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Opioids

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.

 

References

Alford, D. P., P. Compton and J. H. Samet (2006). “Acute pain management for patients receiving maintenance methadone or buprenorphine therapy.” Ann Intern Med 144(2): 127-134.

Atluri S, Sudarshan G, Manchikanti L. Assessment of the trends in medical use and misuse of opioid analgesics from 2004 to 2011. Pain Physician. 2014 Mar-Apr;17(2):E119-28.

Baka NE, Bayoumeu F, Boutroy MJ, Laxenaire MC. Colostrum morphine concentrations during postcesarean intravenous patient-controlled analgesia. Anesth Analg. 2002 Jan;94(1):184-7.

Baldo, B. A. and N. H. Pham (2012). “Histamine-releasing and allergenic properties of opioid analgesic drugs: resolving the two.” Anaesth Intensive Care 40(2): 216-235.

Benthuysen, J. L., N. T. Smith, T. J. Sanford, N. Head and H. Dec-Silver (1986). “Physiology of alfentanil-induced rigidity.” Anesthesiology 64(4): 440-446.

Bernstein, K. J. (1994). “Inappropriate use of transdermal fentanyl for acute postoperative pain.” J Oral Maxillofac Surg 52(8): 896.

Bernstein, K. Z. and M. A. Klausner (1994). “Potential dangers related to transdermal fentanyl (Duragesic) when used for postoperative pain.” Dis Colon Rectum 37(12): 1339-1340.

Borland, M., I. Jacobs, B. King and D. O’Brien (2007). “A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department.” Ann Emerg Med 49(3): 335-340.

Borland, M., S. Milsom and A. Esson (2011). “Equivalency of two concentrations of fentanyl administered by the intranasal route for acute analgesia in children in a paediatric emergency department: a randomized controlled trial.” Emerg Med Australas 23(2): 202-208.

Bosilkovska, M., B. Walder, M. Besson, Y. Daali and J. Desmeules (2012). “Analgesics in patients with hepatic impairment: pharmacology and clinical implications.” Drugs 72(12): 1645-1669.

Bulow, H. H., M. Linnemann, H. Berg, T. Lang-Jensen, S. LaCour and T. Jonsson (1995). “Respiratory changes during treatment of postoperative pain with high dose transdermal fentanyl.” Acta Anaesthesiol Scand 39(6): 835-839.

Butler SF, Black RA, Cassidy TA, Dailey TM, Budman SH. Abuse risks and routes of administration of different prescription opioid compounds and formulations. Harm Reduct J. 2011 Oct 19;8:29.

Casati, A. and M. Putzu (2005). “Anesthesia in the obese patient: pharmacokinetic considerations.” J Clin Anesth 17(2): 134-145.

Cascorbi, I. (2003). “Pharmacogenetics of cytochrome p4502D6: genetic background and clinical implication.” Eur J Clin Invest 33 Suppl 2: 17-22.

CDC (2014)(a). “National Center for Health Statistics. Therapeutic drug use.” https://www.cdc.gov/nchs/fastats/drug-use-therapeutic.htm

CDC (2014)(b). “Substance Abuse and Mental Health Services Administration, National Survey on Drug Use and Health.” https://www.samhsa.gov/data/sites/default/files/NSDUH-FRR1-2014/NSDUH-FRR1-2014.pdf

Cepeda, M. S., J. T. Farrar, M. Baumgarten, R. Boston, D. B. Carr and B. L. Strom (2003). “Side effects of opioids during short-term administration: effect of age, gender, and race.” Clin Pharmacol Ther 74(2): 102-112.

Chambers, R. A., J. R. Taylor and M. N. Potenza (2003). “Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability.” Am J Psychiatry 160(6): 1041-1052.

Chang, D. J., J. R. Fricke, S. R. Bird, N. R. Bohidar, T. W. Dobbins and G. P. Geba (2001). “Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial.” Clin Ther 23(9): 1446-1455.

Chang, G., L. Chen and J. Mao (2007). “Opioid tolerance and hyperalgesia.” Med Clin North Am 91(2): 199-211.

Charney, R. L., Y. Yan, M. Schootman, R. M. Kennedy and J. D. Luhmann (2008). “Oxycodone versus codeine for triage pain in children with suspected forearm fracture: a randomized controlled trial.” Pediatr Emerg Care 24(9): 595-600.

Chou R, Fanciullo GJ, Fine PG, Adler JA, Ballantyne JC, Davies P, Donovan MI, Fishbain DA, Foley KM, Fudin J, Gilson AM, Kelter A, Mauskop A, O’Connor PG, Passik SD, Pasternak GW, Portenoy RK, Rich BA, Roberts RG, Todd KH, Miaskowski C; American Pain Society-American Academy of Pain Medicine Opioids Guidelines Panel. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009 Feb;10(2):113-30.

Clark, E., A. C. Plint, R. Correll, I. Gaboury and B. Passi (2007). “A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma.” Charney.

Comer, S. D., M. A. Sullivan, R. A. Whittington, S. K. Vosburg and W. J. Kowalczyk (2008). “Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers.” Neuropsychopharmacology 33(5): 1179-1191.

Compton, P., V. C. Charuvastra, K. Kintaudi and W. Ling (2000). “Pain responses in methadone-maintained opioid abusers.” J Pain Symptom Manage 20(4): 237-245.

Comstock, M. K., J. G. Carter, J. R. Moyers and W. C. Stevens (1981). “Rigidity and hypercarbia associated with high dose fentanyl induction of anesthesia.” Anesth Analg 60(5): 362-363.

Dahan, A., A. Yassen, R. Romberg, E. Sarton, L. Teppema, E. Olofsen and M. Danhof (2006). “Buprenorphine induces ceiling in respiratory depression but not in analgesia.” Br J Anaesth 96(5): 627-632.

Dasgupta N, Freifeld C, Brownstein JS, Menone CM, Surratt HL, Poppish L, Green JL, Lavonas EJ, Dart RC. Crowdsourcing black market prices for prescription opioids. J Med Internet Res. 2013 Aug 16;15(8):e178.

Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004 Nov;28(5):497-504.

Doverty, M., J. M. White, A. A. Somogyi, F. Bochner, R. Ali and W. Ling (2001). “Hyperalgesic responses in methadone maintenance patients.” Pain 90(1-2): 91-96.

Eccles, R., S. Morris and M. Jawad (1992). “Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection.” J Clin Pharm Ther 17(3): 175-180.

Farid WO, Dunlop SA, Tait RJ, Hulse GK. The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data. Curr Neuropharmacol. 2008 Jun;6(2):125-50.

Feilberg VL, Rosenborg D, Broen Christensen C, Mogensen JV. Excretion of morphine in human breast milk. Acta Anaesthesiol Scand. 1989 Jul;33(5):426-8.

Fong, H. K., L. P. Sands and J. M. Leung (2006). “The role of postoperative analgesia in delirium and cognitive decline in elderly patients: a systematic review.” Anesth Analg 102(4): 1255-1266.

Freestone, C. and R. Eccles (1997). “Assessment of the antitussive efficacy of codeine in cough associated with common cold.” J Pharm Pharmacol 49(10): 1045-1049.

Glick, C., O. B. Evans and B. R. Parks (1996). “Muscle rigidity due to fentanyl infusion in the pediatric patient.” South Med J 89(11): 1119-1120.

Grond, S., L. Radbruch and K. A. Lehmann (2000). “Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl.” Clin Pharmacokinet 38(1): 59-89.

Hill JL, Zacny JP. Comparing the subjective, psychomotor, and physiological effects of intravenous hydromorphone and morphine in healthy volunteers. Psychopharmacology (Berl). 2000 Sep;152(1):31-9.

Hill, A. B., M. L. Nahrwold, A. M. de Rosayro, P. R. Knight, R. M. Jones and R. E. Bolles (1981). “Prevention of rigidity during fentanyl–oxygen induction of anesthesia.” Anesthesiology 55(4): 452-454.

Huxtable, C. A., L. J. Roberts, A. A. Somogyi and P. E. MacIntyre (2011). “Acute pain management in opioid-tolerant patients: a growing challenge.” Anaesth Intensive Care 39(5): 804-823.

Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000 Jul 13;343(2):118-26.

Jalili M, Fathi M, Moradi-Lakeh M, Zehtabchi S. Sublingual buprenorphine in acute pain management: a double-blind randomized clinical trial. Ann Emerg Med. 2012 Apr;59(4):276-80.

Johnson KR, Hsueh WA, Glusman SM, Arnett FC. Fibrous myopathy. A rheumatic complication of drug abuse. Arthritis Rheum. 1976 Sep-Oct;19(5):923-6.

Koren, G., J. Cairns, D. Chitayat, A. Gaedigk and S. J. Leeder (2006). “Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother.” Lancet 368(9536): 704.

Kornfeld, H. and L. Manfredi (2010). “Effectiveness of full agonist opioids in patients stabilized on buprenorphine undergoing major surgery: a case series.” Am J Ther 17(5): 523-528.

Kuhlman, J. J., Jr., S. Lalani, J. Magluilo, Jr., B. Levine and W. D. Darwin (1996). “Human pharmacokinetics of intravenous, sublingual, and buccal buprenorphine.” J Anal Toxicol 20(6): 369-378.

Lazaryan, M., C. Shasha-Zigelman, Z. Dagan and M. Berkovitch (2015). “Codeine should not be prescribed for breastfeeding mothers or children under the age of 12.” Acta Paediatr 104(6): 550-556.

Leysen, J. E., W. Gommeren and C. J. Niemegeers (1983). “[3H]Sufentanil, a superior ligand for mu-opiate receptors: binding properties and regional distribution in rat brain and spinal cord.” Eur J Pharmacol 87(2-3): 209-225.

Ling, G. S., D. Paul, R. Simantov and G. W. Pasternak (1989). “Differential development of acute tolerance to analgesia, respiratory depression, gastrointestinal transit and hormone release in a morphine infusion model.” Life Sci 45(18): 1627-1636.

MacGregor, D. A. and L. A. Bauman (1996). “Chest wall rigidity during infusion of fentanyl in a two-month-old infant after heart surgery.” J Clin Anesth 8(3): 251-254.

Macintyre, P. E., R. A. Russell, K. A. Usher, M. Gaughwin and C. A. Huxtable (2013). “Pain relief and opioid requirements in the first 24 hours after surgery in patients taking buprenorphine and methadone opioid substitution therapy.” Anaesth Intensive Care 41(2): 222-230.

Marks, C. E., Jr. and R. M. Goldring (1973). “Chronic hypercapnia during methadone maintenance.” Am Rev Respir Dis 108(5): 1088-1093.

Mazoit, J. X., P. Sandouk, P. Zetlaoui and J. M. Scherrmann (1987). “Pharmacokinetics of unchanged morphine in normal and cirrhotic subjects.” Anesth Analg 66(4): 293-298.

