of usual starting dose and closely monitor for CNS and respiratory depression; a longer interdose interval is also recommended. Hydromorphone should be avoided in patients with severe liver failure.  

Onset: Oral (IR) 15-30 min; IV 5 min
Time to Peak: Oral (IR) 30-60 min; IV 10-20 min
Analgesic Duration: Oral: 3-4 hr; IV 3-4 hr
Absorption: Rapid oral absorption with extensive first-pass metabolism
Volume of Distribution: 4L/kg
Metabolism: Hepatic glucuronidation to inactive metabolites
Elimination T1/2: Adults 2-3 hr
Excretion: Urine (primarily as glucuronide conjugates); minimal unchanged drug is excreted in urine (7%) and feces (1%)

Fentanyl is a synthetic opioid and acts as a full opioid agonist with high affinity for the mu opioid receptor. It is 75-100x more potent than morphine as an analgesic. Fentanyl is highly lipid-soluble with a rapid onset of action (30 seconds) when administered IV, and a short duration of action owing to redistribution to fat and skeletal muscle. With repeated dosing or continuous infusion, saturation of fat and muscle depots occurs; the resulting systemic accumulation from fat sequestration can lead to a prolonged effect. For this reason, the apparent half-life of fentanyl varies based on the duration of administration. Muscle rigidity can occur with rapid intravenous administration of large doses. Fentanyl does not result in the release of tissue histamine and provides a high degree of cardiovascular stability. Most recommendations state that no dosing change is required for fentanyl in the setting of liver or renal failure, (Tegeder 1999, Bosilkovska 2012) but some recommend considering dose reduction. (Murphy 2005) The general principles of dose titration and clinical monitoring (with capnometry and pulse oximetry) should be followed.

Onset: IV immediate; IM 7-8 min; IN (Children 3-12 yrs) 5-10 min
Time to Peak: IV 10 min; IM 10-20 min
Analgesic Duration: IV 0.5-1 hr; IM 1-2 hr
Absorption: well absorbed transmucosal route
Volume of Distribution: Adult 4-6L/kg; Children 15L/kg
Metabolism: Hepatic via CYP3A4 by N-dealkylation and hydroxylation to inactive metabolites
Elimination T1/2: Adults 2-4 hr; when administered as a continuous infusion the apparent half-life prolongs due to redistribution from fat stores
Excretion: Urine 75% (primarily as metabolites, <7-10% as unchanged drug); feces 9%

Oxycodone is a semi-synthetic opioid available only in oral formulation in the United States either alone or in combination with acetaminophen. Oxycodone has higher bioavailability than morphine and is metabolized in the liver to the active metabolite oxymorphone (10%), through O-demethylation by the cytochrome P-450 enzyme CYP2D6. Lipid solubility is similar to that of morphine. When combination products are used at supra-therapeutic dose, hepatotoxicity from acetaminophen is a concern. In the setting of renal or liver failure, reduced initial dosing and careful titration are recommended. Extended-release oxycodone products should not be administered or prescribed for acute pain management due to mismatched pharmacokinetics and the elevated risk of misuse, abuse, and overdose. Oral oxycodone appears to be more abuse-prone compared to oral morphine and oral hydrocodone. (Comer 2008, Zacny 2009, Stoops 2010, Wightman 2012)

Onset: Oral (IR) 10-15 min
Time to Peak: Oral (IR) 0.5-1 hr
Analgesic Duration: Oral: 3-6 hr
Absorption: Oral rapidly absorbed with extensive first-pass metabolism
Volume of Distribution: 2.6 L/kg
Metabolism: Hepatic metabolism via CYP3A4 and CYP2D6 to oxymorphone and noroxycodone
Elimination T1/2: Adults 3.7 hr
Excretion: Urine (19% as parent; >64% as metabolites)

Hydrocodone is a semi-synthetic opioid derived from codeine. All immediate-release hydrocodone is formulated for oral use in combination with acetaminophen. A single entity (no acetaminophen) extended release hydrocodone formulation is available but not for use for treatment of acute pain. It is important that providers inform all patients that acetaminophen raises the risk of hepatotoxicity at supratherapeutic doses (> 4 g/day). In the setting of renal or liver failure reduced initial dosing and careful titration are recommended.

Onset: Oral 10-20 min
Time to Peak: Oral 1-1.6 hr
Analgesic Duration: Oral: 4-6 hr
Absorption: rapid
Volume of Distribution: 2.6 L/kg
Metabolism: Hepatic metabolism via CYP3A4 and CYP2D6 to hydromorphone
Elimination T1/2: Adults 4 hr
Excretion: Urine

Tramadol is a synthetic opioid structurally related to morphine and codeine. It is a centrally acting opioid agonist with some selectivity for the mu receptor and weak affinity for kappa and delta receptors. Additionally it exerts activity on the monoamine system by inhibiting the reuptake of norepinephrine and serotonin, raising the risk for seizures and serotonin toxicity. These risks highlight why tramadol should be avoided in patients taking MAO inhibitors, serotonin re-uptake inhibitors, or any agent with serotonergic activity. For patients with a creatinine clearance <30mL/min, the dosing interval of immediate-release tramadol hydrochloride should be increased to 12 hours from 4-6 hours. For patients with ESRD and/or cirrhosis, in addition to increasing the dosing interval the dose of tramadol should be reduced. Tramadol is not safer or less abuse-prone than most alternatives and is burdened by a host of unique, important toxicities. We discourage its use.

Onset: Oral 1 hr
Time to Peak: Oral 2-3 hr
Analgesic Duration: Oral: Single dose 4-6 hr; Multiple dose 3-11 hr
Absorption: 75% bioavailability
Volume of Distribution: 2.6 to 2.9 L/kg
Metabolism: Hepatic metabolism via CYP3A4 and CYP2D6 as well as by N- and O-demethylation glucuronidation or sulfation.
Elimination T1/2: Adults 5.6-6.7 hr
Excretion: Urine (30% unchanged drug; 60% metabolites)

Codeine is widely prescribed as an analgesic and antitussive despite its limited ability to effectively control pain. Codeine is a pro-drug that is itself inactive; opioid activity is conferred through demethylation to morphine via hepatic CYP2D6. The rapidity and extent of metabolism is subject to significant variation in the population complicating the prediction of analgesic efficacy or toxicity for a given individual (see controversies section below). Due to elevated risk of toxicity and questionable analgesic efficacy, we discourage the use of codeine for acute pain management in adults. In children, the likelihood of harm is still greater and codeine should not be used in children.

Buprenorphine is a semisynthetic, highly lipophilic opioid derived from the naturally occurring alkaloid thebaine. It is 25-50x more potent than morphine and is a partial mu agonist and antagonist at the kappa receptor. Buprenorphine is approved by the FDA for management of chronic pain and for substitution therapy for patients with opioid addiction. Because of its partial agonist effects at the mu receptor, buprenorphine can precipitate opioid withdrawal in patients who chronically take any full opioid agonist. Buprenorphine may have a role in the management of acute pain, though data is sparse and preliminary. (Jalil 2012, Payandemehr 2014)

Opioid Prescribing Guidelines

1. NYC DOHMH ED Opioid Guidelines
2. CDC Guideline for Opioid Prescribing for Chronic Pain

Adverse Effects and Management

Respiratory Depression

Respiratory depression is the primary cause of death with therapeutic use, misuse, and overdose of opioids. Opioid mediated-respiratory depression is due to both a decreased central response to hypercarbia as well as loss of the hypoxic respiratory drive. (Weil 1975) Respiratory depression from opioids can involve a decrease in respiratory rate and/or tidal volume, requiring meticulous assessment of both the pace and depth of breathing. Capnography may provide a better assessment of a patient’s minute ventilation in the setting of opioid use as long as breathing is sufficiently deep to allow exhalation of end tidal air. Tolerance to respiratory depression can partially occur over months leading to loss of hypercarbic respiratory drive, although complete tolerance to hypoxia does not occur. For this reason, providing oxygen to opioid tolerant patients may mask respiratory depression as the pulse ox may be reassuring in a patient who is inadequately ventilating, and capnometry or clinical assessment of respiratory rate and mental status must be included. Unfortunately, overall tolerance to respiratory effects of opioids lags behind tolerance to analgesic and psychoactive effects. Dose escalation to maintain analgesic or psychoactive effect is therefore often the inciting factor leading to acute toxicity, somnolence, respiratory depression, or fatal overdose. This is illustrated by the findings of chronic respiratory acidosis in patients maintained on methadone. (Marks 1973, Santiago 1977) A ceiling effect for respiratory depression occurs with some agonist-antagonists and partial agonists and contributes to their enhanced therapeutic to toxic ratio, although even in these agents sparing of respiratory depression is incomplete and overdose leads to hypoventilation. (Dahan 2006) Support of ventilation and oxygenation is the basis of management of respiratory depression from opioids. This can be accomplished mechanically via assisted ventilation (e.g. bag mask ventilation, laryngeal mask ventilation, or endotracheal intubation) or pharmacologically through administration of an opioid antagonist such as naloxone.

Hypotension

Opioids can cause hypotension via histamine release, which leads to arterial and venous dilation. The extent of histamine release varies based on the type of opioid. Hypotensive effects are seen more often with larger doses or more rapid infusion of opioids, and is not a consequence of oral administration. Most opioid related hypotension is transient and can be treated with intravenous fluids. Opioid mediated hypotension is especially problematic in the elderly due to decreased reserve and loss of vessel elasticity. In addition to hypotension, direct local histamine release after morphine injection can cause flushing, urticaria, and/or pruritus. This local reaction can sometimes be misinterpreted as an allergy due to the similarity of findings  to an immediate hypersensitivity reaction or anaphylaxis. True IgE-mediated allergy to opioid analgesics is rare. (Baldo 2012)

Seizures

Seizures are a rare complication associated with several opioid medications: meperidine, propoxyphene, tapentadol and tramadol. Opioid-related seizures should be managed in usual fashion, with benzodiazepines and other supportive measures. Seizures do not occur in patients with abstinence-related opioid withdrawal, except in neonates.

Movement disorders

Acute muscular rigidity can be seen with rapid IV injection of high potency opioids–especially fentanyl and its derivatives. (Comstock 1981, Hill 1981, Benthuysen 1986, Streisand 1993, Glick 1996, MacGregor 1996) Rigidity primarily affects the trunk and may disturb chest wall movement enough to impair ventilation. The mechanism of muscle rigidity may be related to dopamine blockade in the basal ganglia and/or GABA antagonism and NMDA agonism. Rigidity generally responds to naloxone, although neuromuscular blockade may be required. Bag-mask ventilation alone should be used with caution to avoid gastric distention and vomiting; use of a laryngeal mask or endotracheal tube is preferred.

Gastrointestinal effects

Many opioids produce nausea and vomiting when used therapeutically and may lead the patient to discontinue opioid use. Antiemetics, including ondansetron or metoclopramide, are generally effective. Opioid-induced constipation is nearly universal with opioid use and tolerance is very limited. New, expensive medications exist to help improve laxation, but these medications are not indicated for the management of short-term opioid use for acute pain.

Tolerance

Tolerance is a form of adaptation to the effects of chronically administered opioids (or other medications), which is manifested by the need for increasing or more frequent doses of medication to achieve the desired effect of the drug. Tolerance leads decreased apparent opioid potency and only occurs following repeated administration. In practical terms, long term opioid analgesic use typically engenders increasingly higher doses in order to maintain the initial level of analgesia. (Volkow 2016) In particular, tolerance to the analgesic and euphoric effects of opioids develops rapidly, whereas tolerance to respiratory depression develops slowly, which explains why well intended increases in opioid dose to maintain analgesia (or reward) can markedly increase the risk of overdose. (Hill 1981, Ling 1989)

Hyperalgesia

Opioid-induced hyperalgesia is defined as a state of nociceptive sensitization caused by exposure to opioids. This condition is characterized by the paradoxical development of increased pain sensitivity in patients who are taking opioids for treatment of pain. (Compton 2000, Doverty 2001, Chang 2007) As the pain escalates, increasing doses of opioid are required. The similarity between opioid-induced hyperalgesia and tolerance complicates decision-making on whether dose escalation is expected to be effective (tolerance) or counterproductive (hyperalgesia).

Addiction/Abuse

Opioid abuse involves the use of an opioid for the pleasant feeling it provides. Addiction is a state in which one develops compulsive opioid use of a drug despite harm. Harm can be medical (e.g., repetitive overdose, endocarditis) or social (e.g., job loss, divorce).

Pleasurable effects of opioids are linked to opioid stimulation of the central tegmental area of the brain leading to release of dopamine in the mesolimbic system. The euphoric effect of an opioid depends on the lipophilicity of the drug which equates to how quickly the drug crosses the blood brain barrier. (Butler 2011) For example, heroin (diacetylmorphine), which is highly euphoric, rapidly crosses the blood brain barrier whereas morphine, which is less commonly abused, is much less lipophilic and slowly crosses the blood brain barrier. Additionally, opioids may have a direct reinforcing effect on their self-administration through the mesolimbic pathway leading to addiction. Repeated use of opioids strengthens learned associations of the reward pathway and over time becomes part of the drug’s effects (Pavlovian response). Although there are no requisite number of opioid exposures required for addiction to develop, individual susceptibilities vary and can be as little as one dose; genetic vulnerability accounts for a proportion of addiction risk. (Reed 2014, Patriquin 2015) Additionally, adolescents are at increased risk because of enhanced neuroplasticity and the immaturity of the frontal cortex, which modulates self-control. (Chambers 2003) Addiction will not occur in all individuals exposed to opioids, but when it does occur it is a chronic, often lifelong medical condition that will not generally remit with simple cessation of opioid use.

Dependence/Withdrawal

Dependence is defined as physiologic adaptations that are responsible for the emergence of withdrawal on discontinuation of drug. The opioid withdrawal syndrome includes physical findings such as piloerection, chills, insomnia, diarrhea, nausea, vomiting, and muscle aches that occur upon abstinence from opioid use. Perhaps more importantly however, is that withdrawal engenders drug craving. Opioid withdrawal, while uncomfortable for the individual, is not life-threatening nor is it associated with altered mental status. Opioid withdrawal can typically be managed on an outpatient basis with antiemetics, benzodiazepines, and/or clonidine. Although an opioid agonist, usually methadone, can be administered in the ED, the prescription of opioids to manage opioid withdrawal or addiction is not legal except under very specific circumstances (e.g., a methadone clinic or by a buprenorphine waivered physician).

Precipitated or iatrogenic opioid withdrawal occurs after administration of an opioid antagonist in an opioid dependent patient. Precipitated opioid withdrawal results in a catecholamine surge that can be life threatening: myocardial stunning or infarction, pulmonary edema, seizures, and pronounced agitated delirium may occur in addition to the aforementioned findings associated with abstinence related withdrawal. No published guideline for the management of precipitated opioid withdrawal exists, but management considerations should include sedation with benzodiazepines, propofol, or dexmedetomidine; high dose fentanyl may be used to try to overcome the receptor blockade.

Special Populations

Obesity/Sleep Apnea

Patients with sleep apnea and obese individuals are at increased risk for complications of opioid induced respiratory depression. (Casati 2005, Patanwala 2012) Enhanced monitoring should be provided in these patient populations, which frequently overlap. (Yue 2010) Given that these populations are at high risk for complications following discharge on opioids, extra caution using non-opioid regimens or very low doses (based on lead body mass), if opioids are deemed necessary, should be used.

Geriatric/ Comorbidities

Opioids should be used with caution in geriatric patients and patients with multiple comorbidities. Older individuals have less functional reserve because renal and hepatic function decline with age, increasing the risk for adverse drug effects. Elderly individuals are also at increased risk for opioid associated respiratory depression. (Cepeda 2003) CNS effects of opioids can be pronounced or prolonged in the elderly as well as individuals with dementia, brain injury, or cognitive impairment, (Fong 2006) and may lead to oversedation and falls.

Drug Interactions

Polypharmacy increases the likelihood for drug-drug interactions, dosing errors, and side effects. Pharmacokinetic drug interactions can change exposure to an opioid or co-administered medication, which can reduce efficacy and/or increase toxicity. Combining opioids with other sedatives such as benzodiazepines or alcohol can place an individual at increased risk for sedation, respiratory depression, and death due to synergistic effects. Patients with impaired renal and hepatic function are at elevated risk for adverse effects because they may have difficulty metabolizing and/or eliminating opioid medications. (Smith 2010)

Pregnancy and Lactation

Opioids can be used with caution for acute pain management in pregnancy and during labor. Most opioids are Pregnancy Category C and short-term use of opioids to treat acute pain in pregnancy appears safe. Use near term may cause neonatal respiratory depression and long-term use may lead to neonatal abstinence syndrome in the newborn. (Wunsch 2003, Chou 2009, Farid 2009)

Short-term opioid use is generally considered safe during lactation as most opioids are excreted in the breast milk in only low doses. It is, however, important that providers practice caution when using opioids in a breastfeeding mother and closely monitor mother and infant for signs of toxicity as newborn deaths have been reported after maternal use during lactation. (Koren 2006) Morphine has been recommended as the opioid of choice if a potent analgesic is required. (Spigset 2000, Naumburg 1988, Ito 2000, Feilberg 1989, Baka 2002) Approximately 6% of weight-adjusted maternal dose of morphine is transferred in breast milk and oral bioavailability in the infant is low (about 25%) so only small amounts reach the infant. Pharmacokinetic studies suggest that fentanyl and its derivatives are unlikely to cause problems. Codeine, however, should be avoided in lactating mothers due to concern for excess morphine production by rapid codeine metabolizers, which can then be transferred through breast milk.

