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)
| Table 1: Pharmacokinetic Parameters of Alpha-2 Agonists | ||
| Clonidine | Dexmedetomidine | |
| Absorption | Rapid absorption following oral administrationBioavailability of 70 to 80% | Immediate (only available as an intravenous formulation) |
| Distribution | Vd = 1.75 to 2.5 L/kg20% bound to plasma proteins | Vd = 1.33 L/kg94% bound to plasma proteins |
| Metabolism | Liver (~50%)Five known inactive metabolites | Extensive in liver via CYP2A6 and glucuronidation |
| Excretion | Unchanged in urine (40 to 60%), remainder in bile/feces | Unchanged in urine (80 to 90%), remainder in bile/feces |
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:
| Table 2: Dexmedetomidine Dose Considerations for Procedural Sedation | ||
| Initiation | Maintenance | |
| Adult patients with invasive procedures | 1 mcg/kg IV bolus infused over 10 minutes | 0.6 mcg/kg/hrTitrate to effectTypical range: 0.2 to 1 mcg/kg/hr |
| Adult Patients with non-invasive procedures | 0.5 mcg/kg IV bolus infused over 10 minutes | |
| Awake fiberoptic intubation | 1 mcg/kg IV bolus infused over 10 minutes | 0.7 mcg/kg/hr with secured endotracheal tube |
| Patients > 65 years of age | 0.5 mcg/kg IV bolus infused over 10 minutes | Consider dose reduction |
| Patients with impaired hepatic or renal function | Consider dose reduction | Consider dose reduction |
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.