Miller, M., C. W. Barber, S. Leatherman, J. Fonda, J. A. Hermos, K. Cho and D. R. Gagnon (2015). “Prescription opioid duration of action and the risk of unintentional overdose among patients receiving opioid therapy.” JAMA Intern Med 175(4): 608-615.

Murphy, A., R. O’Sullivan, A. Wakai, T. S. Grant, M. J. Barrett, J. Cronin, S. C. McCoy, J. Hom and N. Kandamany (2014). “Intranasal fentanyl for the management of acute pain in children.” Cochrane Database Syst Rev 10: CD009942.

Murphy, E. J. (2005). “Acute pain management pharmacology for the patient with concurrent renal or hepatic disease.” Anaesth Intensive Care 33(3): 311-322.

Naumburg EG, Meny RG. Breast milk opioids and neonatal apnea. Am J Dis Child. 1988 Jan;142(1):11-2.

NIH (2015). “Overdose death rates: the science of drug abuse and addiction.” National Institute on Drug Abuse. http://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates

Patanwala, A. E., C. J. Edwards, L. Stolz, R. Amini, A. Desai and U. Stolz (2012). “Should morphine dosing be weight based for analgesia in the emergency department?” J Opioid Manag 8(1): 51-55.

Patriquin, M. A., I. E. Bauer, J. C. Soares, D. P. Graham and D. A. Nielsen (2015). “Addiction pharmacogenetics: a systematic review of the genetic variation of the dopaminergic system.” Psychiatr Genet 25(5): 181-193.

Patwardhan, R. V., R. F. Johnson, A. Hoyumpa, Jr., J. J. Sheehan, P. V. Desmond, G. R. Wilkinson, R. A. Branch and S. Schenker (1981). “Normal metabolism of morphine in cirrhosis.” Gastroenterology 81(6): 1006-1011.

Payandemehr P, Jalili M, Mostafazadeh Davani B, Dehpour AR. Sublingual buprenorphine for acute renal colic pain management: a double-blind, randomized controlled trial. Int J Emerg Med. 2014 Jan 3;7(1):1.

Pergolizzi, J., A. M. Aloisi, A. Dahan, J. Filitz, R. Langford, R. Likar, S. Mercadante, B. Morlion, R. B. Raffa, R. Sabatowski, P. Sacerdote, L. M. Torres and A. A. Weinbroum (2010). “Current knowledge of buprenorphine and its unique pharmacological profile.” Pain Pract 10(5): 428-450.

Reed, B., E. R. Butelman, V. Yuferov, M. Randesi and M. J. Kreek (2014). “Genetics of opiate addiction.” Curr Psychiatry Rep 16(11): 504.

Roberts, D. M. and M. Meyer-Witting (2005). “High-dose buprenorphine: perioperative precautions and management strategies.” Anaesth Intensive Care 33(1): 17-25.

Rose, P. G., M. S. Macfee and M. V. Boswell (1993). “Fentanyl transdermal system overdose secondary to cutaneous hyperthermia.” Anesth Analg 77(2): 390-391.

Sandler, A. N., A. D. Baxter, J. Katz, B. Samson, M. Friedlander, P. Norman, G. Koren, S. Roger, K. Hull and J. Klein (1994). “A double-blind, placebo-controlled trial of transdermal fentanyl after abdominal hysterectomy. Analgesic, respiratory, and pharmacokinetic effects.” Anesthesiology 81(5): 1169-1180; discussion 1126A.

Santiago, T. V., A. C. Pugliese and N. H. Edelman (1977). “Control of breathing during methadone addiction.” Am J Med 62(3): 347-354.

Sarton, E., L. Teppema and A. Dahan (2008). “Naloxone reversal of opioid-induced respiratory depression with special emphasis on the partial agonist/antagonist buprenorphine.” Adv Exp Med Biol 605: 486-491.

Sistonen, J., A. Sajantila, O. Lao, J. Corander, G. Barbujani and S. Fuselli (2007). “CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure.” Pharmacogenet Genomics 17(2): 93-101.

Smith, H. and P. Bruckenthal (2010). “Implications of opioid analgesia for medically complicated patients.” Drugs Aging 27(5): 417-433.

Soleimanpour, H., S. Safari, K. Shahsavari Nia, S. Sanaie and S. M. Alavian (2016). “Opioid Drugs in Patients With Liver Disease: A Systematic Review.” Hepat Mon 16(4): e32636.

Spigset O, Hägg S. Analgesics and breast-feeding: safety considerations. Paediatr Drugs. 2000 May-Jun;2(3):223-38.

Stein, C., M. Schafer and H. Machelska (2003). “Attacking pain at its source: new perspectives on opioids.” Nat Med 9(8): 1003-1008.

Stoops, W. W., K. W. Hatton, M. R. Lofwall, P. A. Nuzzo and S. L. Walsh (2010). “Intravenous oxycodone, hydrocodone, and morphine in recreational opioid users: abuse potential and relative potencies.” Psychopharmacology (Berl) 212(2): 193-203.

Streisand, J. B., P. L. Bailey, L. LeMaire, M. A. Ashburn, S. D. Tarver, J. Varvel and T. H. Stanley (1993). “Fentanyl-induced rigidity and unconsciousness in human volunteers. Incidence, duration, and plasma concentrations.” Anesthesiology 78(4): 629-634.

Tegeder, I., J. Lotsch and G. Geisslinger (1999). “Pharmacokinetics of opioids in liver disease.” Clin Pharmacokinet 37(1): 17-40.

Volkow, N. D. and A. T. McLellan (2016). “Opioid Abuse in Chronic Pain–Misconceptions and Mitigation Strategies.” N Engl J Med 374(13): 1253-1263.

von Kemp K, Herregodts P, Duynslaeger L, Deleu D, Bruyland M, Cham B. Muscular fibrosis due to chronic intramuscular administration of narcotic analgesics. Acta Clin Belg. 1989;44(6):383-7.

Weil, J. V., R. E. McCullough, J. S. Kline and I. E. Sodal (1975). “Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man.” N Engl J Med 292(21): 1103-1106.

Wightman, R., J. Perrone, I. Portelli and L. Nelson (2012). “Likeability and abuse liability of commonly prescribed opioids.” J Med Toxicol 8(4): 335-340.

Wunsch MJ, Stanard V, Schnoll SH. Treatment of pain in pregnancy. Clin J Pain. 2003 May-Jun;19(3):148-55.

Yamanaka M, Parsa FD. Compression neuropathy from muscle fibrosis induced by repeated meperidine injections. Plast Reconstr Surg. 1985 Apr;75(4):582-3.

Yue, H. J. and C. Guilleminault (2010). “Opioid medication and sleep-disordered breathing.” Med Clin North Am 94(3): 435-446.

Zacny, J. P. and S. Gutierrez (2009). “Within-subject comparison of the psychopharmacological profiles of oral hydrocodone and oxycodone combination products in non-drug-abusing volunteers.” Drug Alcohol Depend 101(1-2): 107-114.

Pain in the Pregnant and Postpartum Patient

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

The authors have no relevant conflicts of interest to disclose.

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

General Information

-General statement about background risk

-Contact information for pregnancy registry if available

Fetal Risk Summary

-Based on all available data, this section characterizes the likelihood that the drug increases the risk of developmental abnormalities in humans and other relevant risks

-More than 1 risk conclusion may be needed

For drugs that are systemically absorbed

-When there are human data, a statement describes the likelihood of increased risk based on this data. This statement is followed by a brief description of the findings

-A standard statement describes the likelihood of increased risk based on animal data

For drugs that are not systemically absorbed

-A standard statement that maternal use is not expected to result in fetal exposure to drug

Clinical Considerations

This section provides information on the following topics:

Inadvertent exposure

-Known or predicted risk to the fetus from inadvertent exposure to drug before pregnancy is known

Prescribing decisions for pregnant women

-Describe any known risk to the pregnant woman and fetus from the disease or condition the drug is intended to treat

-Information about dosing adjustments during pregnancy

-Maternal adverse reactions unique to pregnancy or increased in pregnancy

-Effects of dose, timing, and duration of exposure to drug during pregnancy

-Potential neonatal complications and needed interventions

Drug effects during labor and delivery

Data

Human and animal data are presented separately, with human data presented first

-Describes study type, exposure information (dose, duration, timing), and any identified fetal developmental abnormality or other adverse effects

-For human data, includes positive and negative experiences, number of subjects, and duration of study

-For animal data, includes species studied and describes doses in terms of human dose equivalents (provide basis for calculation)

Table 2: Revised Lactation Subsection Information Drug Labeling

Risk Summary

If appropriate, include a statement that the use of the drug is compatible with breast-feeding.

-Effects of the drug on milk production

-Whether the drug is present in human milk (and if so, how much)

-The effect of the drug on the breast-fed child

Clinical Considerations

-Ways to minimize exposure to the breast-fed child, such as timing or pumping and discarding milk

-Potential drug effects in the child and recommendations for monitoring or responding to these effects

-Dosing adjustment during lactation

Data

-Overview of data on which risk summary and clinical considerations are based

 

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

Physiologic Change Pharmacokinetic Impact
Delayed gastric emptying

Decreased gastrointestinal motility

Delayed but more complete absorption

Lower peak concentrations

Increased cutaneous blood flow Increased dermal absorption
Increased tidal volume Increased pulmonary absorption
Decreased plasma albumin

Decreased hepatic biotransformation

Increased free drug concentration
Increased fat stores, fluid volume Decreased free drug concentrations
Increased cardiac output, glomerular filtration Increased renal elimination

 

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

4 P’s

Parents: Did any of your parents have a problem with alcohol or other drug use?
Partner: Does your partner have a problem with alcohol or drug use?
Past: In the past, have you had difficulties in your life because of alcohol or other drugs, including prescription medications?
Present: In the past month have you drunk any alcohol or used other drugs?
Scoring: Any “yes” should trigger further questions.

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

Physiologic Change Clinical Implication
Increased oxygen consumption Rapid desaturation; supply oxygen, use capnography
Decreased functional residual capacity Rapid desaturation
Airway tissue engorgement/edema Difficult intubation
Weight gain/increased breast size Difficult intubation
Increased gastroesophageal reflux Aspiration risk; raise head of bed
Gravid uterus Hypotension in supine position; tilt onto left side or displace uterus

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

Prophylaxis Treatment
Acupuncture Acetaminophen
Biofeedback Metoclopramide
Co-enzyme Q Phenothiazines

(prochlorperazine, promethazine)

Magnesium supplementation Magnesium sulfate
Beta-blockers

(metoprolol, propranolol)

Sumatriptan
Tricyclic antidepressants

(low-dose amitriptyline)

Nonsteroidal antiinflammatory drug

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.

 

References

Antonucci R, Zaffanello M, Puxeddu E, Porcella A, Cuzzolin L, Pilloni MD, Fanos V. Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn. Curr Drug Metab. 2012 May 1;13(4):474-90.