Chronic Pain

Patients with a history of chronic pain on long-term opioid therapy present a challenge to the ED provider. A single outpatient primary care provider should prescribe all opioids to manage a patient’s chronic pain. Treatment of an acute exacerbation of chronic pain in the ED with opioids is discouraged. If a patient presents to the ED with an acute exacerbation of chronic pain, after evaluation for consequential pathology the patient should be referred to their primary care provider or to a pain specialist for follow up. Non-opioid analgesics are recommended for treatment, particularly if the patient has a patient-provider agreement (“pain contract”) that addresses breakthrough pain. Additionally, emergency clinicians should attempt to contact that patient’s primary care provider or primary opioid prescriber to communicate a summary of the ED visit.

Pain Management for Opioid-Dependent Patients (Patients on Methadone or Buprenorphine)

Effective management of acute pain is more challenging in opioid-dependent individuals compared to their opioid-naïve counterparts. Treatment of acute pain in patients on buprenorphine and/or methadone involves not only management of the acute pain episode, but also prevention of withdrawal. For patients with pre-existing pain, it may be necessary to have a discussion with the patient differentiating acute versus chronic pain and explaining that acute pain management will be the primary focus in the ED. To adequately treat acute pain in this population, high doses of opioids or alternative analgesic agents and significant deviations from standard treatment protocols may be required. Such processes are generally risky, and should be approached with caution and deliberation. Non-opioid analgesic agents such as NSAIDS and acetaminophen or regional anesthesia can be considered as adjunctive therapy, although matching the patient’s expectations for pain relief is typically challenging. Ketamine and sedating butyrophenones (haloperidol or droperidol) may be useful in this population, but additional research is needed to understand the risks, benefits, and specific roles of these therapies in this context.

To prevent the development of opioid withdrawal, providers may give the reported daily dose of opioid maintenance therapy in divided doses while monitoring the response to the alternative pain regimen provided. If the reported usual dose is high or there is doubt about whether or not a verified dose in taken in full, a portion of the daily dose may be given with monitoring. Management in a monitored setting is recommended, as frequent assessment will be necessary to optimize analgesia while maintaining safety. (Huxtable 2011) Respiratory depression remains a concern even in patients tolerant to the analgesic effects of opioids, especially if there is an escalation of dose or intercurrent illness.

Buprenorphine is a partial mu-agonist (and a kappa-antagonist), although clinically, in opioid naïve patients, it behaves as a full mu-agonist analgesic. In addition, buprenorphine may have anti-hyperalgesic properties. Buprenorphine has high opioid receptor affinity and slow offset kinetics, resulting in blockade of the opioid receptor by a partial agonist that interferes with the effect of full mu-opioid agonists. In patients dependent on opioids and not in withdrawal, buprenorphine administration leads to precipitated withdrawal as the partial agonist replaces a full agonist on the opioid receptor.  

Published guidelines for pain management in patients on buprenorphine offer conflicting recommendations. (Roberts 2005, Alford 2006, Kornfeld 2010, Pergolizzi 2010, Macintyre 2013) At this time it is unclear if high-dose buprenorphine should be discontinued in the setting of acute pain requiring management. Although cessation of buprenorphine will not affect emergency pain management due to the long half life of buprenorphine,  it could simplify pain control later in a hospital course. In patients who require opioid analgesia, one approach is for cessation of buprenorphine and titration of fentanyl, which is the only commonly used opioid with higher receptor affinity than buprenorphine. The analgesic effect for buprenorphine lasts 6-12 hours, although it has a terminal elimination half life of ~24 hours.(Kuhlman 1996)

Alternative Routes of Delivery

Transdermal fentanyl is frequently used in the treatment of chronic pain. It is contraindicated for use in patients with acute pain due to their lack of opioid tolerance and the mismatch between the pharmacokinetics of transdermal delivery and the pain trajectory. (Bernstein 1994, Sandler 1994, Bulow 1995) That is, the slow onset and prolonged duration of action combined with the inability to titrate to effect makes transdermal fentanyl poorly suited for the rapidly changing pain requirements in patients with acute pain. (Grond 2000) Deaths from use of transdermal fentanyl for acute pain are avoidable.(Rose 1993, Bernstein 1994)

Intranasal fentanyl is increasingly employed in the prehospital setting and ED for analgesia in children, or for patients with difficult intravenous access. The rich venous plexus of the nasal mucosa is easily accessible and facilitates rapid drug absorption into the systemic circulation. Intranasal absorption avoids gastrointestinal degradation and hepatic first pass metabolism. Several randomized placebo controlled studies have found that intranasal fentanyl in children is an acceptable alternative to intramuscular or intravenous morphine for pain control. (Borland 2007, Borland 2011, Murphy 2014)

Controversies

Codeine

Codeine is a pro-drug that is itself an inactive opioid agonist. In order to have opioid activity codeine must be metabolized to morphine via CYP2D6 in the liver. Analgesic efficacy and safety of codeine are determined by CYP2D6 polymorphisms, which vary widely between different ethnic groups. (Cascorbi 2003, Sistonen 2007) For individuals without the CYP2D6 enzyme codeine is devoid of analgesic properties. Conversely, ultra-rapid metabolizers at the CYP2D6 enzyme rapidly produce greater than expected amounts of morphine, increasing the risk of life-threatening opioid toxicity. (Lazaryan 2015) Multiple studies evaluating the analgesic efficacy of codeine fail to demonstrate benefit for pain, and the antitussive action of codeine is poor to nil. (Eccles 1992, Freestone 1997, Chang 2001, Koren 2006, Clark 2007, Charney 2008) As discussed above, due to the known elevated risk of toxicity from codeine and lack of clear analgesic or antitussive efficacy, use of codeine is discouraged for acute pain management in the ED or outpatient settings in adults, and should not be used in children.

Abuse deterrent formulations

Abuse deterrent formulations (ADFs) are specific opioid formulations designed to decrease the ease of abuse by parenteral and intranasal routes. Currently several extended-release formulations of various opioids with ADFs are available, and one  such formulation is available for an immediate-release oxycodone product.  ADFs unfortunately are not devoid of abuse potential as they can still be ingested in larger than therapeutic amounts. Additionally ADFs are more expensive, have unproven effectiveness in reducing abuse, and, in most cases, the ADF formulation can be compromised.

Discharge

Opioid analgesics should not be considered as the primary approach to pain management in discharge planning for patients. Alternative effective interventions for acute pain exist, including NSAIDs, acetaminophen, nerve blocks, and gabapentin. If felt necessary, providers should recommend a non-opioid pain reliever first and instruct patients to use an opioid only for uncontrolled pain. When prescribing an opioid analgesic, limit the prescription to the lowest effective dose for the shortest effective duration. This generally means 3 days of a short acting opioid formulation, with a minority of patients requiring up to 7 days. If your state has a prescription drug-monitoring program, consider querying  patients to determine their opioid prescription history.  

Discuss the addiction risk of opioids with your patients and assess their risk for opioid misuse or addiction prior to prescribing. Existing scoring systems for addiction risk are suboptimal and likely do not perform better than clinical gestalt. Do not write prescriptions for extended-release or long-acting opioid analgesics for treatment of acute pain. (Miller 2015) Educate your patients regarding the increased risk of overdose and respiratory depression if opioids are taken with other sedatives (e.g. benzodiazepines or alcohol). Discuss safe storage and proper disposal of unused medications with all patients prescribed opioids. Warn your patients not to drive, operate machinery, or perform any potentially dangerous task while taking an opioid.

Sample Discharge Instructions for Patients Receiving an Opioid

You have had a severe painful episode. You can expect the worst pain to last a few more days. You will receive a prescription for an opioid medication and a non-opioid medication. Opioid medications, although good for treatment of acute severe pain, carry a risk of addiction and in higher doses can cause slowed breathing and even death. Opioid medications should only be used for a short period of time to manage severe pain. Please take the non-opioid medication first and reserve use of the opioid medication for uncontrolled or breakthrough pain only. Over the next few days you should aim to decrease or eliminate use of opioid medications and rely only on non-opioid pain medications such as nonsteroidal anti-inflammatory drugs or acetaminophen.  Store opioid medications in sealed containers outside of reach of children. Dispose of all unused opioid medications in medication disposal centers once your acute pain episode is over. Because of the increased risk of injury, you should not drive, operate machinery, or perform any potentially dangerous task while taking an opioid.

Naloxone

Naloxone is an opioid antagonist that competitively inhibits the binding of opioid agonists at the opioid receptor, reducing the effects of the opioid agonist. In patients without prior opioid exposure, naloxone has virtually no clinical effect. The goal of naloxone therapy in the acutely opioid-poisoned patient is to improve minute ventilation, and not full reversal of other opioid effects such as analgesia or sedation. In an opioid naïve individual (i.e., non chronic opioid user) naloxone can be given in large doses without adverse effect, but in chronic opioid users naloxone can precipitate opioid withdrawal, which can lead to life-threatening catecholamine release and agitated delirium. For this reason an initial dose of naloxone in a patient with severe opioid intoxication (e.g., respiratory depression) of 0.04mg (40 mcg) is recommended with titration of the dose to achieve a respiratory rate greater than ten with adequate depth. If capnography is available, maintaining a normal end tidal CO2 is an appropriate goal. Higher doses of naloxone may be required for certain opioids such as sufentanil and buprenorphine. (Leysen 1983, Sarton 2008)

Any patient receiving naloxone should be monitored closely for signs of both opioid withdrawal and for recrudescence of opioid intoxication as the naloxone effect wanes. If withdrawal occurs (piloerection, pupillary dilation, tachycardia, hypertension, emesis, diarrhea), naloxone administration should be stopped and, if the patient still requires respiratory assistance, intubation or other advanced respiratory support maneuvers should be performed.

For reversal of short acting opioids such as fentanyl or heroin a single dose of naloxone may be sufficient to improve respiratory status while opioid metabolism occurs. For longer acting opioids such as morphine or methadone multiple doses of naloxone may be required or the patient may be placed on a naloxone drip at 2/3 the respiratory depression reversal dose given per hour.

The authors report no conflicts of interest.

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Maryann Mazer-Amirshahi, PharmD, MD, MPH
Assistant Professor of Emergency Medicine
Georgetown University School of Medicine
Department of Emergency Medicine,
MedStar Washington Hospital Center

Tamika Auguste, MD
Associate Professor of Obstetrics and Gynecology
Georgetown University School of Medicine
Women’s and Infants’ Services
MedStar Washington Hospital Center

Introduction

Although pain is a common complaint in the acute care setting, the treatment of pain in the pregnant and postpartum patient is complicated by the limited data regarding the safe and efficacious use of medications in pregnancy and lactation. This is largely because few clinical trials are undertaken during pregnancy due to ethical and legal concerns surrounding drug exposures during pregnancy. At the same time, up to 80% of pregnant women report having taken a medication during the first trimester, when vital organs and bodily structures are being formed. (Mitchell 2011) In addition, the percentage of women taking medications during pregnancy is expected to increase in coming years because women bear children later in life and older pregnant women are more likely to need medications for acute and chronic illness. (CDC 2015)

When prescribing medications for pregnant and postpartum patients, providers must consider–with little guidance–the potential for fetal (or neonatal) and maternal adverse effects as well as the harms of untreated maternal illness or disease. There have been efforts to optimize the use of medications in pregnancy and lactation, including Food and Drug Administration (FDA) guidance for industry to establish registries, improve pregnancy labeling, and promote clinical pharmacokinetic studies in pregnant women. (FDA 2002) One of the most notable recent changes was the abolishment of the traditional A, B, C, D, and X pregnancy categories for prescribing information. The new labeling system that was introduced is based on the complexity of the risk assessment of a drug to be used in pregnancy and underscores that a narrative discussion with consideration of the benefits of the drug is more appropriate than a simple letter designation. (FDA 2004) (Tables 1, 2). This chapter will focus on the management of pain in the acute setting in the pregnant and postpartum patient. Peripartum and chronic pain management will not be discussed.

Regional poison centers (800-222-1222) or drug information centers are up to date resources for pregnancy-related drug questions, as is the MotherRisk Helpline.

Table 1. Revised Pregnancy Information Drug Labeling

Table 2: Revised Lactation Subsection Information Drug Labeling

Drug Therapy in the Pregnant and Postpartum Patient

There are several physiologic changes that occur during pregnancy and in the postpartum periods that have the potential to affect the pharmacokinetics of medications administered during pregnancy and postpartum. A comprehensive list of these changes is provided in Table 3. Although these changes do not uniformly alter the administration of medications, providers must be cognizant of potential dosage adjustments and consult the appropriate references when prescribing, as well as perform therapeutic drug monitoring when indicated to optimize efficacy and avoid toxicity.

The physiologic changes that occur during pregnancy (Table 3) can persist well into the postpartum period. Increased glomerular filtration rate (GFR) and decreases in serum albumin persist in the immediate postpartum period. (Sims 1958). Cardiovascular changes can persist as long as 12 weeks postpartum. (Capless 1991) The reversal of the effects of pregnancy on drug metabolizing enzymes is much more variable, with the activity of some enzymes returning to the pre-pregnancy state nearly immediately and others returning over the course of weeks to months. (Dam 1979)

In addition to the physiologic changes that occur in the mother during pregnancy, one must also consider the impact of pharmacotherapy in the developing fetus. Many small, lipid-soluble, non-polar molecules readily cross the placenta via passive diffusion, whereas larger polar molecules do not. (Plonait 2004) The point during pregnancy at which the exposure to the pharmaceutical occurs is also important. Early in pregnancy, there may be an “all or none” response where the pregnancy may either terminate or continue normally. Most vital organs form between 3 and 8 weeks gestation, so exposures that occur during this time have the potential to cause significant structural malformations. Exposures later in pregnancy may have a greater impact on fetal growth. Medication use near term can also impact the neonate following delivery. For example, maternal use of opioid analgesics near term can cause respiratory depression in the neonate and non-steroidal anti-inflammatory drugs (NSAIDs) may cause premature closure of the ductus arteriosus. Additionally, the duration of exposure may be clinically relevant, as occurs when prolonged use of opioid analgesics results in neonatal abstinence syndrome. (Brent 1995, Tolia 2015) Finally, during the postpartum period, providers should inquire as to whether the infant is being breast-fed and investigate whether the medication is excreted in the breast milk. 

Table 3. Major Physiologic Changes that Occur During Pregnancy and Impact on Pharmacokinetic Parameters

Considerations for Commonly Used Analgesics in Pregnancy

The use of over the counter and prescription analgesics during pregnancy is controversial and poorly informed by data. Few strong recommendations can be made in this domain, and we endorse the position of the United States Food and Drug Administration: “Severe and persistent pain that is not effectively treated during pregnancy can result in depression, anxiety, and high blood pressure in the mother. Medicines including nonsteroidal anti-inflammatory drugs, opioids, and acetaminophen can help treat severe and persistent pain.  However, it is important to carefully weigh the benefits and risks of using prescription and OTC pain medicines during pregnancy.” Specific agents are discussed below.

Acetaminophen

Acetaminophen is the most widely used analgesic during pregnancy. It is administered primarily for the treatment of mild to moderate pain and as an antipyretic. Although the use of acetaminophen has not been associated with fetal malformations, recent epidemiologic studies have suggested a link between maternal acetaminophen use during pregnancy and hyperkinetic and behavioral disorders in children. (Liew 2014) At the same time, there are significant limitations to these data and the associations are weak, reinforcing the need for better controlled trials in the future. Until there are additional high quality data to the contrary, acetaminophen is still considered the safest first line medication for the treatment of mild to moderate pain and fever in pregnancy and during lactation. (de Fays 2015)

Non-Steroidal Anti-Inflammatory Drugs

Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) have not been associated with major congenital malformations; however, their effects on prostaglandin and platelet function can have significant implications for their use during pregnancy. Prostaglandins maintain the patency of the ductus arteriosus and use of NSAIDs near term may cause premature closure of the ductus. Administration of NSAIDs may also prolong labor due to prostaglandin inhibition. (Moise 1988) Peripartum hemorrhage in the mother and neonate may occur due to anti-platelet effects of aspirin and NSAIDs when these medications are administered near term. (Stuart 1982)  It is for these reasons that the use of NSAIDs is not recommended in the third trimester of pregnancy.

Data are conflicting but generally support the safety of NSAIDs in the first two trimesters; (Daniel 2014, Damase-Michel 2014) however recommendations and practice patterns are varied. (Babb 2010, Shah 2015, Antonucci 2012)  Acknowledging the limitations of the data and absence of consensus, we feel the use of a short course of NSAIDs in early pregnancy is safe and appropriate when thoughtfully applied to patients in pain, including a consideration of the benefits and harms of alternatives (and the harms of under-treating pain).  We do not endorse the practice of routine pregnancy testing in women of childbearing age not known to be pregnant prior to the administration of NSAIDs.

There is little evidence to support or discourage the use of topical NSAIDs during pregnancy. Because systemic absorption of these preparations is lower than oral NSAIDs, it is reasonable to use them in the first two trimesters. NSAIDs are considered safe during lactation and are a mainstay in the management of postpartum pain.

Opioid Analgesics

Opioid analgesics are commonly prescribed for moderate to severe pain, particularly when non-opioid therapies fail. Opioids have also been used during pregnancy and in the postpartum period to manage acute and chronic pain. Opioid use in pregnant patients is relatively common, with over 1 in 20 pregnant women receiving an opioid during the first trimester. (Bateman 2014) In addition, opioid analgesic use during pregnancy has nearly doubled in the past two decades. (Epstein 2013) Despite the widespread use of opioid analgesics during pregnancy, there are limited data regarding teratogenic effects. The use of codeine during pregnancy has been associated with a small increased risk of cardiac and respiratory malformations. (Shaw 1992). More recent data found that maternal opioid use during pregnancy, particularly during the first trimester was associated with a small but significant increase in congenital heart disease and spina bifida. The most commonly implicated opioids were hydrocodone and codeine. (Broussard 2011) Maternal opioid use at term may cause decreased variability in fetal heart rate and respiratory depression in the newborn. (Rayburn 1989) In women with chronic opioid use during pregnancy, the newborn is at increased risk of developing neonatal abstinence syndrome (NAS), which can lead to a prolonged period of opioid detoxification in the infant after birth. Clinical findings in newborns with of NAS  include irritability, poor feeding, and seizures. (Zelson 1973, Tolia 2015)

In recent years, there were exponential increases in opioid analgesic prescribing across a wide variety of demographics, including women of childbearing age. This increase in prescribing was accompanied by a profound increase in opioid misuse, abuse, and fatalities. (Warner 2011) Pregnant women were not exempt from the consequences of opioid use. One study demonstrated that 1% of pregnant near-term women  admitted to non-medical use of a prescription opioid analgesic within the past 30 days. (Bateman 2014) Another showed that 6% of pregnant women admitted nonmedical use of opioid analgesics during pregnancy and opioid users had significantly higher rates of psychiatric comorbidities. Prescription drug abuse in women of childbearing age can have significant consequences including unprotected sex, domestic violence, and child abuse. Although prescription drug abuse may not affect parenting ability, it is intuitive that treatment and abstinence are preferred. Unfortunately, patients may be hesitant to disclose their addiction for fear of losing custody of their children. (Committee 2012) Universal screening with brief intervention and referral to treatment is currently recommended for all prenatal patients to improve maternal and fetal outcomes. (Committee 2017).

For these reasons it is important for providers to employ safe and rational opioid prescribing practices when treating pregnant and postpartum patients. Opioid analgesics can be used for similar indications as in the non-pregnant patient, primarily for the treatment of moderate to severe pain when non-opioid therapies fail or are contraindicated. (Committee 2017) If an opioid analgesic is indicated, codeine should be avoided due to its link to cardiac and respiratory malformations. (Shaw 1992) Like prescribing in the non-pregnant patient, pregnant patients should have a risk assessment for prenatal substance abuse performed. An example of a tool for risk assessment for prenatal abuse is presented in Table 4, but all such tools have significant limitations, and clinical judgment should prevail. It is also recommended when opioids are prescribed to use the lowest possible dose for the shortest period of time using only immediate release, short acting formulations, with frequent reassessment and close follow up. Near term, neonatal respiratory depression is the most dangerous consequence of maternal opioid use while in earlier pregnancy, NAS and the development of maternal long term use are the harms of dominating concern.

Table 4.  Clinical Screening Tools for Prenatal Substance Use and Abuse

Ewing H. A practical guide to intervention in health and social services with pregnant and postpartum addicts and alcoholics: theoretical framework, brief screening tool, key interview questions, and strategies for referral to recovery resources. Martinez (CA): The Born Free Project, Contra Costa County Department of Health Services; 1990.

When an opioid use disorder (either prescription or illicit) is identified in a pregnant patient, she should promptly be referred to a provider with experience in managing addiction, as substance abuse during pregnancy is associated with adverse maternal and fetal outcomes. (Committee 2012, Committee 2017, Messinger 2004, Kaltenbach 1998) Until recently, methadone had been the standard treatment for pregnant patients with opioid addiction. Although methadone maintenance therapy in pregnancy is accompanied by  improved fetal outcomes, access to therapy is often limited and requires daily trips to the clinic, which can be burdensome. (Kaltenbach 1998, Winklbaur 2008) More recently, buprenorphine has emerged as a therapeutic alternative to methadone. Buprenorphine has demonstrated effectiveness for medical management of opioid addiction, has fewer restrictions, and a wider safety margin than methadone. (Jones 2012) In addition, buprenorphine maintenance during pregnancy is associated with longer gestation as well as decreased incidence and severity of neonatal abstinence syndrome. (Jones 2010, Meyer 2015) In general, opioid agonist therapy is preferred to medically supervised withdrawal because of lower relapse rates. (Committee 2017)

Opioid analgesics are often used in combination with NSAIDs for the treatment of pain during the postpartum period. Until recently, codeine had been used for the treatment of postpartum pain; however, its use has fallen out of favor due to mounting case reports of infants experiencing toxicity and even death when breastfed by mothers with cytochrome (CYP) 2D6 genetic polymorphisms. (Koren 2006, Madadi 2007) Mothers who are ultra-rapid CYP 2D6 metabolizers of codeine will excrete toxic concentrations of morphine (the active metabolite of codeine) into the breast milk. (Madadi 2009) There are reports of neonatal toxicity associated with maternal oxycodone use, (Timm 2013) and hydrocodone and hydromorphone are also excreted in the breast milk though the actual risk to the neonate is uncertain. (Sauberan 2011) Current evidence suggests it is prudent to avoid codeine altogether during breastfeeding, with efforts to minimize drug exposure to the infant and close monitoring for signs of toxicity when other opioids are used to treat maternal pain. (Lazaryan 2015)

Muscle Relaxants

The use of skeletal muscle relaxants in pregnancy remains controversial. Skeletal muscle relaxants such as cyclobenzaprine and methocarbamol were historically categorized as “B” or “C” drugs but quality human data regarding their safe use in pregnancy are lacking. Although it has not been associated with fetal malformations, cyclobenzaprine is associated with premature ductal closure and pulmonary hypertension when used near term. (Moreira 2014) As such, it is recommended to avoid using cyclobenzaprine in the third trimester. There are limited data regarding the use of non-benzodiazepine skeletal muscle relaxants in breastfeeding, although there is not a clear contraindication. The benzodiazepine diazepam is commonly used as a muscle relaxant, but its use in pregnancy is associated with congenital inguinal hernias and cleft palate, although controlled data are lacking. (Rosenberg 1983, Enato 2011) In addition, as with opioids, long-term benzodiazepine use during pregnancy is associated with a NAS and use just prior to delivery can result in respiratory depression of the newborn. (Scanlon 1975) Diazepam is also excreted in the breast milk and can cause sedation because active metabolites accumulate in the newborn. As such, its use is generally not recommended during pregnancy or lactation unless the benefits clearly outweigh the harms. (Erkolla 1972)

Local Anesthetics and Agents Used to Treat Neuropathic Pain

Local anesthetics, such as lidocaine and bupivacaine, are commonly used for analgesia during procedures, and have not demonstrated teratogenic effects when administered during pregnancy. Local anesthetics are also safely used during labor and delivery without adverse effects to the fetus. (Heinonen 1977) They are also used chronically, often topically in patch form, for neuropathic pain, although their efficacy for the latter indication is modest. Their safety is not well studied, but they are presumed to be of minimal risk given their minimal systemic bioavailability, and topical lidocaine has been historically considered a category “B” medication. There is negligible excretion of local anesthetics in breast milk and these medications are considered compatible with breastfeeding. (Zeisler 1986)

Gabapentin, an agent used extensively to treat neuropathic pain, has been used in pregnancy with some success and no evidence of significant fetal toxicity; however, data are limited. (Guttuso 2014) Tricyclic antidepressants have also been used to treat neuropathic pain, but the data regarding safety in pregnancy is limited. There is an association with tricyclic use in pregnancy and prenatal antidepressant exposure syndrome although it appears to be less severe than observed with selective serotonin reuptake inhibitors. (Gentile 2014)

Procedural Sedation in the Pregnant Patient

Pregnant patients may experience illnesses or injuries that require procedural sedation. When managing a pregnant patient who requires procedural sedation, providers must be cognizant of both the physiologic changes that may affect sedation as well as the safety of the medications used. (Table 5) Consultation with a provider with experience in obstetric anesthesia is prudent for patients in late pregnancy who require procedural sedation, particularly in more complicated cases.

Table 5. Physiologic Considerations for Procedural Sedation in Pregnancy

There are several medications that may be used safely and effectively for procedural sedation in the pregnant patient. Rapid-acting benzodiazepines such as midazolam and opioid analgesics such as fentanyl, as well as the sedative propofol can be used without risk of fetal malformations. They do however, carry the risk of respiratory and central nervous system depression in the newborn when used at term. Propofol is pregnancy category “B” and has been used in pregnancy; however, long term outcome and developmental are limited. Propofol may cause maternal hypotension which may compromise the fetus, which requires careful titration and monitoring. (Tajchman 2010)

Low dose ketamine may be considered for use in pregnancy near term, but its use has been associated with uterine contractions and exacerbation of hypertension, and therefore it is not considered a first-line agent. It also carries the risk of neonatal central nervous system depression. (Neuman 2013) Ketamine has also been associated with neuroapoptosis in animal studies, although this phenomenon has not been observed in humans and is likely only relevant during early gestation. Whether there is a risk with use of low-dose ketamine for analgesic purposes has also not been determined. (Bambrink 2012)

Nitrous oxide exposure during the first trimester of pregnancy has been associated with teratogenic effects and spontaneous abortion; however these data are controversial. Given the availability of safer alternatives, nitrous oxide should only be used when there is a contraindication to other therapies or at term. (Neuman 2013)

Non-Pharmacologic Therapy

There are several alternatives to pharmacologic therapy for pain relief in pregnant patients. Biofeedback is a series of educational sessions that increase relaxation and increase awareness of physiologic processes that has been used safely during pregnancy. Acupressure is a massage method that focuses on specific pressure points, and it has been successfully used during pregnancy to treat pain. Acupuncture uses needles to provide intense stimulation to specific points in the body to relieve pain and has been tolerated well in pregnancy. Transcutaneous electric nerve stimulation (TENS) works by stimulating afferent nerves, decreasing pain sensation. Although TENS has been widely used for a variety of painful complaints in pregnancy without any reported adverse effects, controlled data are limited. Should any of these therapies be employed for pain management during pregnancy, patients should be referred to a provider that has experience in treating pregnant patients. (Brucker 1988)  

Common Acutely Painful Conditions in Pregnancy

Back Pain

Pelvic girdle pain and low back pain are common complaints occurring in approximately 45% of pregnant patients and up to 25% of postpartum patients. (Wu 2004) Non-pharmacologic therapies can be helpful in treating these conditions. Demonstrating good posture, engaging in targeted exercise, taking frequent breaks from activity, and using proper lifting techniques can prevent exacerbations. (Ostgaard 1994) Use of wedge-shaped pillows during sleep and supportive devices have also been shown to be safe and effective interventions. Physical therapy, TENS, and acupuncture are safe non-pharmacologic options for the treatment of pelvic girdle and low back pain. When pharmacologic therapy is required, acetaminophen is considered first-line therapy. NSAIDs are generally not recommended in third trimester, when these conditions primarily occur. In pregnant patients without evidence of or risk factors for opioid misuse who have severe pain that is refractory to other therapies, it is reasonable to prescribe opioids judiciously, as discussed in other chapters. For refractory pain, epidural anesthesia has been used. (Vermani 2010)

Headache

Migraine headaches are the most common type of headache encountered in women of reproductive age, affecting nearly 20% of this patient population. Although the frequency of migraine headaches actually decreases due to hormonal changes during pregnancy, many women will still require treatment during this time. (Granella 2000) Migraines may occur during labor and worsen during the postpartum period, particularly in women who do not breastfeed. Any headache in the pregnant patient should prompt a standard investigation for dangerous causes, in addition to pregnancy related causes such as cerebral venous thrombosis or preeclampsia. (Kvisvik 2011, Banhidy 2007)

Women with migraines can use selected prophylactic therapies during pregnancy; however, some may require acute migraine treatment as well. For mild pain, acetaminophen is considered first-line therapy. For more severe attacks, antiemetics, such as phenothiazines or metoclopramide, can be used. Intravenous magnesium sulfate has also been used as abortive therapy. (Demirkaya 2001) Sumatriptan appears to be safe during pregnancy and lactation and may be considered after other therapies have failed. As with nonpregnant headache patients, opioids should be reserved for those refractory to all other therapies (see headache chapter). (MacGregor 2014) Ergotamine is contraindicated during pregnancy, due to its effects on fetal growth and its association with preterm labor. (Bánhidy 2007b) (Table 6)

Table 6. Preferred Migraine Prophylaxis and Treatment for Pregnant Patients

Sickle Cell Pain Crisis

Pain crises can affect up to 50% of pregnant women with sickle cell disease, with the highest prevalence in the third trimester. These patients often require admission with bed rest, intravenous fluids, and management of hematologic complications. Acetaminophen is the preferred analgesic for mild pain. For moderate to severe pain, cautious use of short acting opioid analgesics (with the exception of meperidine and codeine) is recommended. In order to avoid the aforementioned risks of long-term opioid use in pregnancy. NSAIDs can be used in this population in early pregnancy, but they remain contraindicated in late pregnancy as previously discussed. (Boga 2016)

Lactation Specific Considerations

Drugs are generally transferred into the breast milk via simple diffusion. The amount of drug that diffuses into breast milk is generally less than maternal plasma concentrations and depends on several factors including the molecular weight, lipophilicity, and protein binding of the drug. (Begg 1992) Of commonly used analgesics, acetaminophen and NSAIDs are compatible with lactation. As previously discussed, codeine should be avoided. Ergotamine derivatives are contraindicated during lactation. When prescribing other analgesics to breastfeeding mothers, it is recommended that either the prescribing information or lactation reference be consulted. LactMed is an online reference by the US National Library of Medicine. Infant drug exposure can be minimized by breastfeeding prior to taking medication, when drug levels are the lowest. (Stec 1980)

Summary and Conclusions

Pain is a common complaint during pregnancy and lactation, but data regarding the safety of commonly used medications in this population is limited. Providers should be cognizant of current treatment guidelines as well as fetal risks associated with prescribed medications to ensure safe and efficacious analgesia during pregnancy and lactation. Acetaminophen, local/regional and non-pharmacologic techniques are first line treatments, with NSAIDs appropriate as second line agents except in the third trimester. Opioids carry particular harms in pregnancy and–as in the non-pregnant patient–should be only be used after an explicit consideration of the likelihood of benefit and harm.

The authors report no relevant conflicts of interest. 

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Gillian A. Beauchamp, MD
Emergency Physician, Toxicologist
Lehigh Valley Health Network
Department of Emergency & Hospital Medicine
Assistant Professor, University of South Florida Morsani College of Medicine
beauchamp.gillian@gmail.com
@gillianbchum

Lewis S. Nelson, MD
Professor and Chair
Department of Emergency Medicine
Director, Division of Medical Toxicology
Rutgers New Jersey Medical School
Newark, NJ
@LNelsonMD

An Introduction to the Opioid Epidemic

Drug overdose deaths, primarily due to opioids, are now the leading cause of fatal injury in the United States and have increased steadily for two decades. Appropriately, this has led to a call for revised policies, prevention and treatment programs, changes in prescribing practices, and new directions in medical education to limit iatrogenic addiction and death from overdose. (Okie 2010, Fischer 2013, Perrone 2014, Volkow 2011, Volkow 2014, Beauchamp 2014, Nelson 2015)  The current opioid epidemic has resulted in a doubling of emergency department visits involving non-medical use of opioid medications, an increasing prevalence of substance-use disorders, and increasing numbers of individuals turning to illicit opioids to initiate or support opioid dependence or addiction. (SAMHSA 2011, SAMHSA 2013, Han 2015, Nelson 2015, Perrone 2014, Dowell 2013, Unick 2013, Olsen 2014)  

• In 2014, 47,055 drug overdose deaths occurred in the United States, with 61% (28,647) involving an opioid. (Rudd 2016)  
• The age-adjusted rate of overdose deaths in the United States was 16.3 per 100,000, which was more than 2.5 times the rate in 1999. (Hedegaard 2017)
• Opioid addiction is a clear driver of this epidemic, with 2015 overdose deaths including 20,101 deaths related to prescription opioids, and 12,990 related to heroin – the highest numbers of opioid overdose deaths in over 15 years. (Rudd 2016)
• Drug overdose deaths from synthetic opioids such as fentanyl and tramadol increased from 8% in 2010, to 18% in 2015, while drug overdose deaths involving heroin increased from 8% in 2010 to 25% in 2015. (Hedegaard 2017)

Whether drug poisoning deaths occur due to self-harm, unintentional overdose, medication error, abuse, or non-medical use, medications prescribed for pain have been implicated in this surge in mortality from drug overdose. (Paulozzi 2011) Rising rates of opioid related deaths, increasing rates of emergency department visits related to opioid use, and increasing rates of non-medical use of opioids have accompanied increases in sales and prescribing of these same medications. (Paulozzi 2006, Paulozzi 2015, Dasgupta 2006, Mazer-Amirshahi 2014, Wisniewski 2008) Often prescribed opioids such as oxycodone and hydrocodone continue to be the opioids most commonly involved in drug overdose deaths. (Rudd 2016, Volkow 2011)  