Babb M, Koren G, Einarson A. Treating pain during pregnancy. Can Fam Physician. 2010 Jan;56(1):25, 27.

Bambrink AM, Evers AS, Avidan MS, et al. Ketamine-induced neuroapoptosis in the fetal and neonatal rhesus macaque brain. Anesthesiology 2012;116:372-84.

Banhidy F, Acs N, Horvath-Puho E, et al. Pregnancy complications and delivery outcomes in pregnant women with severe migraine. Eur J Obstet Gynecol Reprod Biol 2007;134:157–63.

Bánhidy F, Acs N, Puhó E, et al. Ergotamine treatment during pregnancy and a higher rate of low birthweight and preterm birth. Br J Clin Pharmacol 2007; 64:510-6.

Bateman BT, Hernandez-Diaz S, Rathmell JP, et al. Patterns of opioid utilization in pregnancy in a large cohort of commercial insurance beneficiaries in the United States. Anesthesiology 2014;120;1216-24.

Begg EJ, Atkinson HC. Duffull SB. Prospective evaluation of a model for the prediction of milk:plasma drug concentrations from physiochemical characteristics. Br J Clin Pharmacol 1992;33:501-5.

Boga C, Ozdogu H. Pregnancy and sickle cell disease: A review of the current literature. Crit Rev Oncol Hematol 2016;98:364-74.

Brent RL: The application of the principles of toxicology and teratology in evaluating the risks of new drugs for the treatment of drug addiction in women of reproductive age. NIDA Res Monogr 1995;149:130-84.

Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011;204:314.e1-11.

Brucker MC. Management of common minor discomforts in pregnancy. Part II: Managing minor pain in pregnancy. J Nurse Midwifery 1988;33:25-30.

Capeless EL, Clapp JF. When do cardiovascular parameters return to their preconception values? Am J. Obstet Gyneol 1991;165:883-6.

CDC. Births: Preliminary data for 2014. National Vital Statistics Reports. Available at: http://www.cdc.gov/nchs/data/nvsr/nvsr64/nvsr64_06.pdf. Accessed January 22, 2016.

Committee on Health Care for Underserved Women, The American College of Obstetricians and Gynecologists. Committee opinion no. 538: nonmedical use of prescription drugs. Obstet Gynecol 2012;120:977-82.

Committee opinion no. 711 summary: Opioid use and opioid use disorder during pregnancy. Obstet Gynecol 2017; 32:488-9.

Dam M, Christiansen J, Munck O, Mygind KI. Antiepileptic drugs: Metabolism in pregnancy. Clinical Pharmacokin 1979;4:53-62.

Damase-Michel C, Hurault-Delarue C. Ibuprofen does not seem to increase global malformation risk but NSAID use in late pregnancy remains a concern. Evid Based Med. 2014 Apr;19(2):74.

Daniel S, Koren G, Lunenfeld E, Bilenko N, Ratzon R, Levy A. Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ. 2014 Mar 18;186(5):E177-82.

de Fays L, Van Malderen K, De Smet K. Use of paracetamol during pregnancy and child neurological development. Dev Med Child Neurol 2015;57:718-24.

Demirkaya S, Vural O, Dora B, et al. Efficacy of intravenous magnesium sulfate in the treatment of acute migraine attacks. Headache 2001;41:171–7.

Enato E, Moretti M, Koren G. The fetal safety of benzodiazepines: an updated meta-analysis. J Obstet Gynaecol Can 2011;33:46-8.

Epstein RA, Bobo WV, Martin PR, et al. Increasing pregnancy-related use of prescribed opioid analgesics. Ann Epidemiol 2013;23:498-503.

Erkolla R, Kanto J. Diazepam and breast-feeding. Lancet 1972;1:1235-6.

Food and Drug Administration. CDER 2004. Pharmacokinetics in pregnancy-study design, data analysis, and recommendations for labeling. Draft guidance for industry. Available at: http://www.fda.gov/downloads/Drugs/…/Guidances/ucm072133.pdf Accessed January 22, 2016.

Food and Drug Administration. CDER, CBER 2002. Establishing pregnancy exposure registries. Guidance for Industry. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071639.pdf. Accessed January 22, 2016.

Gentile S. Tricyclic antidepressants in pregnancy and puerperium. Expert Opin Drug Saf 2014;13:207-25.

Granella F, Sances G, Pucci E, et al. Migraine with aura and reproductive life events: a case control study. Cephalalgia 2000;20:701–7.

Guttuso T, Shaman M, Thornburg LL. Potential maternal symptomatic benefit of gabapentin and review of its safety in pregnancy. Eur J Obstet and Gynecol Reprod Biol 2014;181:280-3.

Heinomen OP, Sloane S, Shapiro S. Birth defects in pregnancy. Littleton MA: Publishing Science Group 1977.

Jones HE, Heil SH, Baewert A, et al. Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review. Addiction 2012;107(suppl 1):5–27.

Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Eng J Med 2010; 363;2320-31.

Kaltenbach K, Berghella V, Finnegan L. Opioid dependence during pregnancy. Effects and management. Obstet Gynecol Clin North Am 1998;25:139–51.

Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of mor- phine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368:704.

Kvisvik EV, Stovner LJ, Helde G, et al. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain 2011;12:443–51.

Lazaryan M, Shasha-Zigelman C, Dagan Z, et al. Codeine should not be prescribed for breastfeeding mothers or children under the age of 12. Acta Paediatr 2015;104:550-6.

Liew Z, Ritz B, Rebordosa C, et al. Acetaminophen use during pregnancy, behavioral problems, and hyperkinetic disorders. JAMA Pediatr 2014;168:313-20.

MacGregor EA. Migraine in pregnancy and lactation. Neurol Sci 2014;35 Suppl 1:61-4.

Madadi, Moretti M, Djokanovic N. Guidelines for maternal codeine use during breastfeeding. Can Fam Physician 2009;55:1077-8.

Medadi P, Koren G, Cairns, et al. Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed infant of a mother prescribed codeine. Can Fam Physician 2007;53:33-5.

Messinger DS, Bauer CR, Das A, et al. The maternal lifestyle study: cognitive, motor, and behavioral outcomes of cocaine-exposed and opiate-exposed infants through three years of age. Pediatrics 2004;113:1677–1685.

Meyer MC, Johnston AM, Crocker AM, et al. Methadone and buprenorphine for opioid dependence during pregnancy: a retrospective cohort study. J Addict Med 2015;9:81-6.

Mitchell AA, Gilboa SM, Werler MM, Kelley KE, Louik, C, Hernandez-Diaz S. Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008. Am J Obstet Gynecol 2011;205:51.e1-8.

Moise KJ, Huhta JC, Sharif DS, et al. Indomethacin in the treatment of premature labor: effects on the fetal ductus arteriosus. N Engl J Med 1988;319:327-31.

Moreira A, Barbin C, Martinez H, et al. Maternal use of cyclobenzaprine (Flexeril) may induce ductal closure and persistent pulmonary hypertension in neonates. J Matern Fetal Neonatal Med 2014;27:1177-9.

Neuman G, Koren G. Safety of procedural sedation in pregnancy. J Obstet Gynaecol Can 2013;35:168-73.
Ostgaard HC, Zetherstrom G, Roos-Hansson E et al. Reduction of back and posterior pelvic pain in pregnancy. Spine 1994;19:894–900.

Plonait SL, Nau H: Physiolochemical and structural properties regulating placental drug transfer. In Polin RA, Fox WW, eds. Fetal and Neonatal Physiology, Vol 1. Philadelphia: Saunders; 2004:197-211.

Rayburn W, Rathke A, Leuschen MP et al. Fentanyl citrate analgesia during labor. Am J Obstet Gynecol 1989;161: 202-6.

Rosenberg L, Mitchell AA, Parsells JA, et al. Lack of relation of oral clefts to diazepam use during pregnancy. N Eng J Med 1983:303;1282-5.

Sauberan JB, Anderson PO, Lane JR, et al. Brest milk hydrocodone and hydromorphone levels in mothers using hydrocodone for postpartum pain. Obstet Gynecol 2011;117:611-7.

Scanlon JW. Effects of benzodiazepines on the neonate. N Engl J Med 1975; 292:649-50.

Shah S, Banh ET, Koury K, Bhatia G, Nandi R, Gulur P. Pain Management in Pregnancy: Multimodal Approaches. Pain Res Treat. 2015;2015:987483.

Shaw GM, Malcoe LH, Swan SH, et al. Congenital cardiac anomalies relative to selected maternal exposures and conditions during early pregnancy. Eur J Epidemiol 1992;8:757–60.

Sims EAH, Krantz KE. Serial studies of renal function during pregnancy and the puerperium in normal women. J Clin Invest 1958;7:1764-74.

Stec GP, Greenberger P, Ruo TI. Kinetics of theophylline transfer to breast milk. Clin Pharmacol Ther 1980;28:404-8.

Stuart JJ, Gross SJ, Elrad H, et al. Effects of acetylsalicylic acid ingestion on maternal and neonatal hemostasis. N Engl J Med 1982;307:909-12.

Tajchman SK, Bruno JJ. Propofol use in a critically-ill pregnant patient. Ann Pharmacother 2010;44:2018-22.

Timm NL. Maternal use of oxycodone resulting in opioid intoxication in her breastfed neonate. J Pediatr 2013;162:421-2.

Tolia VN, Patrick SW, Bennett MM, et al. Increasing incidence of the neonatal abstinence syndrome in U.S. neonatal ICUs. N Eng J Med 2015;372:2118-26.

Vermani E, Mittal R, Weeks A. Pelvic girdle pain and low back pain in pregnancy: a review. Pain Pract 2010;10:60-71.

Warner M , Chen LH , Makuc DM , Anderson RN , Miniño AM. Drug poisoning deaths in the United States, 1980-2008. NCHS Data Brief 2011;81:1-8.

Winklbaur B, Kopf N, Ebner N, et al. Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates. Addiction 2008;103:1429-40.

Wu WH, Meijer OG, Uegaki K, et al. Pregnancy- related pelvic girdle pain (PGP), I: terminology, clinical presentation, and prevalence. Eur Spine J 2004; 13:575–589.

Zeisler JA, Gaarder TD, De Mesquita SA. Lidocaine excretion in breast milk. Drug Intell Clin Pharm 1986;20:691-3.

Zelson M, Lee SJ, Casalino M. Neonatal narcotic addiction. N Engl J Med 1973; 289:1216-20.

The Opioid Epidemic: A Brief History


Gillian A. Beauchamp
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.

References

Adams J, Bledsoe GH, Armstrong JH. Are Pain Management Questions in Patient Satisfaction Surveys Driving the Opioid Epidemic? Am J Public Health. 2016 Jun;106(6):985-6.

Alexander L, Mannion RO, Weingarten B, Fanelli RJ, Stiles GL. Development and impact of prescription opioid abuse deterrent formulation technologies. Drug Alcohol Depend. 2014 May 1;138:1-6.