• According to the 2013 and 2014 National Survey on Drug Use and Health, (NSDUH) 50.5% of individuals with non-medical use of opioids obtain the opioids from an acquaintance, and 22.1% obtain the opioids directly from a physician.  
• A 2014 study of adults aged 18-23 years showed that 47.2% of individuals with non-medical use of opioids obtained the opioids through a prescription from a physician. (Daniulaiyte 2014)  

Nearly all individuals using prescription opioids for medical indications or abuse (defined as use for pleasurable psychoactive purposes) develop dependence (defined by the experience of withdrawal symptoms on attempted cessation) and many develop addiction (such as impaired control over drug use and compulsive drug use despite harm). Many of these prescription opioid users switch to use of illicit drugs, such as heroin. (ASAM 2016, Kolodny 2015, Compton 2016)  According to the NSDUH,  4 out of 5 current heroin users state that addiction to opioid analgesics preceded their heroin use. (Muhuri 2013) The reasons for the transition from prescription opioids to heroin vary, and include heroin’s easier availability, lower cost, or greater euphoria. (Cicero 2014, Kolodny 2015, Compton 2016, Siegal 2003, Lankenau 2012, Pollini 2011, Mars 2014)

The public health concern surrounding the opioid epidemic is witnessed by prescribers in the inpatient, outpatient, and acute care settings, who are presented with the task of balancing the management of acute and chronic pain while mitigating risks of opioid misuse. Key issues faced by prescribers include:

• Physicians have an ethical responsibility to identify clinical scenarios where the benefits of pain management with opioids may outweigh the harms, such as cancer-related pain, end-of-life care, and acute painful conditions.  However, opioids should be avoided or used sparingly where the likelihood of harm outweighs benefit, as is the case with most other chronic pain syndromes. (Dowell 2013)
• Given the weak evidence to support the efficacy of opioids for chronic pain, physicians must ensure that approaches being taken to control pain are adequately improving function and quality of life, and should reconsider long-term opioid use if efficacy is not being achieved. (Dowell 2016)
• Prescribers of opioids should be trained in both effective pain management and risk mitigation strategies to prevent iatrogenic addiction and to monitor for opioid abuse. (Keller 2012, Coffin 2014, Sehgal 2012, Baumblatt 2014, Cantrill 2012)  
• The rate of long-term opioid use is greater among patients who are treated by emergency physicians who prescribe opioids more frequently. (Barnett 2017) The ability to predict which patients are at greatest risk for developing long-term opioid use is limited. (Brummett 2017)

A 2009 study analyzing prescribing practices in the Unites States showed that the most frequent prescribers of opioids included primary care physicians, internists, dentists, orthopedic surgeons, and emergency physicians, and that 56% of patients receiving an opioid prescription had recently received another prescription for opioids. (Volkow 2011)  IMS Health’s national prescription audit for the years 2007-2012 revealed that primary care specialties accounted for almost half of the 289 million opioid prescriptions dispensed in America. (Levy 2015)  A subsequent study found that the three most common Medicare prescriber specialties responsible for opioid prescriptions were family medicine, internal medicine, and orthopedic surgery, (Chen 2015) though it should be noted that most patients receiving Medicare are elderly. A retrospective cohort study of patients from one large U.S. health insurer found that 91% of patients with a history of a non-fatal opioid overdose were prescribed additional opioids following their overdose. (Larochelle 2016) This lack of consideration for overdose risk factors places patients at risk of subsequent overdose and death.   

How We Got Here: The Trajectory from Permissive Prescribing to the Opioid Epidemic

The potential for addiction and abuse potential in the use of opioids was described in the 19th and early 20th century. (Courtwright 2001, Berridge 1987) The first opioid epidemic in the United States began in the late 1800s, when the public had access to a variety of readily available opioid medications, including opium and morphine, and opioid use continued to rise with a peak in the mid-1890s. (Kolodny 2015) In response, the 1914 Harrison Narcotics Tax Act was implemented to regulate the production and sale of opioids, and essentially prohibit their use to treat opioid addiction. As a result, by 1920, opioid use had dramatically declined. (Courtwright 2015) Further attempts to reduce rates of opioid addiction resulted in several subsequent Supreme Court rulings that held physicians responsible for prescribing opioids to patients with known addiction. During the 1920s, the nation’s first addiction treatment clinics were opened, which became increasingly available throughout the mid-1900s.  

By 1962, ongoing efforts to control the rate of drug abuse led to the White House Conference on Narcotic and Drug Abuse under Kennedy’s presidency. (Lewis 1964)  In parallel, by the 1980s, several papers written by early pain medicine and palliative care clinicians actually encouraged long-term opioid therapy in patients with painful conditions, and reported a low risk of addiction in such patients. (Minozzi 2013, McAuliffe 2013, Portenoy 1986, Porter 1980)  A retrospective study published in 1986 by Portenoy and Foley noted a very low risk of iatrogenic addiction in 38 patients whose non-malignant chronic pain was managed with opioid analgesics. (Portenoy 1986)  This small study was cited frequently throughout the late 1980s and 1990s in support of aggressive opioid pain management, despite significant limitations to the study including small sample size and low doses of opioids by today’s standards: specifically, 73% of the patients studied were treated with under 21 milligram morphine equivalents (MME) per day.  A five-sentence letter to the editor published in 1980 (Porter 1980) was cited over 400 times as evidence that addiction is rare in patients treated with opioids; most of these citations occurred after the introduction of Oxycontin in 1995. (Leung 2017) The senior author of that letter later reported that he was “mortified” at how this publication was used. (AP 2017)

The mid-1990s saw an increase in aggressive marketing efforts by the pharmaceutical industry that targeted both providers and patients, including the promotion of novel extended-release (ER) formulations. (Van Zee 2009, Dowell 2013, USGAO 2004, Kolodny 2015) These preparations were marketed around the concept that compliance would be improved by requiring only daily or twice daily dosing, rather than the 5 or 6 daily doses required by the immediate release (IR) opioid formulations. Although of still unproven efficacy, ER formulations turned out to be highly profitable, and also highly addictive. (Cicero 2005) Pharmaceutical companies provided financial contributions to regulatory organizations such as Federation of State Medical Boards (FSMB) and the Joint Commission Accreditation of Healthcare Organizations (JCAHO), as well as professional organizations such as the American Pain Society (APS), American Academy of Pain Medicine (AAPM), and the American Academy of Pain Management (now called the Academy of Integrative Pain Management).  These organizations encouraged opioid use as part of aggressive campaigns to reduce pain.

• In 1995, the American Pain Society introduced the “Pain as the 5th Vital Sign” campaign, promoting increased assessment and treatment of pain. (Kolodny 2015, Campbell 1996)
• A 1997 consensus statement from the AAPM and APS reported that evidence was lacking to support the widespread belief that the use of opioids to treat pain could result in opioid dependence or addiction. (Haddox 1997)  
• By 1998, the Veteran’s Health Administration had also declared pain a ‘fifth vital sign’ as part of a national strategy to emphasize the assessment and management of pain. (US Veterans Affairs 1999)
• Quality improvement guidelines released in the late 1990s focused on patient satisfaction, emphasized pain relief, and encouraged opioid-based analgesia without weighing the risks of opioid adverse events and dependency. (American Pain Society 1995, Leddy 2005, Zgierska 2012, Lembke 2012)  Based on such guidelines, physicians were urged to treat pain aggressively in order to remain compliant with JCAHO standards. (Dowell 2013, Pizzo 2012, Lanser 2001)
• In 1998, guidelines released by the FSMB stated that “physicians should not fear disciplinary action” from the FSMB, for “prescribing, dispensing, or administering controlled substances, including opioid analgesics, for a legitimate medical purpose and in the usual course of professional practice,” (Neal 2007) which likely contributed to or even encouraged the permissive prescribing of opioids.

Starting in 2008, advocates of pain management inappropriately cited the results of the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys of patients discharged from hospitals, suggesting that pain management with opioids improved patient scoring despite the lack of evidence to support this assertion. (Adams 2016) While effective pain control is an important quality issue for patients, there is no evidence to suggest that the use of opioids is the optimal approach to improving scores. (Tefera 2016)

Several studies emerged in the 1990’s and early 2000’s that suggested a low risk of iatrogenic addiction with opioid prescribing.  One retrospective study of medically-used opioid analgesic cases published in 2000 reported that the increased medical use of opioid analgesics did not contribute to the rising rate of opioid abuse. (Joranson 2000) As late as 2010, a Cochrane Database review of 26 studies of long-term opioid management of chronic non-cancer pain reported little risk (0.27%) of developing addiction in chronic opioid use – a study that was markedly limited by the fact that addiction rates were not reported in about 70% of studies assessed in this review. (Noble 2010)  Evolving healthcare practices such as increased emphasis on opioid pain management in lieu of comprehensive rehabilitation services and non-pharmacologic approaches to chronic pain management also likely contributed to the over-prescribing of opioid therapies.  This was enabled by a lack of reimbursement by insurance companies for multi-modal or interdisciplinary approaches to pain management including physical therapy, rehabilitative care, complementary and alternative medicine (CAM) and psychosocial support services, which significantly limits effective and comprehensive pain care. (Coffin 2014, Kirschner 2014, Institute of Medicine 2011)  

Rising rates of chronic pain, expansion of the boundaries of treatable pain disorders through pharmaceutical industry efforts (akin to ‘disease mongering’), promotion of aggressive diagnosis and management by pain-related advocacy groups, and passive early approaches by the Food and Drug Administration to develop Risk Evaluation and Mitigation Strategies (REMS), have all likely contributed to rising rates of prescription opioid use and misuse.(Institute of Medicine 2011, Doran 2008, Okie 2010, Moynihan 2002)  A recent example of the normalization of chronic opioid use was a pharmaceutical industry advertisement for opioid-induced constipation therapy, which cost millions of dollars and aired during the 2016 Super Bowl, which was viewed by over 100 million viewers.

The Opioid Epidemic: A Wake up Call for the Medical Community

In 2007, drug overdose deaths surpassed motor vehicle collisions as the leading cause of death by injury in the United States – a startling wake-up call to the rising epidemic of drug deaths. (Paulozzi 2011)  Subsequent reports from the Centers for Disease Control documented the alarming contribution of opioid prescriptions to these increasing opioid deaths. (CDC 2011, CDC 2013) While the United States represents approximately 5% of the world’s population, roughly three quarters of worldwide opioid use is by Americans. (International Narcotics Control Board 2010)  A response at local, state, and federal levels by healthcare professionals, policymakers, legislators, patient advocates, and educators led to increasing prevention, education, and enforcement approaches to reduce morbidity and mortality from this health crisis. (CDC 2011)  Efforts to address the high rates of overdose, addiction, and death in the current opioid epidemic include:

• Monitoring of prescribing practices, including the use of prescription drug monitoring programs, as surveillance for over-prescribing and for the prevention of diversion and ‘doctor-shopping’; and the elimination of paper prescriptions, which are susceptible to tampering and misuse. (Baumblatt 2014, McDonald 2013, FSMB 2013, Paulozzi 2015, Davis 2015, Hahn 2011) [See upcoming chapter on PDMPs] Insurers, pharmacy benefit managers, and other groups have been monitoring prescription opioid use as well.
• The development of tamper-resistant and abuse-deterrent opioid formulations (which hold some, though limited, benefit), the use of black box warnings and explicit indication labeling, and the requirement for appropriately conducted post-market surveillance for both immediate release and extended release opioid formulations. (Havens 2014, Alexander 2014, Nelson 2014)
• Calls for the incorporation of training in appropriate prescribing, multimodal approaches to pain management, as well as risk assessment and mitigation into medical school and graduate medical education curricula. (Beauchamp 2014, Alford 2016, Olsen 2016)  Medical educators have recommended specific approaches such as lecture-style didactics, small group learning sessions, case-based learning, bedside teaching, and asynchronous electronic learning. (Poon 2014, Motov 2011)  In 2016 the four medical schools in Boston, at the urging of the Governor, created a joint standardized pain management curriculum that will be implemented immediately.
• Continuing education programs for prescribers that promote safe prescribing and prevention of adverse outcomes in support of  the Food and Drug Administration REMS program. (Slatko 2015) These programs, which are generally funded by pharmaceutical companies, are required to adhere to a predetermined, though loosely defined, structure.
• Overdose fatality prevention with naloxone distribution and education. (Doe-Simkins 2014, Moore 2014, Zaller 2013, Winstanley 2016) In 2012, the Centers for Disease Control published the results of a survey that documented the impact of opioid overdose prevention programs created in response to the growing opioid death epidemic, including ‘overdose prevention’ training and the public distribution of naloxone as an antidote. (CDC MMWR 2012) It should be noted that naloxone prevents death from overdose, but does not prevent overdose itself.  Thus the CDC’s use of the term ‘overdose prevention’ is a misnomer, and ‘fatality prevention’ is more appropriate.
• Under the Affordable Care Act, access to treatment for addiction and substance use disorders was expanded using medication-assisted treatments such as buprenorphine, naltrexone, and methadone. (Rieckmann 2016)
• Supervised injection sites for intravenous opioid users are becoming more prevalent, and are being established to help stem the tide of opioid overdose deaths. (Kennedy 2017)

The research agenda has also shifted. For example, researchers have begun to evaluate individual physician prescribing strategies including the use of PDMPs, and the role of prescribers in the development of iatrogenic addiction. (Beauchamp 2014, Sehgal 2012, Nelson 2015, Perrone 2014, Butler 2016, Dasgupta 2006, Mazer-Amirshahi 2014, Volkow 2011, Hoppe 2015) Many medical centers have similar internal programs to evaluate the benefit of interventions to reduce prescribing, such as lowering default tablet values and providing audit and feedback data.

Both specialty-specific and general guidelines have been developed at institutional, local, state, and national levels in response to the urgent need for provider guidance regarding appropriate management of pain in the context of the opioid epidemic.  Guideline recommendations for chronic pain management have included single-prescriber management for chronic pain conditions (such as by primary care physicians or pain specialists); patient provider agreements; multi-modal and non-pharmacologic pain management strategies; risk-stratification and mitigation approaches; targeting opioid use to clinically meaningful improvements in pain and function; initiation of therapy with immediate release formulations; use of lowest effective dosing; tapering of opioid therapy over time; monitoring with PDMP and urine drug screening; and initiation of medication-assisted therapy for substance use disorders. (CDC chronic pain guideline 2016, National Pain Strategy 2016)  Recommendations for the acute care setting have included emphasis on the use of oral rather than parenteral opioids; avoidance of refilling lost or stolen prescriptions; avoidance of extended-release and long-acting opioids (ER/LA); limiting prescription opioids in the acute setting to a specific duration, typically 3 days; and screening, bedside education, and brief interventions surrounding opioid use. (Olsen 2014, Juurlink 2013, Ohio 2010, Cantrill 2012, REMS 2012, Nelson 2012, FSMB 2013, Poon 2014) In several states, legislators have enacted laws with specific prescribing limits and other activities, such as patient provider agreements, for the prescribing of opioids.

Balancing Pain Management with Preventing Harm

While management of pain and suffering remains a cornerstone of patient care in medicine, the emerging lessons of the opioid epidemic continue to shape provider practices.  Thoughtful prescribing practices such as screening for addiction risk factors, judicious prescribing accounting for harms as well as benefits, and preventing misuse and diversion through monitoring and education are becoming part of the therapeutic milieu in medicine.  By re-shaping education, research, and clinical practice in order to prevent worsening morbidity and mortality from overdose deaths and addiction, the medical community continues to evolve in the face of this startling public health epidemic.

The authors report no relevant conflicts of interest.

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Christopher Hicks, MD
Emergency Physician, Trauma Team Leader
St. Michael’s Hospital
Education Research Scientist, Li Ka Shing Knowledge Institute
Assistant Professor, Department of Medicine
University of Toronto
hicksc@smh.ca
@HumanFact0rz

Andrew Petrosoniak, MD
Emergency Physician, Trauma Team Leader
St. Michael’s Hospital
Assistant Professor, Department of Medicine
University of Toronto
petrosoniaka@smh.ca
@petrosoniak

Background

Major trauma or polytrauma is defined as multiple or severe life or limb-threatening injuries, or an Injury Severity Score (ISS) greater than 15. (Baker 1974) Pain or severe pain is a near universal feature of major trauma, with greater than 9 in 10 trauma patients reporting pain on initial assessment in the emergency department. (Berben 2008) Despite this, pain in the polytrauma patient is frequently under-recognized and inadequately managed. (Gueant 2011) The reasons for this include failure to adequately assess pain, failure to identify pain management as a treatment priority, and lack of familiarity with analgesic options and dosing in the hemodynamically compromised patient. (Berben 2011) Severe or inadequately treated acute pain is associated with a greater incidence of chronic pain and post-traumatic stress disorder following major trauma, (Woolf 2000) pulmonary complications, (Wu 2006) prolonged hospital and intensive care stays, (Liu 1995) poor functional recovery, (Trevino 2014) and needless suffering.

We present an algorithm for pain management in the polytrauma patient that divides patients into three groups: (Figure 1) profound or refractory shock (Condition RED), moderate or occult shock (Condition YELLOW), and the patient with normal hemodynamics (Condition GREEN), with an approach outlined for each.