Alford DP. Opioid Prescribing for Chronic Pain — Achieving the Right Balance through Education. N Engl J Med 2016;374(4):301-3.

American Pain Society Quality of Care Committee. Quality improvement guidelines for the treatment of acute pain and cancer pain. JAMA. 1995;274:1874–80.

American Society of Addiction Medicine. Definition of addiction. ASAM Quality and Practice. 2016. Available at: http://www.asam.org/quality-practice/definition-of-addiction

Barnett, M. L., Olenski, A. R., & Jena, A. B. (2017). Opioid-Prescribing Patterns of Emergency Physicians and Risk of Long-Term Use. New England Journal of Medicine, 376(7), 663–673. http://doi.org/10.1056/NEJMsa1610524

Beauchamp GA, Winstanley E, Ryan S, Lyons M. Moving Beyond Misuse and Diversion: The urgent need to consider the role of iatrogenic addiction in the current opioid epidemic. Am J Public Health. 2014;104(11):2023-9.

Berridge V., Edwards G. Opium and the people: Opiate use in nineteenth century England. Yale University Press, 1987. Print.

Brummett, C. M., Waljee, J. F., Goesling, J., Moser, S., Lin, P., Englesbe, M. J., et al. (2017). New Persistent Opioid Use After Minor and Major Surgical Procedures in US Adults. JAMA Surgery, e170504. http://doi.org/10.1001/jamasurg.2017.0504

Butler MM, Ancona RM, Beauchamp GA, Yamin CK, Winstanley EL, Hart KW, Ruffner AH, Ryan SW, Ryan RJ, Lindsell CJ, Lyons MS. ED prescription opioids as an initial exposure preceding addiction. Ann Emerg Med 2016. doi: 10.1016/j.annemergmed.2015.11.033. [Epub ahead of print]

Campbell JN. 1996. APS 1995 presidential address. Pain Forum 5:85–88.

Cantrill SV, Brown MD, Carlisle RJ, Delaney KA, Hays DP, Nelson LS, O’Connor RE, Papa A, Sporer KA, Todd KH, Whitson RR, American College of Emergency Physicians Opioid Guideline Writing Panel. Clinical Policy: Critical issues in the prescribing of opioids for adult patients in the emergency department. Ann Emerg Med. 2012;60(4):499-525.

Centers for Disease Control and Prevention. CDC guideline for prescribing opioids for chronic pain – United States, 2016. Recommendations and Reports 2016;65(1):1-49. Available at: http://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm

Centers for Disease Control and Prevention. Opioids drive continued increase in drug overdose deaths. Drug overdose deaths increase for 11th consecutive year. Available at: http://www.cdc.gov/media/releases/2013/p0220_drug_overdose_deaths.html. Accessed February 12, 2016.

Centers for Disease Control and Prevention. Public Health Grand Rounds. Prescription Drug Overdoses: An American epidemic. Available at: https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm. Accessed February 12, 2016.

Chen LH, Hedegaard H, Warner M. QuickStats: Rates of deaths from drug poisoning and drug poisoning involving opioid analgesics-United States, 1999-2013. MMWR Morb Mortal Wkly Rep. 2015;64(1):32.

Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. The changing face of heroin use in the United States: a retrospective analysis of the past 50 years. JAMA Psychiatry 2014;71:821–26

Cicero TJ, Inciardi JA, Munoz A. Trends in abuse of Oxycontin and other opioid analgesics in the United States: 2002-2005. J Pain 2005;6(10):662-72.

Coffin P, Banta-Green C. The dueling obligations of opioid stewardship. Ann Intern Med 2014;160(3):207.

Compton WM, Jones CM, Baldwin GT. Relationship between nonmedical prescription-opioid use and heroin use. N Engl J Med. 2016;374:154-163.

Courtwright D. T. Dark Paradise – A history of opiate addiction in America. Harvard University Press, 2001. Print.

Courtwright DT. Preventing and treating narcotic addiction – a century of federal drug control. N Engl J Med 2015;373:2095-2097.

Daniulaiyte R, Falck R, Carlson RG. Sources of pharmaceutical opioids for non-medical use among young adults. J Psychoactive Drugs. 2014;46(3):198-207.

Dasgupta N, Kramer ED, Zalman MA, Carino S Jr, Smith MY, Haddox JD, Wright C 4th. Association between non-medical and prescriptive usage of opioids. Drug Alc Depend 2006;82(2):135-42.

Davis CS, Johnston JE, Pierce MW. Overdose epidemic, prescription monitoring programs, and public health: A review of state laws. Am J Public Health. 2015;105(11):e9-e11.

Doe-Simkins M, Quinn E, Xuan Z, Sorensen-Alawad A, Hackman H, Ozonoff A, Walley AY. Overdose rescues by trained and untrained participants and change in opioid use among substance-using participants in overdose education and naloxone distribution programs: a retrospective cohort study. BMC Public Health. 2014 Apr 1;14(1):297.

Doran E, Henry D. Disease mongering: expanding the boundaries of treatable disease. Intern Med J. 2008;38(11):858-61.

Dowell D, Kunins HV, Farley TA. Opioid analgesics – Risky drugs, Not risky patients. JAMA 2013;309(21):2219-20.

Federation of State Medical Boards. Model policy on the use of opioid analgesics in the treatment of chronic pain. 2013. Available at: http://www.fsmb.org/Media/Default/PDF/FSMB/Advocacy/pain_policy_july2013.pdf. Accessed February 12, 2016.

Fischer B, Keates A, Bühringer G, Reimer J, Rehm J. Non-medical use of prescription opioids and prescription opioid-related harms: why so markedly higher in North America compared to the rest of the world? Addiction 2013; doi: 10.1111/add.12224

Gwira Baumblatt JA, Wiedeman C, Dunn JR, Schaffner W, Paulozzi LJ, Jones TF. High-risk use by patients prescribed opioids for pain and its role in overdose deaths. JAMA Intern Med 2014. 174(5):796-801.

Haddox JD, Joranson D, Angarola RT, Brady A, Carr DB, Blonsky ER, Burchiel K, Gitlin M, Midcap M, Payne R, Simon D, Vasudevan S, Wilson P, The American Academy of Pain Medicine and the American Pain Society. The use of opioids for the treatment of chronic pain. A consensus statement from the American Academy of Pain Medicine and the American Pain Society. 1997. Clin J Pain 1997;13(1):6-8.

Hahn KL. Strategies to prevent opioid misuse, abuse, and diversion that may also reduce the associated costs. Am Health Drug Benefits 2011;4(2):107-114.

Han B, Compton WM, Jones CM, Cai R. Nonmedical prescription opioid use and use disorders among adults aged 18 through 64 in the United States, 2003-2013. JAMA. 2015;314(14):1468-78.

Havens JR, Leukefeld CG, Deveaugh-Geiss AM, Coplan P, Chilcoat HD. The impact of a reformulation of extended-release oxycodone designed to deter abuse in a sample of prescription opioid abusers. Drug Alcohol Depend 2014;139:9-17.

Hedegaard H, Warner M, Minino AM. Drug overdose deaths in the United States, 1999-2015, National Center for Health Statistics (NCHS) Data Brief No. 273, February 2017. Accessed May 2, 2017. Available at: https://www.cdc.gov/nchs/products/databriefs/db273.htm

Hoppe JA, Kim H, Heard K. Association of emergency department opioid initiation with recurrent opioid use. Ann Emerg Med. 2015;65:493-499.e4.

Institute of Medicine (US) Committee on Advancing Pain Research Care and Education. Institute of Medicine (US) Committee on Advancing Pain Research Care and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: National Academies Pr; 2011.

Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington (DC): National Academies Press (US); 2011. 2, Pain as a Public Health Challenge. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92516/

International Narcotics Control Board. Narcotic drugs: Estimated world requirements for 2010: Statistics for 2009. United Nations: 2010b.

Joranson DE, Ryan KM, Gilson AM, Dahl JL. Trends in medical use and abuse of opioid analgesics. JAMA 2000;283(13):1710-4.

Juurlink DN, Dhalla IA, Nelson LS. Improving Opioid Prescribing: The New York City Recommendations. JAMA.2013;309(9):879-880.

Keller CE., Ashrafioun L, Neumann AM, Van Klein J, Fox CH, Blondell RD. Practices, perceptions, and concerns of primary care physicians about opioid dependence associated with the treatment of chronic pain. Substance Abuse 2012;33:103-113.

Kennedy MC, Kerr T. Overdose prevention in the United States: A call for supervised injection sites. AJPH 2017;107(1):42-43

Kirschner N, Ginsburg J, Snyder Sulmasy L. Prescription drug abuse: executive summary of a policy position paper from the American College of Physicians. Ann Intern Med. 2014; 160:198-200.

Kolodny A, Courtwright DT, Hwant CS, Kreiner P, Eadie JL, Clark TW, Alexander GC. The prescription opioid and heroin crisis: a public health approach to an epidemic of addiction. Annu Rev Public Health 2015;36:559-74.

Lankenau SE, Teti M, Silva K, Jackson Bloom J, Harocopos A, Treese M. Initiation into prescription opioid misuse amongst young injection drug users. Int J Drug Policy 2012;23:37-44

Lanser P, Gesell S. Pain management: the fifth vital sign. Health Benchmarks. 2001;8;62, 68-70.

Larochelle MR, Liebschutz JM, Zhang F, Ross-Degnan D, Wharam JF. Opioid prescribing after nonfatal overdose and association with repeated overdose: a cohort study. Ann Intern Med 2016;164(1):1-9.

Leddy, K.M., Wolosin, R.J. Patient satisfaction with pain control during hospitalization. Jt Comm J Qual Patient Saf 2005; 31(9):507-13.

Lembke A. Why doctors prescribe opioids to known opioid abusers. N Engl J Med. 2012;367(17):1580-81.

Leung PTM, Macdonald EM, Stanbrook MB, Dhalla IA, Juurlink DN. A 1980 Letter on the Risk of Opioid Addiction. N Engl J Med. 2017 Jun 1;376(22):2194-2195.

Levy B, Paulozzi L, Mack KA, Jones CM. Trends in opioid analgesic-prescribing rates by specialty, U.S., 2007-2012. Am J Prev Med 2015;49(3):409-13.

Lewis DC, Zinberg NE. Narcotic usage. N Engl J Med. 1964;270:1045-1050.

Mars SG, Bourgois P, Karandinos G, Montero F, Ciccarone D. “Every ‘never’ I ever said came true”: transitions from opioid pills to heroin injecting. Int J Drug Policy 2014;25:257-266

Mazer-Amirshahi M, Mullins PM, Rasooly I, van den Anker J, Pines JM. Rising opioid prescribing in adult U.S. emergency department visits: 2001-10. Acad Emerg Med 2014;21:236–42.

McAuliffe WE. A critique of Minozzi et al.’s pain relief and dependence systematic review, and authors’ response. Addiction 2013; 108: 1162–71.

McDonald DC, Carlson KE. Estimating the prevalence of opioid diversion by “doctor shoppers” in the United States. PLoS One 2013;8(7):e69241.

Minozzi S, Amato L, Davoli M. Development of dependence following treatment with opioid analgesics for pain relief: a systematic review. Addiction 2013; 108: 688–98.

Moore C, Lloyd G, Oretti R, Russell I, Snooks H. Paramedic-supplied ‘Take Home’ Naloxone: protocol for cluster randomised feasibility study. BMJ Open. 2014 Mar 20;4(3):e004712.

Motov SM, Marshall JP. Acute pain management curriculum for emergency medicine residency programs. Acad Emerg Med. 2011;18:S87-S91.

Moynihan R, Henry D. Selling sickness: the pharmaceutical industry and disease mongering. BMJ 2002;324(7342):886-891.

Muhuri PK, Gfroerer JC, Davies MC. Associations of nonmedical pain reliever use and initiation of heroin use in the United States. Center for Behavioral Health Statistics and Quality. CBHSQ Data Rev. 2013. Available at: https://www.samhsa.gov/data/sites/default/files/DR006/DR006/nonmedical-pain-reliever-use-2013.htm

Neal JM, Bernards CM, Hadzic A, Hebl JR, Hogan QH, Horlocker TT, Lee LA, Rathmell JP, Sorenson EJ, Suresh S, Wedel DJ. ASRA Practice Advisory on Neurologic Complications in Regional Anesthesia and Pain Medicine. Reg Anesth Pain Med. 2008 Sep-Oct;33(5):404-15.
Nelson LS, Juurlink DN, Perrone J. Addressing the opioid epidemic. JAMA. 2015;314(14):1453-4.

Nelson LS, Perrone J, Juurlink DN. Painful decision-making at FDA. Expert Opin Drug Saf 2014;13(4);407-10.

Nelson LS, Perrone J. Curbing the opioid epidemic in the United States. The Risk Evaluation and Mitigation Strategy (REMS). JAMA 2012;308(5):457-458.

Noble M., Treadwell JR, Tregear SJ, Coates VH, Wiffen PJ, Akafomo C, Schoelles KM. Long-term opioid management for chronic non cancer pain. Cochrane Database of Syst Rev 2010, Issue 1. Art. No.: CD006605. DOI: 10.1002/14651858.CD006605.pub2.

Ohio Prescription Drug Abuse Taskforce. Final Report – Task Force Recommendations. October 1, 2010.

Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med 2010; 363(21):1981-5.

Olsen Y, Sharfstein JM. Chronic Pain, Addiction, and Zohydro. N Engl J Med 2014;370(22):2061-3.

Olsen Y. The CDC Guideline on Opioid Prescribing: Rising to the Challenge. JAMA. 2016 Apr 19;315(15):1577-9.

Paulozzi LJ, Budnitz DS, Xi Y. Increasing deaths from opioid analgesics in the United States. Pharmacoepidemiol Drug Saf. 2006;15(9):618-627.

Paulozzi LJ, Jones CM, Mack KA, Rudd FA. Vital signs: Overdoses of prescription opioid pain relievers-United States, 1999-2008. MMWR Morb Mortal Wkly Rep. 2011;60(43):1487-1492.

Paulozzi LJ, Strickler GK, Kreiner PW, Koris CM, Centers for Disease Control and Prevention (CDC). Controlled substance prescribing patterns-prescription behavior surveillance system, eight states 2013. MMWR Surveill Summ. 2015;64(9):1-14.

Perrone J, Mycyk, M. A challenging crossroad for emergency medicine: the epidemics of pain and pain medicine deaths. Acad Emerg Med 2014;21(3):334-336.

Pizzo PA, Clark NM. Alleviating suffering 101-pain relief in the United States. N Engl J Med. 2012;366:197-199.

Pollini RA, Banta-Green CJ, Cuevas-Mota J, Metzner M, Teshale E, Garfein RS. Problematic use of prescription-type opioids prior to heroin use among young heroin injectors. Subst Abuse Rehabil 2011;2:173-180

Poon SJ, Greenwood-Ericksen MB. The opioid prescription epidemic and the role of emergency medicine. Ann Emerg Med 2014;64(5):490-495.

Portenoy RK, Foley KM. Chronic use of opioid analgesics in non-malignant pain: Report of 38 cases. Pain 1986; 25;(2) 171-86.

Porter J, Jick H. Addiction rare in patients treated with narcotics. New Engl J Med 1980; 302:123.

Rieckmann T, Muench J, McBurnie MA, Leo MC, Crawford P, Ford D, Stubbs J, O’Cleirigh C, Mayer KH, Fiscella K, Wright N, Doe-Simkins M, Cuddeback M, Salisbury-Afshar E, Nelson C. Medication-assisted treatment for substance use disorders within a national community health center research network. Subst Abus 2016;37(4):625-634

Rudd RA, Aleshire N, Zibbell JE, Gladden M. Increases in drug and opioid overdose deaths – United States, 2000-2014. MMWR Morb Mortal Wkly Rep. 2016;64(50);1378-82.

Rudd RA, Seth P, David F, Scholl L. Increases in Drug and Opioid-Involved Overdose Deaths – United States, 2010-2015. MMWR Morb Mortal Wkly Rep 2016;65:1445-1452.

Sehgal N, Manchikanti L, Smith HS. Prescription opioid abuse in chronic pain: A review of opioid abuse predictors and strategies to curb opioid abuse. Pain Physician 2012;15:ES67-ES92.

Siegal HA, Carlson RG, Kenne DR, Swora MG. Probable relationship between opioid abuse and heroin use. Am Fam Physician 2003;67:942-945.

Slatko GH. Risk evaluation and mitigation strategy (REMS): FDA perspective on what physicians need to know. Am Fam Physician. 2015;92(9):771-2.

Substance Abuse and Mental Health Services Administration. Results from the 2013 national survey on drug use and health: summary of national findings. Available at: http://www.samhsa.gov/data/sites/default/files/NSDUHresultsPDFWHTML2013/Web/NSDUHresults2013.pdf. Accessed February 11, 2016.

Substance Abuse and Mental Health Services Agency. Drug Abuse Warning Network, 2011: National estimates of drug-related emergency department visits. Available at http://www.samhsa.gov/data/sites/default/files/DAWN2k11ED/DAWN2k11ED/DAWN2k11ED.pdf. Accessed February 11, 2016.

Tefera L, Lehrman WG, Conway P. Measurement of the patient experience: clarifying facts, myths, and approaches. JAMA 2016; doi: 10.1001/jama.2016.1652. [Epub ahead of print]

The Office of the Assistant Secretary for Health at the US Department of Health and Human Services. National Pain Strategy. 2016. Available at: http://iprcc.nih.gov/National_Pain_Strategy/NPS_Main.htm

Unick GJ, Rosenblum D, Mars S, Ciccarone D. Intertwined epidemics: national demographic trends in hospitalizations for heroin- and opioid-related overdoses, 1993-2009. PLoS One 2013;8:e54496.

United States Department of Veteran’s Affairs. Pain as a fifth vital sign toolkit. 1999, revised 2000. Available at: http://www.va.gov/PAINMANAGEMENT/docs/Pain_As_the_5th_Vital_Sign_Toolkit.pdf. Accessed February 11, 2016.

United States General Accounting Office. Prescription Drugs: OxyContin Abuse and Diversion and Efforts to Address the Problem. Published January 22, 2004. Available at http://www.gao.gov/new.items/d04110.pdf (Accessed February 12, 2016).

US Centers for Disease Control and Prevention. Community-based opioid overdose prevention programs providing naloxone—United States, 2010. MMWR Morb Mortal Wkly Rep. 2012;61(6):101–105.

US Food and Drug Administration. Risk evaluation and mitigation strategy (REMS) for extended-release and long-acting opioids. 2012. Available at: http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm163647.htm. Accessed February 12, 2016.

Van Zee A. The promotion and marketing of OxyContin: commercial triumph, public health tragedy. Am J Public Health. 2009:99(2):221-227.

Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-assisted therapies – Tackling the opioid overdose epidemic. N Engl J Med. 2014; 370(22):2063-6.

Volkow ND, McLellan TA, Cotto JH. Characteristics of opioid prescriptions in 2009. JAMA. 2011;305:1299-1301.

Winstanley EL, Clark A, Feinberg J, Wilder CM. Barriers to implementation of opioid overdose prevention programs in Ohio. Subst Abus. 2016;37(1):42-6.

Wisniewski AM, Purdy CH, Blondell RD. The epidemiologic association between opioid prescribing, non-medical use, and emergency department visits. Journal of Addictive Diseases. 2008;27(1):1-11.

Zaller ND, Yokell MA, Green TC, Gaggin J, Case P. The feasibility of pharmacy-based naloxone distribution interventions: a qualitative study with injection drug users and pharmacy staff in Rhode Island. Subst Use Misuse. 2013 Jun;48(8):590-9.

Zgierska A, Miller M, Rabago D. Patient satisfaction, prescription drug abuse and potential unintended consequences. JAMA 2012;307(13):1377-1378.

Pain in the Polytrauma Patient

Christopher Hicks
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
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. 

 

References


Baker SP, O’Neill B, Haddon W Jr, Long WB. The injury severity score: a method for describing patients with multiple injuries and evaluating emergency care. J Trauma. 1974 Mar;14(3):187-96.

Ballow SL, Kaups KL, Anderson S, Chang M. A standardized rapid sequence intubation protocol facilitates airway management in critically injured patients. J Trauma Acute Care Surg. 2012 Dec;73(6):1401-5.

Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, Coursin DB, Herr DL, Tung A, Robinson BR, Fontaine DK, Ramsay MA, Riker RR, Sessler CN, Pun B, Skrobik Y, Jaeschke R; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013 Jan;41(1):263-306.

Berben SA, Meijs TH, van Dongen RT, van Vugt AB, Vloet LC, Mintjes-de Groot JJ, van Achterberg T. Pain prevalence and pain relief in trauma patients in the Accident & Emergency department. Injury. 2008 May;39(5):578-85. Epub 2007 Jul 20.

Berben SA, Schoonhoven L, Meijs TH, van Vugt AB, van Grunsven PM. Prevalence and relief of pain in trauma patients in emergency medical services. Clin J Pain. 2011 Sep;27(7):587-92.

Blow O, Magliore L, Claridge JA, Butler K, Young JS. The golden hour and the silver day: detection and correction of occult hypoperfusion within 24 hours improves outcome from major trauma. J Trauma. 1999 Nov;47(5):964-9.

Curtis KM, Henriques HF, Fanciullo G, Reynolds CM, Suber F. A fentanyl-based pain management protocol provides early analgesia for adult trauma patients. J Trauma. 2007 Oct;63(4):819-26.

Dar R,  Leventhal H. Schematic processes in pain perception. Cogn Ther Res. 1993 Aug;17(4): 341-357.