General resuscitative measures. As with all critically ill or injured patients, resuscitative measures to preserve life and limb hold primacy over other therapeutic interventions. Early endotracheal intubation, general anesthesia, and mechanical ventilation should be considered in all critically ill patients as an adjunct to resuscitation, in particular if early operative intervention or ongoing hemodynamic instability is anticipated, or egress from the trauma room to a less controlled environment (diagnostic imaging or interventional radiology) is planned. Additionally, injuries causing uncontrollable pain or distress–such as a traumatic limb amputation or multiple severe orthopedic injuries–may indicate endotracheal intubation and the use of a general anesthesia-dose sedation and analgesia in order to facilitate management and limit immediate suffering. Ketamine is an outstanding analgesic as well as an induction agent; a rapid sequence intubation protocol using ketamine and rocuronium has been found to produce favorable intubating conditions in trauma patients, while minimizing the hemodynamic response to laryngoscopy and intubation. (Lyon 2015, Ballow 2012) If an increase in heart rate or blood pressure is not desired, fentanyl may be added to the rapid sequence intubation (RSI) package as a sympatholytic. For patients presenting with severe agitation (due to a painful condition or otherwise), a delayed sequence intubation approach, where the patient is first dissociated with ketamine, adequately preoxygenated by non-invasive means and subsequently paralyzed to facilitate intubation, is an option. (Weingart 2015) Following intubation, care must be taken to provide ongoing adequate analgesia and sedation, especially if rocuronium is used (refer to Box F).

Assessment of pain in the patient with multiple or severely painful injuries. All trauma patients who are alert and responsive with suspected painful injuries should have their pain assessed early in their treatment arc, and reassessed frequently. Critical illness does not mitigate the imperative to identify and treat painful conditions, but may modify the selection, dosing, and timing of analgesia delivery (refer to Boxes B-D).

Non-pharmacological adjuncts to alleviate pain. The practice of routine spinal immobilization using a long spinal board and rigid cervical collar for all trauma patients is a common and often unnecessary source of discomfort and distress without any clear evidence of benefit. (Kwan 2001) In patients with penetrating trauma, cervical spine immobilization is associated with worse outcomes and should be discontinued early in the resuscitation. (Theodore 2013) Long spinal boards are useful in some circumstances as an adjunct to extrication but should be removed as early as possible once the patient arrives in hospital. Assessable patients with blunt injuries who meet validated C-spine clearance criteria should have their collars removed as early as feasible. (Theodore 2013) Rigid immobilization using plaster or mechanical splints should be considered for all painful extremity injuries, including fractures, burns, and significant soft tissue injuries. Although a pelvic binder is typically applied to close the pelvic diameter and limit hemorrhage in patients with hemodynamically unstable pelvic injuries, a well-applied binder can also be used to stabilize and splint pelvic fractures and may limit pain caused by patient movement. In contradiction to ATLS recommendations, logrolling a patient with a known or suspected pelvic fracture can cause clot disruption and unnecessary pain, and should be avoided. (Lee 2007, Scott 2013)

Pain schemas are in part subjective, meaning perception can be modified by providing preparatory information, or encouraging awareness and self-monitoring.  When painful procedures are anticipated, a pre-procedure briefing to explain the nature of the intervention and the expected outcomes can significantly alter a patient’s perception of a painful stimulus. (Dar 1993, Williams 2004)  This should include a short description of the nature and duration of the procedure, an estimate of the degree of discomfort anticipated, and what will be done to minimize pain.  

Profound or refractory shock (Condition RED). Profound shock in trauma may be defined as the loss of central pulses or a systolic blood pressure <70 mmHg despite appropriate resuscitative measures. In the absence of obstructive causes (tension pneumothorax, pericardial tamponade), this clinical syndrome is most likely due to massive and ongoing hemorrhage, and attention should be focused on rapidly restoring circulation by way of massive transfusion and source control (usually in the operating room). All parenteral analgesics have the potential to reduce sympathetic outflow and therefore cardiac output, which may be poorly tolerated in patients with profound shock. (Dutton 2010) Therefore, we recommend that parenteral analgesia be withheld in this subset of patients until perfusion is restored, at which time the patient’s pain should be rapidly reassessed. The majority of patients in profound shock will have a reduced level of consciousness and require early endotracheal intubation, which is safely accomplished with paralytic only or using non-vasodilatory induction agents such as ketamine or etomidate at reduced dosing. Unless there is immediate airway compromise or respiratory failure not overcome by non-invasive means, we advocate for aggressive resuscitation prior to sedation and/or intubation, so as to minimize the hemodynamic effects of both.

If the patient’s hemodynamics stabilize following aggressive resuscitation, pain should be rapidly and systematically managed per Condition Yellow (refer to Box C).

Shock and occult shock states (Condition YELLOW). Shock may be defined as inadequate end-organ tissue perfusion, as evidenced by cool, poorly perfused extremities, loss of peripheral pulses, or altered mental status. Occult shock, defined as elevated serum lactate or abnormal base deficit, may be present in patients who lack overt signs of hypovolemia. (Blow 1999)

For the injured patient in pain, rapid and accurate assessment of shock states and early response to volume resuscitation is relevant to analgesic selection and dosing, as the use of these agents may worsen blood pressure and tissue perfusion. (Dutton 2010) This appears to be true even for agents generally thought to preserve cardiovascular tone, such as ketamine and fentanyl. (Miller 2015)

For the purposes of analgesic dosing we recommend a threshold systolic blood pressure of less than 105 mmHg (transient or otherwise), base deficit (BD) less than or equal to -6 or Shock Index > 0.9 in addition to clinical assessment as a means of identifying shock or occult shock. Serial assessments of BD, lactate or mixed venous oxygen saturation can be used to evaluate the adequacy of resuscitation. (Regnier 2012)

When shock or occult shock is suspected, we recommend intravenous boluses of fentanyl 0.5 mcg/kg or a short infusion of ketamine 0.1-0.3 mg/kg over 10-20 minutes. Our standard approach is to administer up to three boluses of fentanyl, followed by ketamine 0.25 mg/kg over 10 minutes if adequate pain relief is not achieved. There are no controlled, head-to-head comparisons of fentanyl with other longer-acting opioid analgesics such as morphine that address which agent has the least deleterious effect on hemodynamic status. However, a short half-life and low incidence of hypoxemia and hypotension (Krauss 2011) allows for rapid and cautious titration of fentanyl to effect, making it our preferred choice for analgesia in hemodynamically compromised patients. Fentanyl may also be used as a component of sympatholytic resuscitation in trauma anesthesia, whereby improved tissue perfusion is thought to be achieved by way of early and frequent fentanyl boluses to promote vasodilation. (Dutton, 2005) It should be noted that this approach has not yet been systematically tested in human subjects.  

Analgesia titration should proceed in-line with volume resuscitation, and pain needs reassessed frequently. If the hemodynamic response is favorable, maintenance infusions may be indicated to provide consistent pain relief (refer to Box F).

The normotensive trauma patient (Condition GREEN). In a patient in whom shock or major hemorrhage is suspected but not proven, or the extent and severity of injuries is unknown, we recommend analgesic approach and dosing as with Condition Yellow (refer to Box C). For the normotensive patient in pain who lack signs of both shock and occult shock, and whose injuries can be accurately assessed by a combination of clinical and radiographic means, concern regarding the potential cardiovascular effects of parenteral analgesia are lessened. Fentanyl 1 mcg/kg IV, morphine 0.1 mg/kg IV, or ketamine 0.25 mg/kg over 10 minutes are all appropriate choices, titrated to effect. Our standard approach for these patients is up to three boluses of an opioid analgesic, followed by the addition of ketamine in analgesic doses (0.25 mg/kg IV over 10 minutes, then 0.25 mg/kg/hour, titrated to effect). As these patients typically have a less immediate mandate for egress from the trauma room, we suggest thorough and systematic consideration be given to non-pharmacologic adjuncts to alleviate pain, in particular adequate reduction and splinting of all significant pelvic and extremity injuries (refer to Box C).

Maintenance infusions in intubated patients. Recently intubated unstable trauma patients require deep sedation and analgesia during their initial resuscitation. For intubated trauma patients, who have been stabilized, we recommend an “analgesia-first” approach; (Barr 2013) ketamine 1 mg/kg/h, titrated to effect, has the advantage of both dissociative anesthesia and analgesia and is an ideal choice in this circumstance. Fentanyl infusions may be administered alone or in combination with a short-acting benzodiazepine infusion (eg. midazolam 2-10 mg/h), although prolonged fentanyl infusions are associated with significant drug accumulation, (Reardon 2015) hyperalgesia, (Lyons 2015) tolerance, dependence and withdrawal. (Wanzuita 2012) Combining a low-dose ketamine infusion (0.1-0.3 mg/kg/h) with intermittent boluses of morphine or fentanyl may in part mitigate the adverse effects of opioid infusions while leveraging the sedative and analgesic advantages of both agents. (Visser 2006)

Regional analgesia

The options for regional analgesia in trauma are myriad, and this modality is likely underutilized in patients with significant thoracic or extremity trauma. Single shot techniques, continuous peripheral nerve blocks, and epidural infusions may be used alone or in combination with parenteral analgesia as part of an opioid-sparing strategy.  Four of the most common and useful peripheral nerve blocks are fascia iliaca block, hand block, rib block, and posterior tibial nerve block.

Systems-based solutions

Trauma care checklists. Introducing a trauma care checklist may provide a means by which to capture frequently forgotten or poorly performed interventions, including pain management. The inclusion of checklist prompts such as, “Has the patient’s pain been adequately addressed?” and “Have the necessary medications, including analgesia and sedation, been prepared for transport?” can help prevent a task-overloaded team from omitting pain management from ongoing resuscitation. (Nolan 2014, Thomassen 2014)

Order sets and pain protocols. Pain management is significantly improved in institutions with pre-established pain management protocols. (Curtis 2007, Gawthorne 2010, Haley 2016) When applied on a routine and consistent basis, a thoughtful, institutionally-derived pain protocol may improve the assessment of pain and decrease the time to analgesia in severely injured patients.

Multidisciplinary pain service. Access to a multidisciplinary pain service, including physicians, physiotherapy, occupational therapy, and rehabilitation is crucial to ensure that severe pain continues to be effectively managed beyond the initial resuscitative and operative stages of care. Most pertinent to acutely injured patients is early consideration for regional anesthesia following significant thoracic trauma, including epidural and intercostal nerve blocks. (Truitt 2011, Moon 1999) Excessive opioid analgesia in these patients is associated with respiratory depression and adverse outcomes, (Moon 1999) which may in part be mitigated by the provision of timely and effective regional analgesia.

Summary

Pain in the severely injured trauma patient is often poorly assessed and managed. Caring for the polytrauma patient presents multiple priorities and a dynamic clinical scenario that can make effective analgesia a secondary consideration. This pitfall can be avoided by using a systematic approach to pain management for all patients, regardless of injury severity. For the purpose of analgesia decision-making, we propose categorizing trauma patients based on their hemodynamic status: profound or refractory shock, shock or occult shock, or normotensive. This will facilitate an informed choice concerning the timing, dose and analgesic agent. Non-pharmacologic measures, including early discontinuation of spinal immobilization and pre-briefing for painful procedures, should be considered for all patients regardless of hemodynamic status. Finally, given the dynamic nature of trauma resuscitation, frequent re-assessment of hemodynamics and pain is mandatory as part of safe and humane trauma practice.

The authors report no relevant conflicts of interest. 

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Joshua Long, MD
Christina Shenvi, MD, PhD

Managing acute pain in elderly patients presents a unique challenge, especially in a busy Emergency Department (ED). Altered  physiology and pharmacokinetics, as well as polypharmacy, comorbidities, and practitioner experience with older patients all affect the care of this population. According to US Census data from 2012, adults age 65 years and older will total 70 million and make up nearly 20% of the entire US population by 2030,  up from 13% of the population in 2010 (US Census Bureau).  Older adults are projected to make up 25% of ED patients by the year 2030. Some institutions have developed specialized treatment areas or protocols to address the specific needs of the older population (Wilber 2003). However, all emergency providers should be able to safely and effectively manage pain in older adults.

Older adults are less likely to receive opioid analgesia, either oral or parenteral, both in the ED and on discharge, when compared to their younger counterparts (Shah 2015, Platts-Mills 2012, Terrell 2010). Even with improved pain assessment strategies, only a fraction of patients receive opioid pain medication, and those who do receive treatment are often undertreated  (Herr 2009, Terrell 2010). While treating chronic pain with opioid medication has come under recent scrutiny from the Centers for Disease Control (Dowell 2016), and opioid-related deaths are increasing in the general population, there are several appropriate uses for opioids analgesics in elderly patients in the acute setting. In addition, there are concerns in the elderly with some of the alternative medications used for acute pain. However, special caution is needed in older patients because of the risk of introducing a drug-drug or drug-disease interaction or another consequential adverse effect from a pain reliever upon ED discharge (Hastings 2007).

While there are harms associated with the use of pain medications, under-treatment of pain can also be problematic. Untreated, chronic pain can lead to decreased mobility, functional decline, increased dependency on family or care providers, delayed healing, compromised immune response, and has even been shown to increase tumor growth rate and metastasis (Berry 2000, Ferrell 1990, Sasamura 2002). Poorly controlled pain is one of the leading predictors of functional decline in older adults. In addition, older adults with acute pain are more likely to develop chronic pain further complicating their clinical course and emotional health, with greater healthcare costs (Dworkin 1997, Hughes 1997). Acute pain should be aggressively managed with non-opioids and short courses of opioids if needed. Chronic pain should be managed with a multi-modal approach including non-pharmacologic modalities such as physical therapy, and opioids used only after a careful consideration of the likelihood of the patient to benefit and be harmed.

Pharmacology

There are many barriers to appropriate assessment and management of pain in older adults. One area of particular concern is changes in normal physiology as people age and the risk of side effects from medications. Physiologic changes in aging can put older adults at higher risk of side effects from commonly used medications such as NSAIDs and opioids.  Drug absorption, distribution, metabolism, and elimination are all different in older adults. Gastric motility, pH, and blood flow change as people age and alter drug absorption profiles. Older people experience a 20-40% increase in body fat and 10-15% decrease in body water changing drug distribution volumes (Crome 2003). Older adults, in general, have lower concentrations of serum albumin, leading to reduced protein binding and increased free (unbound) concentrations of protein-bound drugs in the serum (Grandison 2000).

Drug clearance rates are affected by the reduced ability of the liver and kidney to metabolize and clear medications. Age, blood flow, genetics, lifestyle, and underlying hepatic disease all contribute to decreased hepatic clearance, which may reach 50% of baseline. (Zeeh J 2002).  Renal clearance is similarly affected, especially by non opioid pain medications. Non-steroidal anti-inflammatory drugs (NSAIDs) as a class tend to inhibit prostaglandin-mediated renal vasodilation thereby reducing renal blood flow, which is directly linked to renal drug clearance (Swedko PJ 2003).  

In addition to these pharmacokinetic changes, older adults are also at much greater risk for experiencing adverse drug events, drug-drug interactions, and drug-disease interactions (Yang 2001). As medication lists grow with age, older patients are at even greater risk of being prescribed a medication that interacts in a dangerous way with an existing medication or disease state. One study looking at older patients treated in a Veterans Administration Emergency Department found that 11.6% of patients were given a “drug to avoid” based on Beers Criteria guidelines. [Hastings 2007] Furthermore, a potential  drug-drug interaction was introduced in 12.6% of patients, and 5.7% introduced a potential drug-disease interaction (Hastings 2007). Although introducing new potential interactions is sometimes unavoidable, in other instances, there are potential alternative medications that may be safer. Providers must be aware of this altered pharmacology whenever considering medication administration, dosing, and appropriate monitoring.

Acetaminophen

Acetaminophen is considered first-line therapy in older adults for both acute and chronic pain. It has a better safety profile than other analgesics and is widely available. Cardiovascular, gastrointestinal, and renal side effects are minimal when compared to NSAIDs. Despite the marked hepatotoxicity when taken in excessive doses,  there is no evidence that long-term therapeutic acetaminophen use leads to liver damage (Watkins 2006). The total daily dose is 3-4g per day unless the patient has an underlying liver disease or is a heavy user of alcohol. Acetaminophen is available in oral and rectal forms, and an intravenous formulation is available in many hospitals. The provider must use caution and specifically warn patients to avoid excessive doses of acetaminophen, particularly because it is included in many other analgesics and cough/cold formulations. For example, to better calculate the dose of acetaminophen, it is preferable to prescribe acetaminophen and an opioid separately if needed than to prescribe a combination medications such as oxycodone/acetaminophen (Percocet) or hydrocodone/acetaminophen (Vicodin, Norco, Lortab), because patients who take a combination analgesic must increase their acetaminophen intake if an increase in opioid dose is required. Patients on coumadin who are started on regular acetaminophen therapy should have their INR checked 3-5 days later. (Lopes 2011)

NSAIDs

Non-steroidal medications are routinely listed as a medication to avoid by the AGS due to the risk of gastrointestinal bleeding, renal failure, and acute coronary syndrome with chronic use. Special caution should be taken in prolonged use in individuals over the age of 75, those on corticosteroids, anticoagulants, or anti-platelets (American Geriatrics Society 2015). Renal impairment and resulting hyperkalemia may also occur, even with brief courses of treatment. (Platts-Mills 2013, Bowling CB 2012). Indomethacin can cause drowsiness and impaired motor coordination and is specifically cited in the 2015 Beers Criteria update as a drug to avoid. Ketorolac is associated with increased risk of cardiovascular events (Kim 2015). If an NSAID is thought to be indicated in an elderly patient despite these risks, the AGS recommends that a proton pump inhibitor be prescribed concurrently. However, use of PPIs for more than 8 weeks is not recommended because of the increased risk of C. difficile, bone loss, and fractures (Ro Y 2016). As physicians move away from chronic NSAID use for osteoarthritis pain they are increasingly prescribing opioid medications, which have been linked to an increased risk of falls and fractures in elderly adults (Rolita L 2013) as well as constipation, confusion, and depression. As with all analgesics, providing the lowest dose for the shortest duration to achieve adequate pain relief is the overall goal.