Dutton RP. Damage Control Anesthesia. Int Trauma Care. 2005 Fall:197-201.

Dutton RP, McCunn M, Grissom TE. Anesthesia for trauma. In: Miller RD, ed. Miller’s Anesthesia, 7th Ed. Philadelphia: Elsevier Churchill Livingstone, 2010; 2277–311.

White KE, Szumita PM, Gilboy N, Keenan HA, Arbelaez C. Implementation of a guideline for the treatment of pain, sedation, agitation and neuromuscular blockade in the mechanically ventilated adult patient in the emergency department. Open Access Emerg Med. 2011;3:21–27.

Guéant S, Taleb A, Borel-Kühner J, Cauterman M, Raphael M, Nathan G, Ricard-Hibon A. Quality of pain management in the emergency department: results of a multicentre prospective study. Eur J Anaesthesiol. 2011 Feb;28(2):97-105.

Haley KB, Lerner EB, Guse CE, Pirrallo RG. Effect of System-Wide Interventions on the Assessment and Treatment of Pain by Emergency Medical Services Providers. Prehosp Emerg Care. 2016 Nov-Dec;20(6):752-758.

Krauss WC, Shah S, Shah S, Thomas SH. Fentanyl in the out-of-hospital setting: variables associated with hypotension and hypoxemia. J Emerg Med. 2011 Feb;40(2):182-7.

Kwan I, Bunn F, Roberts IG. Spinal immobilisation for trauma patients. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD002803.

Lee C, Porter K. The prehospital management of pelvic fractures. Emerg Med J. 2007 Feb;24(2):130-3.

Liu SS, Carpenter RL, Mackey DC, Thirlby RC, Rupp SM, Shine TS, Feinglass NG, Metzger PP, Fulmer JT, Smith SL. Effects of perioperative analgesic technique on rate of recovery after colon surgery. Anesthesiology. 1995 Oct;83(4):757-65.

Lyons PJ, Rivosecchi RM, Nery JP, Kane-Gill SL. Fentanyl-induced hyperalgesia in acute pain management. J Pain Palliat Care Pharmacother. 2015 Jun;29(2):153-60.

Miller M, Kruit N, Heldreich C, Ware S, Habig K, Reid C, Burns B. Hemodynamic Response After Rapid Sequence Induction With Ketamine in Out-of-Hospital Patients at Risk of Shock as Defined by the Shock Index. Ann Emerg Med. 2016 Aug;68(2):181-188.

Moon MR, Luchette FA, Gibson SW, Crews J, Sudarshan G, Hurst JM, Davis K Jr, Johannigman JA, Frame SB, Fischer JE. Prospective, randomized comparison of epidural versus parenteral opioid analgesia in thoracic trauma. Ann Surg. 1999 May;229(5):684-91.

Nolan B, Zakirova R, Bridge J, Nathens AB. Barriers to implementing the World Health Organization’s Trauma Care Checklist: A Canadian single-center experience. J Trauma Acute Care Surg. 2014 Nov;77(5):679-683.

Reardon DP, Anger KE, Szumita PM. Pathophysiology, assessment, and management of pain in critically ill adults. Am J Health Syst Pharm. 2015 Sep 15;72(18):1531-43.

Régnier MA, Raux M, Le Manach Y, Asencio Y, Gaillard J, Devilliers C, Langeron O, Riou B. Prognostic significance of blood lactate and lactate clearance in trauma patients. Anesthesiology. 2012 Dec;117(6):1276-88.

Richard M Lyon, Zane B Perkins, Debamoy Chatterjee, David J Lockey, Malcolm Q Russell, and on behalf of Kent, Surrey & Sussex Air Ambulance Trust. Significant modification of traditional rapid sequence induction improves safety and effectiveness of pre-hospital trauma anaesthesia. Crit Care. 2015;19(1): 134. Published online 2015 Apr 1.

Scott I, Porter K, Laird C, Greaves I, Bloch M. The prehospital management of pelvic fractures: initial consensus statement. Emerg Med J. 2013 Dec;30(12):1070-2.

Theodore N, Hadley MN, Aarabi B, Dhall SS, Gelb DE, Hurlbert RJ, Rozzelle CJ, Ryken TC, Walters BC. Prehospital cervical spinal immobilization after trauma. Neurosurgery. 2013 Mar;72 Suppl 2:22-34

Thomassen Ø, Storesund A, Søfteland E, Brattebø G. The effects of safety checklists in medicine: a systematic review. Acta Anaesthesiol Scand. 2014 Jan;58(1):5-18.

Trevino C, Harl F, Deroon-Cassini T, Brasel K, Litwack K. Predictors of chronic pain in traumatically injured hospitalized adult patients. J Trauma Nurs. 2014 Mar-Apr;21(2):50-6.

Truitt MS, Murry J, Amos J, Lorenzo M, Mangram A, Dunn E, Moore EE. Continuous intercostal nerve blockade for rib fractures: ready for primetime? J Trauma. 2011 Dec;71(6):1548-52.

Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006 Aug;60(7):341-8.

Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care. 2012 Dec 12;16(2):R49.

Weingart SD, Trueger NS, Wong N, Scofi J, Singh N, Rudolph SS. Delayed sequence intubation: a prospective observational study. Ann Emerg Med. 2015 Apr;65(4):349-55.

Williams DC, Golding J, Phillips K, Towell A. Perceived control, locus of control and preparatory information: effects on the perception of an acute pain stimulus. Pers Ind Diff. 2004 May;36(7):1681-1691.

Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000 Jun 9;288(5472):1765-9.

Wu CL1, Sapirstein A, Herbert R, Rowlingson AJ, Michaels RK, Petrovic MA, Fleisher LA. Effect of postoperative epidural analgesia on morbidity and mortality after lung resection in Medicare patients. J Clin Anesth. 2006 Nov;18(7):515-20.

Pain and PSA in Older Adults

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.

 

References

Andolfatto G, Abu-Laban RB, Zed PJ, Staniforth SM, Stackhouse S, Moadebi S, Willman E. Ketamine-propofol combination (ketofol) versus propofol alone for emergency department procedural sedation and analgesia: a randomized double-blind trial. Ann Emerg Med. 2012 Jun;59(6):504-12.

Berry PH, Dahl JL. The new JCAHO pain standards: implications for pain management nurses. Pain Manag Nurs. 2000 Mar;1(1):3-12.

Black E, Campbell SG, Magee K, Zed PJ. Propofol for procedural sedation in the emergency department: a qualitative systematic review. Ann Pharmacother. 2013 Jun;47(6):856-68.

Bowling CB, O’Hare AM. Managing Older Adults With CKD: Individualized Versus Disease-Based Approaches. Am J Kidney Dis. 2012; 59(2), 293–302.

Campbell RL, Smith PB. Intravenous sedation in 200 geriatric patients undergoing office oral surgery. Anesth Prog. 1997 Spring;44(2):64-7.

Crome P. What’s different about older people. Toxicology. 2003 Oct 1;192(1):49-54.

Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49.

Dworkin R. Which individuals with acute pain are most likely to develop a chronic pain syndrome? Pain Forum. 1997; 6(2):127-36.

Ferrell BA, Ferrell BR, Osterweil D. Pain in the nursing home. J Am Geriatr Soc. 1990 Apr;38(4):409-14.

Funk L. A prospective trial to compare three anaesthetic techniques used for the reduction of fractures of the distal radius. Injury. 1997 Apr;28(3):209-12.

Godoy Monzon D, Iserson KV, Vazquez JA. Single fascia iliaca compartment block for post-hip fracture pain relief. J Emerg Med. 2007 Apr;32(3):257-62.

Grandison MK, Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet. 2000 Mar;38(3):271-90.

Hastings SN, Sloane RJ, Goldberg KC, Oddone EZ, Schmader KE. The quality of pharmacotherapy in older veterans discharged from the emergency department or urgent care clinic. J Am Geriatr Soc. 2007 Sep;55(9):1339-48.

Hastings SN, Sloane RJ, Goldberg KC, Oddone EZ, Schmader KE. The quality of pharmacotherapy in older veterans discharged from the emergency department or urgent care clinic. J Am Geriatr Soc. 2007 Sep;55(9):1339-48.

Herr K, Titler M. Acute pain assessment and pharmacological management practices for the older adult with a hip fracture: review of ED trends. J Emerg Nurs. 2009 Jul;35(4):312-20.

Høgh A, Dremstrup L, Jensen SS, Lindholt J. Fascia iliaca compartment block performed by junior registrars as a supplement to pre-operative analgesia for patients with hip fracture. Strategies Trauma Limb Reconstr. 2008 Sep;3(2):65-70.

Hughes S, Gibbs J, Dunlop D, Edelman P, Singer R, Chang RW. Predictors of decline in manual performance in older adults. J Am Geriatr Soc. 1997 Aug;45(8):905-10.

Kim J, Lee J, Shin CM, Lee DH, Park BJ. Risk of gastrointestinal bleeding and cardiovascular events due to NSAIDs in the diabetic elderly population. BMJ Open Diabetes Res Care. 2015 Dec 18;3(1):e000133.

Kitagawa E, Iida A, Kimura Y, Kumagai M, Nakamura M, Kamekura N, Fujisawa T, Fukushima K. Responses to intravenous sedation by elderly patients at the Hokkaido University Dental Hospital. Anesth Prog. 1992;39(3):73-8.

Lees D, Harrison WD, Ankers T, A’Court J, Marriott A, Shipsey D, Chaplin A, Reed MR. Fascia iliaca compartment block for hip fractures: experience of integrating a new protocol across two hospital sites. Eur J Emerg Med. 2016 Feb;23(1):12-8.

Lopes RD, Horowitz JD, Garcia DA, Crowther MA, Hylek EM. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility. Blood. 2011 Dec 8;118(24):6269-73.

Maneglia R, Cousin MT. A comparison between propofol and ketamine for anaesthesia in the elderly. Haemodynamic effects during induction and maintenance. Anaesthesia. 1988 Mar;43 Suppl:109-11.

Morrison RS, Dickman E, Hwang U, Akhtar S, Ferguson T, Huang J, Jeng CL, Nelson BP, Rosenblatt MA, Silverstein JH, Strayer RJ, Torrillo TM, Todd KH. Regional Nerve Blocks Improve Pain and Functional Outcomes in Hip Fracture: A Randomized Controlled Trial. J Am Geriatr Soc. 2016 Dec;64(12):2433-2439.

Mouzopoulos G, Vasiliadis G, Lasanianos N, Nikolaras G, Morakis E, Kaminaris M. Fascia iliaca block prophylaxis for hip fracture patients at risk for delirium: a randomized placebo-controlled study. J Orthop Traumatol. 2009 Sep;10(3):127-33.

Patanwala AE, Christich AC, Jasiak KD, Edwards CJ, Phan H, Snyder EM. Age-related differences in propofol dosing for procedural sedation in the Emergency Department. J Emerg Med. 2013 Apr;44(4):823-8.

Platts-Mills TF, Esserman DA, Brown DL, Bortsov AV, Sloane PD, McLean SA. Older US emergency department patients are less likely to receive pain medication than younger patients: results from a national survey. Ann Emerg Med. 2012 Aug;60(2):199-206.

Platts-Mills TF, Richmond NL, Hunold KM, Bowling CB. Life-threatening hyperkalemia after 2 days of ibuprofen. Am J Emerg Med. 2013 Feb;31(2):465.e1-2.

Ro Y, Eun CS, Kim HS, Kim JY, Byun YJ, Yoo KS, Han DS. Risk of Clostridium difficile Infection with the Use of a Proton Pump Inhibitor for Stress Ulcer Prophylaxis in Critically Ill Patients. Gut Liver. 2016 Jul 15;10(4):581-6.

Rolita L, Spegman A, Tang X, Cronstein BN. Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults. J Am Geriatr Soc. 2013 Mar;61(3):335-40.

Ross A, Catanzariti AR, Mendicino RW. The hematoma block: a simple, effective  technique for closed reduction of ankle fracture dislocations. J Foot Ankle Surg. 2011 Jul-Aug;50(4):507-9.

Sasamura T, Nakamura S, Iida Y, Fujii H, Murata J, Saiki I, Nojima H, Kuraishi Y. Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation. Eur J Pharmacol. 2002 Apr 26;441(3):185-91.

Serrano Falcón B, Barceló López M, Mateos Muñoz B, Álvarez Sánchez A, Rey E. Fecal impaction: a systematic review of its medical complications. BMC Geriatr. 2016 Jan 11;16:4.

Shah AA, Zogg CK, Zafar SN, Schneider EB, Cooper LA, Chapital AB, Peterson SM, Havens JM, Thorpe RJ Jr, Roter DL, Castillo RC, Salim A, Haider AH. Analgesic Access for Acute Abdominal Pain in the Emergency Department Among Racial/Ethnic Minority Patients: A Nationwide Examination. Med Care. 2015 Dec;53(12):1000-9.

Stefánsson T, Wickström I, Haljamäe H. Hemodynamic and metabolic effects of ketamine anesthesia in the geriatric patient. Acta Anaesthesiol Scand. 1982 Aug;26(4):371-7.

Swedko PJ, Clark HD, Paramsothy K, Akbari A. Serum creatinine is an inadequate screening test for renal failure in elderly patients. Arch Intern Med.2003 Feb 10;163(3):356-60.

Terrell KM, Hui SL, Castelluccio P, Kroenke K, McGrath RB, Miller DK. Analgesic prescribing for patients who are discharged from an emergency department. Pain Med. 2010 Jul;11(7):1072-7.

The American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11): 2227-2246.

Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006 Jul 5;296(1):87-93.

Weaver CS, Terrell KM, Bassett R, Swiler W, Sandford B, Avery S, Perkins AJ. ED procedural sedation of elderly patients: is it safe? Am J Emerg Med. 2011 Jun;29(5):541-4.

Wickström I, Holmberg I, Stefánsson T. Survival of female geriatric patients after hip fracture surgery. A comparison of 5 anesthetic methods. Acta Anaesthesiol Scand. 1982 Dec;26(6):607-14.

Wilber ST, Gerson LW. A research agenda for geriatric emergency medicine. Acad Emerg Med. 2003 Mar;10(3):251-60.

Willman EV, Andolfatto G. A prospective evaluation of “ketofol”(ketamine/propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2007 Jan;49(1):23-30.

Yang JC, Tomlinson G, Naglie G. Medication lists for elderly patients: clinic-derived versus in-home inspection and interview. J Gen Intern Med. 2001 Feb;16(2):112-5.

Yano H, Iishi H, Tatsuta M, Sakai N, Narahara H, Omori M. Oxygen desaturation during sedation for colonoscopy in elderly patients. Hepatogastroenterology. 1998 Nov-Dec;45(24):2138-41.

Zeeh J, Platt D. The aging liver: structural and functional changes and their consequences for drug treatment in old age. Gerontology. 2002 May-Jun;48(3):121-7.

Procedural Sedation in Adults

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.

 

Acknowledgement

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

 

References

AAAAI. Soy-allergic and egg-allergic patients can safely receive propofol anesthesia. https://www.aaaai.org/conditions-and-treatments/library/allergy-library/soy-egg-anesthesia. Accessed October 8, 2016.

Afshan G. Are We, Anesthesiologists, Aware About the Incidence of Muscle Stiffness Associated With Remifentanil? Anesth Pain. 2012;1(3):218.

Andolfatto G, Abu-Laban RB, Zed PJ, Staniforth SM, Stackhouse S, Moadebi S, Willman E. Ketamine-propofol combination (ketofol) versus propofol alone for emergency department procedural sedation and analgesia: a randomized double-blind trial. Ann Emerg Med. 2012 Jun;59(6):504-12.e1-2.

Bailey PL, Pace NL, Ashburn MA, et al. Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology. 1990;73:826-830.

Bellolio MF, Gilani WI, Barrionuevo P, Murad MH, Erwin PJ, Anderson JR, Miner JR, Hess EP. Incidence of Adverse Events in Adults Undergoing Procedural Sedation in the Emergency Department: A Systematic Review and Meta-analysis. Acad Emerg Med. 2016 Feb;23(2):119-34.

Cheong SH, Lee KM, Lim SH, Cho KR, Kim MH, Ko MJ, Shim JC, Oh MK, Kim YH, Lee SE. Brief report: the effect of suggestion on unpleasant dreams induced by ketamine administration. Anesth Analg. 2011 May;112(5):1082-5.

Chudnofsky CR, Weber JE, Stoyanoff PJ, Colone PD, Wilkerson MD, Hallinen DL, Jaggi FM, Boczar ME, Perry MA. A combination of midazolam and ketamine for procedural sedation and analgesia in adult emergency department patients. Acad Emerg Med. 2000 Mar;7(3):228-35.

CMS Revisions to Recently Updated Interpretive Guidelines for Anesthesia Services; January 14, 2011. https://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/SurveyCertificationGenInfo/downloads/scletter11_10.pdf. Accessed October 8, 2016

Dunn MJ, Mitchell R, Souza CD, Drummond G. Evaluation of propofol and remifentanil for intravenous sedation for reducing shoulder dislocations in the emergency department. Emerg Med J. 2006 Jan;23(1):57-8.

Elliott P, O’Hare R, Bill KM, Phillips AS, Gibson FM, Mirakhur RK. Severe cardiovascular depression with remifentanil. Anesth Analg. 2000 Jul;91(1):58-61.

Euasobhon P, Dej-Arkom S, Siriussawakul A, Muangman S, Sriraj W, Pattanittum P, Lumbiganon P. Lidocaine for reducing propofol-induced pain on induction of anaesthesia in adults. Cochrane Database Syst Rev. 2016 Feb 18;2:CD007874.

European Society of Anaesthesiology task force on use of nitrous oxide in clinical anaesthetic practice. The current place of nitrous oxide in clinical practice: An expert opinion-based task force consensus statement of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2015 Aug;32(8):517-20.

Falk J, Zed PJ. Etomidate for procedural sedation in the emergency department. Ann Pharmacother. 2004 Jul-Aug;38(7-8):1272-7.

Ferguson I, Bell A, Treston G, New L, Ding M, Holdgate A. Propofol or Ketofol for Procedural Sedation and Analgesia in Emergency Medicine-The POKER Study: A Randomized Double-Blind Clinical Trial. Ann Emerg Med. 2016 Jul 22.

Gharavifard M, Tafakori A, Zamani Moghadam H. Remifentanil versus Fentanyl/Midazolam in Painless Reduction of Anterior Shoulder Dislocation; a Randomized Clinical Trial. Emerg (Tehran). 2016 Spring;4(2):92-6.

Godwin SA, Burton JH, Gerardo CJ, Hatten BW, Mace SE, Silvers SM, Fesmire FM; American College of Emergency Physicians. Clinical policy: procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2014 Feb;63(2):247-58.e18.

Green SM, Andolfatto G, Krauss BS. Ketofol for procedural sedation revisited: pro and con. Ann Emerg Med. 2015 May;65(5):489-91.

Green SM, Roback MG, Kennedy RM, Krauss B. Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. Ann Emerg Med. 2011 May;57(5):449-61.

Krauss B, Hess DR. Capnography for procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2007 Aug;50(2):172-81. Epub 2007 Jan 12.

Larson CP Jr. Laryngospasm–the best treatment. Anesthesiology. 1998 Nov;89(5):1293-4.

Miner JR, Gray RO, Stephens D, Biros MH. Randomized clinical trial of propofol with and without alfentanil for deep procedural sedation in the emergency department. Acad Emerg Med. 2009 Sep;16(9):825-34.

Miner JR, Moore JC, Austad EJ, Plummer D, Hubbard L, Gray RO. Randomized, double-blinded, clinical trial of propofol, 1:1 propofol/ketamine, and 4:1 propofol/ketamine for deep procedural sedation in the emergency department. Ann Emerg Med. 2015 May;65(5):479-488.e2.

Miner JR, Moore JC, Plummer D, Gray RO, Patel S, Ho JD. Randomized clinical trial of the effect of supplemental opioids in procedural sedation with propofol on serum catecholamines. Acad Emerg Med. 2013 Apr;20(4):330-7.

Mohr NM, Wessman B. Continuous capnography should be used for every emergency department procedural sedation. Ann Emerg Med. 2013 Jun;61(6):697-8.

Patanwala AE, Christich AC, Jasiak KD, Edwards CJ, Phan H, Snyder EM. Age-related differences in propofol dosing for procedural sedation in the Emergency Department. J Emerg Med. 2013 Apr;44(4):823-8.

Pediatric Sedation Blog. “Egg Anaphylaxis and Propofol.” Society for Pediatric Sedation, 15 June 2010. Web. 02 Jan. 2017. <http://blog.pedsedation.org/?p=136>.

Phillips WJ, Halpin J, Jones J, McKenzie K. Remifentanil for procedural sedation in the emergency department. Ann Emerg Med. 2009 Jan;53(1):163.

Porhomayon J, El-Solh AA, Pourafkari L, Jaoude P, Nader ND. Applications of Nasal High-Flow Oxygen Therapy in Critically ill Adult Patients. Lung. 2016 Oct;194(5):705-14.

Poulton DA, Schmölzer GM, Morley CJ, Davis PG. Assessment of chest rise during mask ventilation of preterm infants in the delivery room. Resuscitation. 2011 Feb;82(2):175-9.

Remick J, Sacchetti A, Bages G, Delagol K. Noninvasive positive pressure ventilation in procedural sedation. Am J Emerg Med. 2010 Jul;28(6):750.e1-3.

Sacchetti A, Jachowski J, Heisler J, Cortese T. Remifentanil use in emergency department patients: initial experience. Emerg Med J. 2012 Nov;29(11):928-9.