Opioids

Opioid analgesics are effective for some elderly patients with acute pain, but are associated with significant morbidity and mortality. The 2016 CDC guideline for prescribing opioids for chronic pain strongly discouraged their routine use. (Dowell 2016)  

The 2015 Beers list recommends avoiding ≥ 3 CNS-active drugs (antipsychotics, benzodiazepines, tricyclic antidepressants, selective serotonin reuptake inhibitors, and other opioids) if opioids are to be used,  citing an increased fall risk with multiple centrally acting medications. (American Geriatric Society 2015) Treatment with opioids in the monitored ED setting or at home may be appropriate in certain situations and providers should consider the patient’s existing medication list, living situation, baseline mental and ambulation status, and nature of the underlying painful condition prior to prescribing these medications.

An additional concern when prescribing opioids is the resulting constipation, which can lead to significant morbidity in the elderly population. This alone can precipitate delirium, poor feeding, and physician visits. All patients treated with opioids should receive additional medication to stimulate gastrointestinal tract  motility in addition to a stool softener. Senna is a common stimulant laxative and can be prescribed in combination with docusate, a stool softener. Prescribing both a stimulant laxative along with a stool softener is recommended for older patients prescribed even a brief course of opioids. (Serrano 2016)

Topical Pain Medications

For patients with musculoskeletal pain, there are several additional options for pain control. Topical NSAIDs, such as diclofenac gel, can be used, specifically to decrease the pain associated with knee osteoarthritis. Back pain or post-herpetic neuralgia can be treated topically with a lidocaine patch. These topical medications can be highly effective, and have fewer side effects than systemically administered medications.

Regional Anesthesia

Another alternative to pain medication while in hospital is nerve or compartment blocks.  The femoral nerve block or fascia iliaca block is effective and recommended as routine care following hip and proximal femur fractures (Lees 2014, Mouzopulos 2009, Hogh 2008, Monzon 2007, Morrison 2016). Hematoma blocks may provide effective analgesia, replacing or reducing the need for oral/parental agents, following wrist and ankle fractures. (Ross 2011, Funk 1997)

Procedural Sedation

Older adults are more likely to suffer dangerous complications during procedural sedation; performing PSA in this group is therefore a challenge for even the experienced provider. In this section we will provide a literature-based review of the common procedural sedation drugs as they pertain to the elderly population.

Propofol

Propofol’s rapid onset and brief duration of action make it an attractive procedural sedation agent, although its dosing and safety profile are different in the elderly. One ED study comparing midazolam with propofol for procedural sedation in elderly patients found no significant difference in complication rates between younger age groups and those over age 65. They did find, however, that lower doses were sufficient in the ≥ 65 age group (Weaver 2011). Another ED study found that, on average, patients ≥ 65 years of age required a lower induction dose (0.9 mg/kg) compared to  younger adults (1.4 mg/kg). The total dose given was also lower in the older group (1.2 mg/kg compared to 2 mg/kg). (Patanwala 2013)

Respiratory depression and loss of airway reflexes are important dangerous effects of propofol administration. Though one review of multiple RCTs found that propofol administered alone had no statistically significant increase of respiratory depression when compared to other agents combining propofol with opioids led to more hypotension and respiratory adverse events. (Black 2013) Given the lower doses needed for effective sedation in older adults it is prudent to reduce the induction dose and prepare for airway and respiratory support.

Ketamine

Ketamine is a dissociative sedative popular among emergency physicians for procedural sedation, especially in pediatrics. It uniquely provides amnesia, analgesia, and sedation while preserving airway reflexes, increasing blood pressure, and raising heart rate. The standard adult induction dosing is 1-2 mg/kg IV followed by 0.25-0.5 mg/kg as needed for continued sedation.

Literature evaluating the safety and efficacy of ketamine for procedural sedation in the older adult population is sparse. There are several small, older studies in the anesthesiology literature evaluating this issue. One study examined the hemodynamic effects in elderly patients, mean age of 83 years, undergoing procedural sedation in the operating room for reduction of hip fractures. Patients were noted to have elevated blood pressure and cardiac index with no serious adverse events (Stefánsson 1982, Wickström 1982).  Additional small studies have found that ketamine increases myocardial oxygen demand, although this was not associated with any hemodynamic instability (Maneglia 1988).

The combination of ketamine and propofol as “ketofol” has been adopted by many providers as an alternative approach to procedural sedation. Some studies suggest that using this combination is safe and that the catecholamine release caused by ketamine may counter the hypotension associated with propofol. Smaller doses of each medication are required to achieve appropriate sedation when using this combination (Andolfatto 2012, Willman 2007). While promising, few older adults were enrolled in these studies making generalization difficult.

Benzodiazepines +/- an Opioid

Benzodiazepines, as a class, are generally regarded as drugs to avoid for outpatient use in the older adult population . However, they are effective and have been used for decades for procedural sedation.  Several studies have examined procedural sedation in older adults with either diazepam or midazolam plus fentanyl. One common theme in the literature is that lower doses of drug are necessary in older patients. In one study from the dentistry literature, to achieve the same level of sedation, patients > 80 years old required 0.1 mg/kg of midazolam while those 30-39 years of age required 0.25 mg/kg. Desaturation events, however, we also more common in the older age group although no one required intubation or experienced a serious adverse event as a result (Kitagawa 1992). A similar study evaluated 200 adults ≥ 65 years of age and found no serious complications when using intravenous diazepam or midazolam along with 100 mcg of fentanyl. These patients remained NPO prior to sedation and received an intravenous fluid bolus prior to medication administration (Campbell 1997). Recognizing the need for lower dosing in older adults, Yano et al looked at adults under 60 and those over 60 years old undergoing sedation for colonoscopy. The younger age group received midazolam 0.05 mg/kg while those > 60 years received 0.025 mg/kg. Even with the decreased dosing, more desaturation events occurred in the older patients. (Yano 1998) The provider must recognize the need to use a lower initial dose in older adults, pretreat with intravenous fluids, and anticipate respiratory complications. Midazolam has a shorter duration of action than diazepam and is generally preferred for procedural sedation, as benzodiazepines can have prolonged effects in older adults and can contribute to delirium. Flumazenil is available as a possible benzodiazepine reversal agent but must be used cautiously in patients using benzodiazepines chronically, because flumazenil may precipitate benzodiazepine withdrawal including refractory seizures in this group.

Summary

The management of acute pain and procedural sedation in older adults can be challenging. Several guiding principles can help physicians provide safe, adequate pain control.

In the ED for pain control:

• Be aware of the tendency to under-treat pain in older adults, and the importance of assessing pain in patients who are cognitively intact as well as those with cognitive impairment, in whom you may have to rely on non-verbal clues as to their pain, such as facial expression, vocalizations, posture, and vital signs.
• Start with lower doses of medication but reassess frequently and re-dose as needed in order to provide adequate analgesia with the lowest dose possible.
• Consider using nerve blocks or topical medications when appropriate to reduce the risk of side effects from systemic administration.
• When giving IV opioids, place the patient on a monitor in case of respiratory suppression or hypotension.

In the ED for procedural sedation:

• Most medications are reasonably safe and tolerated well in older adults, though evidence is sparse for ketamine.
• Older adults usually need a lower dose for procedural sedation and medication effect may be longer-acting, so patients should be monitored closely until their mental status returns to baseline.

At discharge:

• When prescribing a medication at discharge, review a patient’s home medications and past medical history to assess for potential drug-drug interactions or complications such as acute renal failure with NSAIDs.
• When prescribing opioids, prescribe scheduled acetaminophen, possibly with a PRN opioid that does not contain acetaminophen, at a low dose. Warn patients about the risk of sedation and falls.
• When prescribing opioids, also prescribe a short course of a stimulant laxative such as Senna and stool softener, such as Colace.
• Try to help ensure early follow up for older adults with their primary care physician both to reassess the condition causing their pain, the adequacy of their pain control, as well as for any side effects from the newly prescribed medications.

The authors report no relevant conflicts of interest.

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Reuben J. Strayer, MD
Maimonides Medical Center
Brooklyn, New York

Introduction

Procedural sedation and analgesia (PSA) is the use of anesthetic drugs to facilitate procedures that are painful or otherwise intolerable to the patient. Painful procedures performed by emergency providers typically requiring PSA include joint reduction, fracture management, cardioversion, and tube thoracostomy. The provision of procedural sedation has conventionally been guided by the sedation continuum, (Table 1) and in many settings non-anesthesiologists were credentialed to provide only minimal sedation (where the patient responds normally to verbal commands) and moderate sedation (where the patients responds purposefully to verbal commands or light tactile stimulation). However, humanely performing many painful procedures requires deep planes of sedation, and in 2011 the Center for Medicare & Medicaid Services stipulated that

“The ED is a unique environment where patients present on an unscheduled basis with often very complex problems that may require several emergent or urgent interventions to proceed simultaneously to prevent further morbidity or mortality. In addition, emergency medicine-trained physicians have very specific skill sets to manage airways and ventilation that is necessary to provide patient rescue. Therefore, these practitioners are uniquely qualified to provide all levels of analgesia/sedation and anesthesia (moderate to deep to general).” (CMS 2011)

The term conscious sedation is synonymous with moderate sedation; since contemporary best practice in emergency medicine includes deep sedation, dissociative sedation, and general anesthesia–where patients are unconscious–conscious sedation is no longer an appropriate term to describe this technique and should not be used.

The use of modern anesthetic agents to effect deep sedation in emergency departments has reduced patient suffering and improved procedural success; this represents an elevation in the quality of emergency care, but entails airway, breathing, and circulatory risk. Emergency clinicians–who provide PSA across the entire sedation continuum–must therefore be expert in recognizing and managing the potentially dangerous effects of drug-induced unconsciousness so that painful procedures can be performed both humanely and safely.

Preparation

Providers often focus on selecting the right drug and dose, but cognitive and material preparation are more important; when PSA adverse effects are anticipated and optimally addressed, nearly any anesthetic agent can be used safely and effectively. We recommend the use of a PSA checklist which, by prompting the clinician along the many steps and details in preparing for and executing PSA, allows cognitive energies to be conserved for more complex tasks.

The most important question for the emergency provider to consider prior to initiating procedural sedation is whether the patient is a good candidate for emergency department-based procedural sedation. Unlike endotracheal intubation, PSA is rarely an emergent procedure; It is therefore even more crucial that emergency providers assess anesthetic risk prior to PSA by estimating cardiorespiratory reserve and difficult airway features (including obstructive sleep apnea), weigh this risk against procedural urgency, and consider alternatives to ED-based PSA when appropriate.

The need for fasting prior to procedural sedation is controversial. In 2014, the American College of Emergency Physicians published a clinical policy stating, as a level B recommendation, “Do not delay procedural sedation in adults or pediatrics in the ED based on fasting time.” Preprocedural fasting for any duration has not demonstrated a reduction in the risk of emesis or aspiration when administering procedural sedation and analgesia.” (Godwin 2014) Whereas the benefits of preprocedural fasting are theoretical and undemonstrated, whenever PSA is delayed for fasting, there is harm: The patient may be in pain longer as well as hungry/thirsty, the procedure may become more difficult by the delay, and ED resources are stretched as length of stay is extended.

Personnel will vary by environment, but a medical professional not performing the procedure should be present to monitor the patient. If the procedure is predicted to be long or if the patient has a higher anesthetic risk, a resuscitation and airway-skilled clinician dedicated to monitoring is advised. Compromise of airway and breathing are by far the most important complications during PSA; since these events are definitively managed by endotracheal intubation, preparation for PSA therefore always includes being fully prepared for endotracheal intubation–all relevant airway equipment should be brought to bedside, and appropriate RSI medications readily available.

If the patient is in pain (e.g. from an orthopedic injury), aggressive preprocedural analgesia allows for lower sedative doses during PSA, in addition to being proper care for patients in pain. Titrated parenteral opioids are often appropriate in this context, but opioid alternatives (including analgesic-dose ketamine),  may also be used.

The use of supplemental oxygen during procedural sedation is also the subject of some debate. Hypoxia is the most important dangerous complication of PSA; providing supplemental oxygen prolongs the time to desaturation during hypoventilation, affording a theoretically important margin of procedural safety. However, providing supplemental oxygen diminishes the ability of pulse oximetry to detect hypoventilation (Witting 2005), which is the most important monitoring parameter during PSA (see below). If end-tidal capnography (ETCO2) is used, the capnograph measures ventilation independent of oxygen delivery, and providing supplemental oxygen is unequivocally advantageous. If ETCO2 is not used, the benefit of providing an oxygen reservoir with supplemental oxygen is weighed against the benefit of using the pulse oximeter to detect hypoventilation. We feel that patient safety is best maintained by providing supplemental oxygen whether or not ETCO2  is used; however clinicians should be mindful that the pulse oximeter poorly reflects hypoventilation when supplemental oxygen is provided and ventilation must therefore be monitored by alternative means. Routine oxygenation during PSA includes a nasal cannula underneath high-flow face mask oxygen. For patients at particular risk of hypoxia nonetheless thought to be appropriate candidates for ED-based PSA, higher oxygenation can be achieved with humidified, high-flow nasal cannula. (Porhomayon 2016) Limited evidence suggests the safety of using nasal noninvasive ventilation, which augments both oxygenation and ventilation, in high-risk patients. (Strayer 2015, Remick 2010)

Monitoring the patient with capnography during procedural sedation is still another area of controversy. (Mohr 2013, Terp 2013) Capnography detects hypoventilation with high sensitivity and evidence demonstrates that providers recognize hypoventilation earlier when capnography  is used. (Waugh 2011) However, use of capnography has not been demonstrated to reduce the incidence of patient-oriented serious adverse events during ED-based PSA; perhaps because these events are rare. Expired CO2 monitoring may alarm or show a deviated tracing either falsely or in reflection of a change in patient status that, undetected, would have had no consequence. In addition to the cognitive harms of distraction, providers may take actions in response to these capnography “false positives” that may be harmful–most importantly, bag mask ventilation. The ACEP clinical policy makes the following Level B recommendation: “Capnography may be used as an adjunct to pulse oximetry and clinical assessment to detect hypoventilation and apnea earlier than pulse oximetry and/or clinical assessment alone in patients undergoing procedural sedation and analgesia in the ED.” (Godwin 2014) Because capnography allows hypoventilation to be easily detected while supplemental oxygen is provided, we recommend capnography monitoring, combined with a stepwise approach to hypoventilation that minimizes the chance that over-detection of hypoventilation will cause harm.

PSA Adverse Events

The safe performance of procedural sedation rests on anticipating its dangerous complications and intervening skillfully when they are detected. The two most important adverse events during PSA are compromise of airway and compromise of breathing. (Figure – Airway and Breathing Adverse Events During PSA)

The airway may be compromised during procedural sedation by two related but distinct mechanisms. Airway obstruction occurs when the flow of air is blocked; compromise of airway patency may arise from malpositioning of the head or neck, collapse of the oropharyngeal soft tissues, pooling of secretions (or a foreign body, such as dentures), or laryngospasm. Failure to protect the airway occurs when the gag, cough, ahem (throat clearing) and swallowing airway reflexes are diminished or abolished (during PSA, by chemically depressing level of consciousness). Loss of airway reflexes is not dangerous in and of itself but may result in the immediately dangerous complications of airway obstruction or aspiration.

Breathing is compromised in PSA by hypoventilation. Oxygenation should not be impaired during PSA–if oxygenation is a problem, i.e. the patient has significant lung disease–that patient is likely not a good candidate for ED-based PSA. Hypoventilation occurs during PSA either from airway obstruction, or centrally, from chemical sedation. Carefully monitoring ventilation and correctly intervening on hypoventilation is the most important aspect of safe procedural sedation, as discussed below.

Circulatory adverse events that require intervention during PSA are uncommon. Many patients who receive ketamine will develop hypertension and tachycardia, patients who receive propofol or a conventional sedative may become hypotensive or bradycardic. These vital sign abnormalities rarely cause patient-oriented sequelae and generally self-resolve.

Emesis is uncommon during dissociative or deep sedation but is an important adverse event because vomiting that occurs while airway reflexes are compromised may result in pulmonary  aspiration. Nausea and vomiting when airway reflexes are intact, such as during or after the patient emerges from procedural sedation, is very common and may be treated with usual antiemetics.

Anaphylaxis to procedural sedation agents is very uncommon but if a PSA patient develops rash, wheezing, angioedema or hypotension, a drug reaction must be considered and if suspected, treated in the usual fashion. Much more common is an idiosyncratic reaction to ketamine; this truncal confluent or patchy erythematous rash is non-allergic and requires no treatment.

A variety of less important adverse events may occur during PSA, depending on the agents used. Hypertonicity or myoclonus are seen frequently with ketamine or etomidate; ketamine is also associated with hypersalivation. Psychiatric adverse events, seen especially on emergence from ketamine dissociation, is discussed separately.

Monitoring Ventilation

The mechanisms that support airway and breathing during PSA are three: airway patency, airway reflexes, and ventilation. Because  ED-based PSA should be performed on patients with good lung function, oxygenation should not be a concern if ventilation is adequate. Hypoxia is the most dangerous common consequence of PSA, so providers performing PSA are rightly attuned to oxygenation, as measured by the pulse oximeter; however, if the patient is receiving supplemental oxygen, using oxygen saturation as the principle marker of safety during PSA is an error. The margin of safety during PSA is reflected not by oxygenation but ventilation, which demonstrates airway patency and demonstrates adequate respiratory effort. Ventilation, not oxygenation, should therefore be the focus of attention during PSA.

Monitoring ventilation is thus a high priority for PSA providers, for which there are a variety of techniques. The most basic is observing chest rise. Though assessing chest rise can be misleading, (Poulton 2011, Soto 2004) it is a fundamental aspect of sedation practice. The patient’s anterior thorax should therefore either be exposed or covered by clothing that is sufficiently form-fitted  that chest and abdominal excursion is easily appreciated. Continuous auscultation of the lungs with a conventional stethoscope is impractical, but breath sounds (and heart sounds) can be effectively monitored during PSA using a precordial stethoscope, which attaches to the patient’s chest and transmits sound to an earpiece worn by the clinician.

Pulse oximetry easily, cheaply, non-invasively and accurately measures blood oxygenation, a crucial endpoint during procedural sedation; the pulse oximeter is therefore a crucial monitoring device. When a well-perfused patient is breathing room air, saturation corresponds well with ventilation. However, as discussed above, providing supplemental oxygen to a patient with normal lungs weakens the relationship between saturation and ventilation. It is therefore a mistake to assume that a well-saturated patient receiving supplemental oxygen during PSA is doing well; such a patient may be profoundly hypoventilating or even apneic, dangerously acidemic, and may have completely abolished airway reflexes. The well-saturated PSA patient may therefore have precarious physiology–physiologic reserve during PSA arises from ventilation.

The most accurate method for monitoring ventilation is capnography. Waveform capnography is the plot of exhaled carbon dioxide over time, an accurate reflection of ventilation. In addition to the waveform, capnographs display the partial pressure of carbon dioxide at the last moment of exhalation (ETCO2), as well as an accurate respiratory rate. The accuracy of capnography can be diminished if the sampling port samples only the mouth or nose and the patient is breathing through the other orifice; better devices sample both. If a source of supplemental oxygen is close to the ETCO2 sampling port, the ETCO2 value may be washed out and therefore falsely low, though the waveform shape is otherwise preserved.

PSA patients develop hypoventilation either by breathing with preserved tidal volumes and a lower respiratory rate (bradypneic hypoventilation), which results in higher expired CO2 values (and therefore a taller waveform), or with reduced tidal volumes and a normal or reduced respiratory rate (hypopneic hypoventilation), which results in lower CO2 values as a larger fraction of expired air never participated in gas exchange (i.e. increased dead space). The tracing and ETCO2 value must therefore be interpreted over time and in the context of other parameters and exam findings. (Krauss 2007) Significant changes in the waveform or increases/decreases in the ETCO2 value ≥20 mmHg during PSA usually represent hypoventilation. The absence of an end tidal tracing less ambiguously demonstrates the cessation of airflow, either from obstruction or central hypoventilation.

The PSA Intervention Sequence

Emergency providers are trained to respond to hypoventilation with bag mask ventilation. While oxygenating the hypoxic patient is essential, performing bag-mask ventilation may insufflate the stomach, predisposing the patient to regurgitation and aspiration. Unlike ill patients being emergently intubated, PSA patients generally do not have active airway or oxygenation problems, PSA patients are not paralyzed and can therefore vomit, and the hypoventilating PSA patient is likely to improve with time. Ill patients being intubated should therefore receive assisted ventilation early, as soon as an intubation attempt is unsuccessful; conversely, PSA patients should receive assisted ventilation more cautiously, as part of a stepwise approach to the management of hypoventilation. (Figure – PSA intervention sequence)

The first step is to detect hypoventilation early, using the monitoring techniques described above. Early detection is the primary task of the PSA provider, as late recognition of hypoventilation–e.g. once the saturation falls–necessitates hurried, aggressive interventions that are more likely to cause harm. When hypoventilation is identified at its outset, the provider can proceed down the PSA intervention sequence slowly, calmly, safely.

The first response to hypoventilation is to stop or slow the drugs. Often the hypoventilating PSA patient is simply poorly positioned. Reposition the patient to maximize ventilation by bringing the head and neck into proper alignment, performing a chin lift, and raising the head of the bed, which both improves respiratory mechanics and reduces aspiration risk.

If ventilation is still inadequate, the next step is to perform a jaw thrust. (Figure – Jaw Thrust) A jaw thrust is correctly performed by displacing the mandible anteriorly, so that the lower incisors are pushed in front of the upper incisors. This is best accomplished by stabilizing the thumbs on the maxilla and placing four fingers posterior to the ramus of the mandible; this allows the strong hand and forearm muscles to be mobilized to overcome the masseters, which may offer considerable resistance in a non-paralyzed patient.

These basic maneuvers will restore ventilation in many patients. If hypoventilation persists, suction of the oropharynx–mindful of a potentially active gag reflex– is indicated if there are significant secretions, and apply pressure at the laryngospasm notch. This pressure point is located behind the earlobe, between the mastoid and mandibular condyle. Bilateral firm pressure applied medially and cephalad with a single finger, while maintaining a jaw thrust, is touted to trigger the superior cervical sympathetic ganglion (Larson 1998) and also provides a very painful stimulus.  

If none of these maneuvers have restored ventilation, prepare for assisted ventilation by inserting two lubricated nasal airways (slowly and gently, to avoid epistaxis), which will make bag mask ventilation more effective and provide another irritating stimulus. Consider administering a reversal agent (flumazenil or naloxone) if the patient has been treated with a benzodiazepine or opioid.

The next step is bag mask ventilation. This should be done only when ventilation is inadequate to support oxygen saturation and with deliberate attention to excellent technique with two hands on the mask, both thumbs down, the other four fingers of each hand gathering the jaw into a jaw thrust. An assistant bags slowly and gently–a patient with normal lungs will reoxygenate with just a few assisted breaths.  Properly performed bag mask ventilation will be effective in almost every case; if bagging is unsuccessful, an oral airway may be inserted, prior to a repeat BVM attempt, with attention paid to the potential for this device to stimulate gagging and possibly emesis. Rarely, a hypoventilating, hypoxic PSA patient cannot be successfully bag mask ventilated, which is an indication for the last step in the PSA intervention sequence, endotracheal intubation.

As an alternative to the bag mask device, assisted ventilation can be performed with a supraglottic device, such as a laryngeal mask airway. Supraglottic device ventilation is more effective than bag mask ventilation, easier to perform, and less likely to insufflate the stomach. These notable advantages must be weighed against the potential for a supraglottic device to cause gagging or, dangerously, vomiting. However, once the obstructive causes of hypoventilation have been addressed by performing the maneuvers at the top of the PSA intervention sequence, hypoventilation is very likely to be central hypoventilation from brainstem sedation; a supraglottic device is therefore likely to be well tolerated. However, if a supraglottic device is used in a non-paralyzed patient, close attention must be paid to signs of discomfort, which suggest that sedation is lightening and the device should be removed.

PSA Pharmacology

Ketamine has emerged as the procedural sedation agent of choice in both adults and children in many centers. Ketamine is not a conventional sedative, it is a dissociative anesthetic that, when used in sufficient doses, produces complete analgesia, amnesia, and unconsciousness by isolating the patient from external stimuli. Ketamine distinguishes itself from alternatives by rendering the patient still and impervious to any painful stimulus at the same time that airway reflexes are preserved and breathing and circulatory tone are augmented. Ketamine has rapid onset and dose-dependent duration of action; at standard dissociative doses (1-2 mg/kg IV), duration of action is 15-30 minutes. Unlike most other PSA agents, ketamine has excellent pharmacokinetics by the intramuscular route, an important advantage when starting an IV is difficult or undesirable, as in children or cognitively disabled adults. Ketamine is less potent when given IM; the dose is 4-6 mg/kg IM.

Though airway reflexes and respiratory drive are maintained, a rapid bolus of dissociative-dose ketamine may cause a brief period of apnea; this is self-resolving and can be avoided by infusing ketamine over 30-60 seconds, which will generally require dilution. Hypoventilation and apnea can occur during ketamine PSA from a variety of mechanisms (head/neck malpositioning, laryngospasm, secretions); monitoring for hypoventilation is therefore no less important with ketamine than with alternatives. Laryngospasm is more common in children and presents across a spectrum from noisy breathing to complete obstruction– chest movement without air movement.

Ketamine causes release of endogenous catecholamines, hypertension and tachycardia are common when dissociative-dose ketamine is used. Hyperdynamic vitals rarely require intervention during ED-based PSA. However, if the patient has significant cardiac disease, an abrupt increase in myocardial oxygen demand may be deleterious. Dissociated patients may have increased muscle tone or even rigidity, which can interfere with with joint and fracture reduction. Hypersalivation occurs more commonly in children, and generally requires no intervention or a brief period of suctioning. Atropine or glycopyrrolate are sometimes used to reduce secretions. Nausea and vomiting are common post-procedure and are effectively treated or prevented with ondansetron.

The adverse effect of greatest interest when ketamine is used for PSA on adults is psychiatric distress on emergence. The fully dissociated patient is unconscious and unaware; however, as ketamine is metabolized the patient will pass through partial dissociation and may feel disconnected from their body and reality as sensory stimuli are reintegrated into perception. Most will pass smoothly through partial dissociation to lucidity, however some will find these psychoperceptual disturbances terrifying and may demonstrate severe emotional distress, often screaming or crying. Although upsetting to all involved, the possibility of psychiatric emergence phenomena should not preclude the use of ketamine, when ketamine would otherwise be the best PSA agent; ketamine-related psychiatric distress can be effectively prevented, anticipated and treated.

How a patient feels during and emerging from ketamine dissociation depends on their expectations of dissociation and how they feel as they enter into dissociation. Pre-induction analgesia is valuable in this regard and is also good patient care, as described above. Use of a benzodiazepine or neuroleptic prior to ketamine dissociation may reduce the incidence of emergency phenomena but may make respiratory complications more likely. (Chudnofsky 2000, Sener 2010). Prophylactic anxiolysis is generally unnecessary unless the patient is particularly anxious or agitated. Pre-induction coaching may reduce the likelihood of emergency distress: (Cheong 2011) explain to the patient that they are going to receive a drug that will cause very vivid dreams, but that they can control their dreaming, so imagine a desirable scenario, like a beautiful beach or mountaintop. Signs of psychiatric distress should be anticipated, and if psychiatric distress develops, it is effectively treated with a conventional sedative such as a small bolus of propofol or a sedating dose of midazolam or droperidol. Propofol in particular also effectively attenuates ketamine-related hypertension, when hypertension is thought to require treatment, as well as hypertonic muscle tone.

Propofol is the other leading procedural sedation agent in contemporary emergency medicine practice. Propofol is a phenol-derived conventional sedative with its primary action as a GABA agonist that features a rapid onset of action and a remarkably brief duration of action. Unlike ketamine, propofol lacks analgesic activity; however, propofol very rapidly and effectively brings patients to a deep plane of sedation, where patients feel neither  pain nor other external stimuli. Ideally, patients in pain will be provided with adequate analgesia prior to PSA, but opioids should not generally be administered concurrently with propofol, as they increase adverse events without decreasing patient perception of pain. (Miner 2013, Miner 2009)

Propofol is a potent sedative and at standard PSA doses can cause hypotension, respiratory depression, and impairment of airway reflexes. Emergency providers can mitigate the likelihood that these dangerous effects will cause harm by taking advantage of propofol’s uniquely brief duration of action. Although propofol can be used effectively in small aliquots or as a continuous infusion, we recommend dosing propofol as a single induction bolus predicted to cause sufficient sedation to perform the procedure. In healthy adults under age 50, a quick bolus of 1 mg/kg usually effects unconsciousness (and often a brief period of hypoventilation). If the first dose is inadequate within 90 seconds, a second dose, generally half the initial dose, should be given promptly so as not to allow the initial dose to dissipate. Further doses should be given cautiously, at one-quarter to one-half the initial dose, as needed.

Older adults can be remarkably sensitive to propofol and may experience prolonged periods of apnea and hypotension with conventional dosing; the induction dose of propofol should therefore be reduced in an age-dependent fashion after age 50. (Patanwalla 2013) An appropriate bolus dose in a normal-sized frail, elderly patient is 20-30 mg. The pain often associated with infusing propofol into a smaller vein can be reduced by adding 1 mL of 1% or 2% lidocaine to every 10 mL propofol in the syringe. (Euasobhon 2016)

Ketofol is the combination of ketamine and propofol in the same syringe for dosing simultaneously as a procedural sedation cocktail. The mixture is designed to augment safety by reducing the dose needed for each individual agent. Furthermore, ketamine’s cardiorespiratory stimulating properties can be used to offset the propensity for propofol to cause hypotension and respiratory depression while propofol may counteract muscle rigidity, psychiatric adverse events, and nausea often seen with ketamine. There are many dosing strategies; the two agents are generally combined in a 1:1 ratio and dosed in boluses of 0.25 mg/kg to 0.75 mg/kg of each agent, repeated every 1-3 minutes until sedation is adequate. (Andolfatto 2012, Ferguson 2016, Miner 2015) Using ketofol in the ED for PSA has been repeatedly demonstrated to be safe and effective, (Godwin 2014) however it has not demonstrated superiority to either propofol or ketamine alone. (Green 2014)

Etomidate is an imidazole non-benzodiazepine, non-barbiturate GABA modulator very widely used as an induction agent for rapid sequence intubation in the US. Etomidate benefits from rapid onset and is the most hemodynamically neutral of all PSA agents. The usual dose for procedural sedation is 0.1-0.2 mg/kg and in that range produces deep sedation of duration between propofol and ketamine; 5-15 minutes. Etomidate is safe and effective in ED-based PSA, (Vinson 2002) though apnea occurs in 5-10% of patients. Nausea and vomiting occur often post-procedure, but the most prevalent concern when using etomidate for PSA is muscle rigidity and myoclonus, which is common and can be severe enough to interfere with the procedure. (Falk 2004) Etomidate is epileptogenic and should be avoided in patients with a seizure disorder.

Fentanyl and midazolam have been used together to facilitate PSA in emergency settings for decades. They are combined because fentanyl produces little sedation in subanesthetic doses and midazolam produces no analgesia. Fentanyl is generally dosed at 0.5-1 mcg/kg (50-100 mcg in a typical adult) and midazolam at 0.025-0.075 mg/kg (2-5 mg in a typical adult). Though this combination has a long record of safe use, it is more likely to cause adverse events than modern alternatives. (Sacchetti 2007, Bellolio 2016, Bailey 1990)  Both fentanyl and midazolam are comparatively difficult to titrate, due to their longer time to onset (2-3 minutes for midazolam and 3-5 minutes for fentanyl), which can lead to either undersedation, exposing the patient to painful stimuli, and oversedation, causing hypoventilation and apnea. Fentanyl and midazolam can both be reversed, however, by naloxone and flumazenil, respectively.

Nitrous Oxide (N2O) is a gas administered with oxygen in 30%-70% admixture to produce mild to moderate sedation, analgesia, amnesia and anxiolysis, with rapid onset and offset. N2O has a long record of efficacy and safety (ESA 2015) and its inhalational route requires no intravenous access nor an IM injection.  N2O does not produce adequate anesthetic depth to facilitate very painful procedures but is an excellent choice for facilitating lesser procedures such as laceration repair and abscess drainage, especially in an anxious patient and in combination with local anesthesia. It must be delivered via a specialized device that can scavenge escaped gas and is contraindicated in closed-compartment lesions such as pneumothorax or bowel obstruction.

Remifentanil is an ultra-short acting, non-accumulating opioid that produces moderate sedation and analgesia. Optimal dosing strategies and indications for ED-based PSA have not been established, but remifentanil may find a role in emergency medicine in less painful procedures when deep sedation is not required/desired, or to facilitate propofol PSA, allowing smaller doses of propofol. (Dunn 2006, Sacchetti 2012, Gharavifard 2016, Phillips 2009) In anesthesia literature, remifentanil has been associated with a comparatively high rate of dangerous adverse events (hypoventilation, hypotension, bradycardia, muscle rigidity) and should be used cautiously. (Smith 1997, Afshan 2012, Elliott 2000)

Dexmedetomidine is sympatholytic α-2 agonist typically delivered by a loading dose infusion followed by a maintenance infusion. Its non-opioid, non-GABA action delivers sedation and analgesia without respiratory depression but with predictable bradycardia and sometimes hypotension. Dexmedetomidine may find a role for non-painful procedures or as an adjunct to other agents such ketamine (Tobias 2012), where it counteracts ketamine’s adverse effects similarly to propofol, without the respiratory depression associated with propofol. As monotherapy, its more complicated dosing and slower onset limit its adoption as an agent for ED-based PSA.

Choosing the right PSA agent. The weight of evidence supports the use of propofol or ketamine (or their combination) as first choices to facilitate painful procedures in the emergency department, with etomidate a third choice due its tendency to cause myoclonus and nausea. We recommend propofol monotherapy for brief procedures, especially when muscle relaxation is important, such as joint reduction or cardioversion of the stable patient. Ketamine’s longer duration of action, cardiorespiratory stability and post-procedural analgesia make it well suited for most other ED-based PSA scenarios. Propofol should be avoided when hypotension or respiratory depression are a particular concern. Despite a listed contraindication in the prescribing information, the literature does not support such an association, and  propofol is widely considered to not be contraindicated in patients with an egg or soy allergy. (AAAAI 2016, Wiskin 2015, SPS 2010)  There are a variety of cited contraindications to ketamine, most of them poorly supported by literature. (Green 2011) However, we would avoid ketamine monotherapy in the uncommon PSA patient where a rise in blood pressure or heart rate would be dangerous. As discussed above, more important than the choice of PSA agent is thoughtful preparation for the procedure, vigilant monitoring during the procedure, and appropriately preventing and intervening on adverse events when they arise.

Post-procedure

There is little evidence to guide post-procedural practice but institutional guidelines are legion. An airway-capable provider should remain at bedside at least until the patient responds to voice. If a reversal agent was given during PSA, a 2-3 hour period of monitoring is indicated; otherwise hemodynamic monitoring should continue until the patient is conversant and has normal respiratory and cardiovascular function.  PSA patients are ideally discharged with a companion. Patients who must leave unaccompanied must be explicitly determined to have completely returned to their cognitive and neuromuscular baseline. Driving is traditionally proscribed for 12-24 hours. Because of the likelihood of amnesia, clear written discharge instructions detailing all relevant aspects of provided care as well as the expected course, followup, and indications for immediate return should be provided.

The author thanks Nicholas Chrimes, MD for his review of the manuscript and thoughtful suggestions.

The author reports no relevant conflicts of interest.

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Emergency Department Management of Acute Headache

Benjamin W. Friedman, MD, MS
Associate Professor of Emergency Medicine
Montefiore Medical Center
Albert Einstein College of Medicine
Bronx, NY, USA

Introduction

Headache causes nearly 5 million visits to US EDs annually and is the fifth most common cause of an ED visit. (Friedman 2014) Headache is sometimes attributable to a pathological process that can acutely threaten life or neurological functioning; identifying such a process is the primary responsibility of the acute care provider. Headache may also be related to a non-dangerous secondary cause, which often requires a specific acute treatment, such as sinus headache, which should be treated with decongestants, or strep throat, treated with antibiotics and anti-inflammatory medications. The focus of this chapter will not be on these secondary headaches but rather on primary headaches, that is, the various chronic episodic headache disorders that cause the majority of ED headache visits. (Friedman 2007) The list of primary headache disorders is extensive. (IHS 2013) This chapter will focus on migraine, the treatment of which is applicable to other primary headaches. We will also discuss two primary headaches that have distinct treatments, cluster headache and medication overuse headache.

Headache management: Initial steps

For patients who present to acute care with headache and desire symptom relief, the acute care provider should focus on analgesia at the same time that dangerous causes of headaches are specifically considered and excluded. Response to symptomatic therapy should not be the only determinant of diagnostic work-up, as heachache therapies are known to relieve pain from headaches of dangerous etiology (Edlow 2008). The diagnosis of a specific primary headache may be deferred to the outpatient setting, however, when symptoms strongly suggest a certain primary headache syndrome, patients benefit from this information and referral to appropriate resources. (Friedman 2016) Assigning the patient a specific headache diagnosis prior to treatment allows for a more elegant and nuanced approach to treatment.

Migraine

Migraine, the most common primary headache seen in the ED, characteristically presents with throbbing, unilateral pain associated with nausea, vomiting, photo and phonophobia. True aura is less common, though many patients describe visual or sensory phenomenon. Although it can be treated with the same parenteral medications as migraine, (Weinman 2014) tension type headache is essentially the opposite of migraine: a bland, bilateral headache, characterized by the lack of nausea and vomiting, and only rarely severe enough to cause an ED visit. Dozens of ED-based randomized clinical trials of migraine have been conducted over the last several decades providing a substantial evidence base on which treatment can be based. (Orr 2015) Two highly efficacious, disease-specific classes of medication have emerged: the triptans and the dopamine antagonists.

Dopamine Antagonists

Parenteral anti-dopaminergics including prochlorperazine 10 mg, chlorpromazine 25 mg, metoclopramide 10mg, haloperidol 5 mg, and droperidol 2.5mg have emerged as first-line therapy for migraine. (Schellenberg 2012) This class of medication is highly efficacious, with headache relief rates near 90%. Intravenous administration is probably more efficacious than intramuscular injection. Oral efficacy has not been established—if these medications are administered orally, they should be combined with an NSAID, aspirin, or acetaminophen. (MCSG 1992, Tfelt 1995, POZEN 2005) All five of the anti-dopaminergics listed above are highly effective; of the five, droperidol 2.5 mg IV is probably the most efficacious, followed by prochlorperazine 10mg IV. (Miner 2001, Weaver 2004 Kelly 2009) Extra-pyramidal effects can occur after administration of these agents. The most common extra-pyramidal effect to occur is akathisia, a profound restlessness that is extremely unpleasant for the patient. The incidence of akathisia can be minimized by administering these medications as a 15 minute infusion. (Regan 2009, Vinson 2001) Prochlorperazine should be administered with diphenhydramine 25mg IV to prevent development of akathisia. (Vinson 2004) Unfortunately, diphenhydramine does not prevent development of akathisia in patients administered metoclopramide. (Friedman 2016, Friedman 2009) Tardive dyskinesia, an irreversible movement disorder is a feared complication of long term use of dopamine antagonists but has not been reported after isolated parenteral doses. Repeated administration of the anti-dopaminergic is reasonable if the patient has not responded to the first round of treatment. (Friedman 2005)

Non-steroidal anti-inflammatory drugs

Parenteral and oral NSAIDs are effective in acute migraine. Ketorolac, dosed at 15 mg IV or 30 mg IM, has a modest evidence base supporting use. (Taggart 2015) It is uncertain if the efficacy of NSAIDs in migraine derives from anti-inflammatory properties or merely by impeding nociception. Many clinicians employ a strategy in which these medications are combined with anti-dopaminergics or triptans. However, patients often arrive in the ED without having taken any medication at all for their migraine. In these patients, demonstrating the efficacy of an oral NSAID, such as ibuprofen or naproxen, may be instructive for the future treatment of the patient.

Triptans

More than half a dozen different types of triptan drugs are marketed in the US, though to date, the only available parenteral version is sumatriptan. (Loder 2010) These serotonin agonists were originally believed to relieve headache through cerebral vasoconstriction, which they cause, but  it is more likely that they disrupt headache nociception within the cranial nerves and brainstem relay nuclei. Subcutaneous sumatriptan, dosed at 6mg, is highly efficacious, with a number needed to treat of two for headache relief. (Oldman 2002) In a multi-center, ED based study, median time to relief after receiving subcutaneous sumatriptan was approximately 30 minutes, meaning that more half of migraine sufferers can be placed in a chair, administered a subcutaneous dose of sumatriptan, and often will be ready to return to work before their registration is completed. (Akpunonu 1995) Unfortunately, subcutaneous sumatriptan has a number of common adverse effects, such as palpitations, flushing, chest discomfort, and paradoxical headache worsening. Also, headache recurrence after initial successful treatment is common with subcutaneous sumatriptan—as many as 2/3rds of patients will report moderate or severe headache in the 24 hours following initial successful treatment. Sumatriptan is also less likely to be efficacious as the acute attack progresses—it is best reserved for patients who present within an hour or two of headache onset. (Burstein 2000) Finally, triptans, because they have vasoconstrictive properties, should be used cautiously in patients with cardiovascular risk factors. Given all these concerns, subcutaneous sumatriptan is best reserved for those who have previously had good response to sumatriptan or those who cannot tolerate the anti-dopaminergics. Oral triptans including sumatriptan 100 mg PO, eletriptan 40 mg PO, and almotriptan 6.25 mg PO are reasonable treatments for patients who prefer oral treatment. These latter medications can be combined with oral NSAIDs, such as naproxen 500 mg PO, for added efficacy.

Corticosteroids

Untreated, an acute migraine headache will linger for up to 72 hours.(IHS 2013) Many patients who present to an ED for management of migraine report continuing recurrent headaches in the days and weeks following the ED visit. Two-thirds of ED migraine patients report headache within 24 hours of ED discharge—half of these are moderate or severe in intensity. (Friedman 2008) Corticosteroids decrease the occurrence of moderate or severe headache post ED-discharge with a number needed to treat of nine and should be offered to all patients who have no contraindications to these medication. (Colman 2008) Corticosteroids do not result in rapid improvement in patients with an acute headache but it is likely that their effects will occur within a six-hour window. (Friedman 2007) Unfortunately, the optimum dose and duration of therapy is not clear. Dexamethasone 10 mg as a one time intravenous, intramuscular, or oral dose is a reasonable choice. Alternatively, patients may be discharged on a short course of oral prednisone (eg, 40-60 mg daily for three days).

Opioids

Opioids are the class of medication used most commonly to treat acute migraine in US EDs; (Friedman 2015) hydromorphone itself is used in 25% of all such ED visits. While they are effective analgesics, use of opioids should be discouraged for several reasons: 1) Opioids are less effective than other parenteral acute medication regimens.(Friedman 2008) 2) The ultimate goal of ED migraine therapy is to return a patient to work or school promptly, which cannot be done after opioid administration due to sedation and disorientation. 3) Opioids have been weakly linked to a variety of downstream headache-related sequelae including an increased number of ED visits, (Colman 2004) development of refractoriness to standard migraine medication, (Burstein 2004) and an increase in an individual’s average number of monthly headache days, (Bigal 2008) in addition to addiction, dependence, and overdose. Opioids should be relegated to the role of rescue medication for patients who have failed multiple other parenteral agents or for use, sparingly, in patients who have contraindications to other classes of medication. If opioids are indicated, intravenous morphine is an appropriate choice at an initial dose of 0.05-0.1 mg/kg. Hydromorphone is best avoided (see Use Of Opioids chapter, to be published).

Barbiturates

Several oral barbiturate combination medications are marketed as migraine therapeutics. As with opioids, these medications are linked to worsening of the underlying headache disorder (Bigal 2008) and should not be offered routinely in the ED. Patients who request an oral barbiturate combination should be counseled that these medications are likely to worsen the underlying headache disorder.

Magnesium

Conflicting evidence precludes a recommendation in support of the routine use of intravenous magnesium. While some studies report benefit, others have shown no benefit or even harm. (Orr 2015) Magnesium is most appropriate for migraine patients with true aura, patients with low magnesium levels, or those who have failed to respond to other acute treatments. If intravenous magnesium is to be used, administer 2 g IV.

Dihydroergotamine (DHE)

DHE, an ergot alkaloid derived from ergotamine, has been used to treat migraine for decades. As triptans and anti-dopaminergics have emerged as effective and well-tolerated treatment of acute migraine, use of DHE has declined. (Friedman 2015) DHE commonly causes nausea. In clinical trials, it has often been combined with anti-migraine anti-dopaminergics such as metoclopramide, thus confusing analyses of efficacy. For patients admitted to an inpatient bed for treatment of status migrainosus, DHE is often administered around the clock in conjunction with an anti-dopaminergic as part of the so-called Raskin protocol. (Raskin 1986) For emergency clinicians, this medication is a useful second or third line therapy, in particular for patients who have not responded to anti-dopaminergics with NSAIDs. DHE 1 mg IV should be administered as a slow intravenous drip in combination with metoclopramide 10 mg IV. It should not be given to patients who have already used a triptan, patients with cardiovascular risk factors, and patients using macrolide antibiotics.

Greater occipital nerve block (GONB)

Though evidence supporting this procedure does not yet exist, many headache specialists believe that a GONB with bupivacaine can relieve the pain of an acute migraine. Three milliliters of 0.5% solution can be administered adjacent to the greater occipital nerve bilaterally. The greater occipital nerve can be targeted 1/3 of the way down a line extending from the occipital protuberance to the mastoid process. For added efficacy, the lesser occipital nerve and the V1 distribution of the trigeminal nerve may be targeted as well. Efficacy is thought to relate to disruption of nociceptive transmission through brainstem nuclei, such as the trigeminal cervical complex, at which both the upper cervical nerves and the trigeminal nerve terminate.

The author’s stepwise protocol for management of migraine in the ED is listed in Table 1. Other potential migraine therapeutics are listed in Table 2. Intravenous fluids, though often used for migraine, do not confer benefit in euvolemic patients. (26825817)

Cluster Headache

Cluster is a rare form of headache so, despite its severity, it is an uncommon cause of ED visit. Cluster is a severe, unilateral, peri-orbital headache. It is associated with autonomic features such as lacrimation, conjunctival injection, ptosis, or nasal congestion. Unlike migraine, patients with cluster feel restless and prefer to move rather than lie in a dark room. Cluster peaks in intensity quickly and does not last longer than three hours. Often, by the time the emergency clinician can see the patient, the headache has mostly dissipated. However, by definition, the acute headache is part of a headache cluster and will return again. Therefore, it is vital that the emergency physician address the continuing headache ailment.  

Acute cluster headache should be treated with high flow oxygen. Oxygen delivered at 12 L/ minute through a non-rebreather mask aborts acute cluster, with a number needed to treat of <2.(Cohen 2009) Subcutaneous sumatriptan, dosed at 6 mg, aborts acute cluster headache, with a number needed to treat of 3. (Law 2013) Anti-dopaminergics are thought to be useful for acute cluster too, though evidence is of lower quality. (Rozen 2001, Caviness 1980) Opioids should be reserved for patients who fail to obtain relief with these interventions. Greater occipital nerve blockade may be effective for this headache too, despite the fact that cluster is felt within the V1 branch distribution of the trigeminal nerve. (Gantenbein 2012)

Once the acute headache has dissipated, the emergency physician should focus on the next headache in the cluster cycle, which in true cluster headache, is very likely to occur within 24 hours. Because of the severity of cluster headache, if follow-up care cannot be arranged within 24 hours, the patient’s continuing needs fall to the emergency physician. Corticosteroids are thought to mitigate the frequency and severity of subsequent headaches. Definitive trials are underway. It is reasonable to provide these patients with a 10 day corticosteroid taper. Some evidence suggests that verapamil, dosed at 120 mg TID, can decrease the frequency of daily attacks and the requirement of analgesics. In a small sample of patients without conduction system disease, this intervention was well tolerated, causing only constipation as a side effect. (Leone 2000)

Medication overuse headache and chronic headache

Most patients who present to an ED with headache have an episodic headache disorder that causes acute headaches infrequently. ED patients often report that they have only several acute headaches per year or several headaches per month. At the other end of the headache frequency spectrum are patients who have headaches on more days than not, patients who are frequently functionally impaired by their headaches, and patients who often cannot participate fully in work or social activities because of their headaches. Chronic migraine, a sub-type of migraine defined by 15 or more days with headache for at least three consecutive months, is experienced by 1-2% of the general population. (Natoli 2010) Often intertwined with chronic headache is medication overuse headache, a downstream complication of the primary headache disorders. Medication overuse headache, also experienced by 1-2% of the general population, is characterized by an upward spiral in headache frequency associated with an increased use of analgesic or headache specific medication (Kristoffersen 2014). Though acute relief is the goal for most patients who present to an ED with headache, when treating patients with chronic headache or medication overuse headache, it is important for the emergency physician to keep one eye on long-term outcomes such as recurrent ED visits and number of monthly headache days. Hopefully, care can be coordinated with an outpatient physician who knows the patient and is savvy about headache management. Chronic migraine should be treated with preventive medication, the goal of which is a modest decrease in the frequency and severity of acute attacks. Anti-hypertensive medications including beta-blockers, and calcium channel blockers can achieve this goal, as can antiepileptic medications including topiramate and valproic acid, and the tricyclic antidepressant amitriptyline. (Pringsheim 2012) Additionally, these patients should be on effective acute medication. The combination of an NSAID with an oral triptan or with oral metoclopramide is a reasonable starting point. For patients with medication overuse headache, discontinuation, generally through a slow taper,  is required. This often requires referral, monitored discontinued use of the offending agent, substitution of a different acute medication, and initiating a preventive therapy. Patients who use opioids chronically and suffer frequent headaches are particularly likely to be harmed by opioids; opioids should therefore be avoided in this group.

*Evidence is preliminary; these therapies are outside standard care. References for Table 2: Nicolodi 1995,  Bigal 2002, Kapicioğlu 1997, Soleimanpour 2012, Friedman 2014.

Summary

• Acute primary headache may present to the ED with a variety of different acute manifestations
• After excluding secondary headache, goal should be on rapid and effective relief of pain
• Disease specific treatments such as anti-dopaminergics and triptans results in better short and long-term outcomes than non-specific analgesics
• Opioids should not be used for management of primary headache disorders unless several other treatments have failed
• Recurrent primary headache after ED discharge is common.

The author reports no relevant conflicts of interest.

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