Sacchetti A, Senula G, Strickland J, Dubin R. Procedural sedation in the community emergency department: initial results of the ProSCED registry. Acad Emerg Med. 2007 Jan;14(1):41-6.

Sener S, Eken C, Schultz CH, Serinken M, Ozsarac M. Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial. Ann Emerg Med. 2011 Feb;57(2):109-114.e2.

Smith I, Avramov MN, White PF. A comparison of propofol and remifentanil during monitored anesthesia care. J Clin Anesth. 1997 Mar;9(2):148-54.

Soto RG, Fu ES, Vila H Jr, Miguel RV. Capnography accurately detects apnea during monitored anesthesia care. Anesth Analg. 2004 Aug;99(2):379-82, table of contents.

Strayer RJ, Caputo ND. Noninvasive ventilation during procedural sedation in the ED: a case series. Am J Emerg Med. 2015 Jan;33(1):116-20.

Terp S, Schriger DL. Routine capnographic monitoring is not indicated for all patients undergoing emergency department procedural sedation. Ann Emerg Med. 2013 Jun;61(6):698-9.

Tobias JD. Dexmedetomidine and ketamine: an effective alternative for procedural sedation? Pediatr Crit Care Med. 2012 Jul;13(4):423-7.

Vinson DR, Bradbury DR. Etomidate for procedural sedation in emergency medicine. Ann Emerg Med. 2002 Jun;39(6):592-8.

Waugh JB, Epps CA, Khodneva YA. Capnography enhances surveillance of respiratory events during procedural sedation: a meta-analysis. J Clin Anesth. 2011 May;23(3):189-96.

Wiskin AE, Smith J, Wan SK, Nally MW, Shah N. Propofol anaesthesia is safe in children with food allergy undergoing endoscopy. Br J Anaesth. 2015 Jul;115(1):145-6.

Witting MD, Hsu S, Granja CA. The sensitivity of room-air pulse oximetry in the detection of hypercapnia. Am J Emerg Med. 2005 Jul;23(4):497-500.

Headache

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.

 

References

Akpunonu BE, Mutgi AB, Federman DJ, Volinsky FG, Brickman K, Davis RL, Gilbert C, Asgharnejad M. Subcutaneous sumatriptan for treatment of acute migraine in patients admitted to the emergency department: a multicenter study. Ann Emerg Med. 1995 Apr;25(4):464-9.

Balbin JE, Nerenberg R, Baratloo A, Friedman BW. Intravenous fluids for migraine: a post hoc analysis of clinical trial data. Am J Emerg Med. 2016 Apr;34(4):713-6.

Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia. 2002 Jun;22(5):345-53.

Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache. 2008 Sep;48(8):1157-68.

Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Ann Neurol. 2004 Jan;55(1):19-26.

Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000 Aug;123 ( Pt 8):1703-9.

Caviness VS Jr, O’Brien P. Cluster headache: response to chlorpromazine. Headache. 1980 May;20(3):128-31.

Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a randomized trial. JAMA. 2009 Dec 9;302(22):2451-7.

Colman I, Friedman BW, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral dexamethasone for acute severe migraine headache: meta-analysis of randomised controlled trials for preventing recurrence. BMJ. 2008 Jun 14;336(7657):1359-61.

Colman I, Rothney A, Wright SC, Zilkalns B, Rowe BH. Use of narcotic analgesics in the emergency department treatment of migraine headache. Neurology. 2004 May 25;62(10):1695-700.

Edlow JA, Panagos PD, Godwin SA, Thomas TL, Decker WW; American College of Emergency Physicians.. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. Ann Emerg Med. 2008 Oct;52(4):407-36.

Friedman BW, Bender B, Davitt M, Solorzano C, Paternoster J, Esses D, Bijur P, Gallagher EJ. A randomized trial of diphenhydramine as prophylaxis against metoclopramide-induced akathisia in nauseated emergency department patients. Ann Emerg Med. 2009 Mar;53(3):379-85.

Friedman BW, Cabral L, Adewunmi V, Solorzano C, Esses D, Bijur PE, Gallagher EJ. Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department-Based Randomized Clinical Trial. Ann Emerg Med. 2016 Jan;67(1):32-39.e3.

Friedman BW, Corbo J, Lipton RB, Bijur PE, Esses D, Solorzano C, Gallagher EJ. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. Neurology. 2005 Feb 8;64(3):463-8.

Friedman BW, Garber L, Yoon A, Solorzano C, Wollowitz A, Esses D, Bijur PE, Gallagher EJ. Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine. Neurology. 2014 Mar 18;82(11):976-83.

Friedman BW, Greenwald P, Bania TC, Esses D, Hochberg M, Solorzano C, Corbo J, Chu J, Chew E, Cheung P, Fearon S, Paternoster J, Baccellieri A, Clark S, Bijur PE, Lipton RB, Gallagher EJ. Randomized trial of IV dexamethasone for acute migraine in the emergency department. Neurology. 2007 Nov
27;69(22):2038-44.

Friedman BW, Hochberg ML, Esses D, Grosberg B, Corbo J, Toosi B, Meyer RH, Bijur PE, Lipton RB, Gallagher EJ. Applying the International Classification of Headache Disorders to the emergency department: an assessment of reproducibility and the frequency with which a unique diagnosis can be assigned to every acute headache presentation. Ann Emerg Med. 2007 Apr;49(4):409-19, 419.e1-9.

Friedman BW, Hochberg ML, Esses D, Grosberg BM, Rothberg D, Bernstein B, Bijur PE, Lipton RB, Gallagher EJ. Recurrence of primary headache disorders after emergency department discharge: frequency and predictors of poor pain and functional outcomes. Ann Emerg Med. 2008 Dec;52(6):696-704.

Friedman BW, Kapoor A, Friedman MS, Hochberg ML, Rowe BH. The relative efficacy of meperidine for the treatment of acute migraine: a meta-analysis of randomized controlled trials. Ann Emerg Med. 2008 Dec;52(6):705-13.

Friedman BW, Mistry B, West JR, Wollowitz A. The association between headache and elevated blood pressure among patients presenting to an ED. Am J Emerg Med. 2014 Sep;32(9):976-81.

Friedman BW, West J, Vinson DR, Minen MT, Restivo A, Gallagher EJ. Current management of migraine in US emergency departments: an analysis of the National Hospital Ambulatory Medical Care Survey. Cephalalgia. 2015 Apr;35(4):301-9.

Friedman BW. Managing Migraine. Ann Emerg Med. 2016 Aug 7. Pii: S0196-0644(16)30301-8. doi: 10.1016/j.annemergmed.2016.06.023. [Epub ahead of print]

Gantenbein AR, Lutz NJ, Riederer F, Sándor PS. Efficacy and safety of 121 injections of the greater occipital nerve in episodic and chronic cluster headache. Cephalalgia. 2012 Jun;32(8):630-4.

Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;33(9):629-808.

Headache Classification Committee of the International Headache Society (IHS).. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013 Jul;33(9):629-808.

Kapicioğlu S, Gökce E, Kapicioğlu Z, Ovali E. Treatment of migraine attackswith a long-acting somatostatin analogue (octreotide, SMS 201-995). Cephalalgia. 1997 Feb;17(1):27-30.

Kelly AM, Walcynski T, Gunn B. The relative efficacy of phenothiazines for the treatment of acute migraine: a meta-analysis. Headache. 2009 Oct;49(9):1324-32.

Kristoffersen ES, Lundqvist C. Medication-overuse headache: epidemiology, diagnosis and treatment. Ther Adv Drug Saf. 2014 Apr;5(2):87-99.

Law S, Derry S, Moore RA. Triptans for acute cluster headache. Cochrane Database Syst Rev. 2013 Jul 17;(7):CD008042.

Leone M, D’Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, Bussone G. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology. 2000 Mar 28;54(6):1382-5.

Loder E. Triptan therapy in migraine. N Engl J Med. 2010 Jul 1;363(1):63-70.

Miner JR, Fish SJ, Smith SW, Biros MH. Droperidol vs. prochlorperazine for benign headaches in the emergency department. Acad Emerg Med. 2001 Sep;8(9):873-9.

Natoli JL, Manack A, Dean B, Butler Q, Turkel CC, Stovner L, Lipton RB. Global prevalence of chronic migraine: a systematic review. Cephalalgia. 2010 May;30(5):599-609.

Nicolodi M, Sicuteri F. Exploration of NMDA receptors in migraine: therapeutic and theoretic implications. Int J Clin Pharmacol Res. 1995;15(5-6):181-9.

Oldman AD, Smith LA, McQuay HJ, Moore RA. Pharmacological treatments for acute migraine: quantitative systematic review. Pain. 2002 Jun;97(3):247-57.

Orr SL, Aubé M, Becker WJ, Davenport WJ, Dilli E, Dodick D, Giammarco R, Gladstone J, Leroux E, Pim H, Dickinson G, Christie SN. Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings. Cephalalgia. 2015 Mar;35(3):271-84.

POZEN 2005. “The Efficacy And Safety Of MT100 (Metoclopramide/Naproxen Sodium) In The Acute Treatment Of Migraine”. Webcache.googleusercontent.com. N.p., 2016. Web. 6 Dec. 2016.

Pringsheim T, Davenport W, Mackie G, Worthington I, Aubé M, Christie SN, Gladstone J, Becker WJ; Canadian Headache Society Prophylactic Guidelines Development Group.. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci. 2012 Mar;39(2 Suppl 2):S1-59.

Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986 Jul;36(7):995-7.

Regan LA, Hoffman RS, Nelson LS. Slower infusion of metoclopramide decreases the rate of akathisia. Am J Emerg Med. 2009 May;27(4):475-80.

Rozen TD. Olanzapine as an abortive agent for cluster headache. Headache. 2001 Sep;41(8):813-6.

Soleimanpour H, Taheraghdam A, Ghafouri RR, Taghizadieh A, Marjany K, Soleimanpour M. Improvement of refractory migraine headache by propofol: case series. Int J Emerg Med. 2012 May 15;5(1):19.

Sumamo Schellenberg E, Dryden DM, Pasichnyk D, Ha C, Vandermeer B, Friedman BW, Colman I, Rowe BH. Acute Migraine Treatment in Emergency Settings [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Nov. Available from http://www.ncbi.nlm.nih.gov/books/NBK115368/

Taggart E, Doran S, Kokotillo A, Campbell S, Villa-Roel C, Rowe BH. Ketorolac in the treatment of acute migraine: a systematic review. Headache. 2013 Feb;53(2):277-87.

Tfelt-Hansen P, Henry P, Mulder LJ, Scheldewaert RG, Schoenen J, Chazot G. The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet. 1995 Oct 7;346(8980):923-6.

The Oral Sumatriptan and Aspirin plus Metoclopramide Comparative Study Group. A study to compare oral sumatriptan with oral aspirin plus oral metoclopramide in the acute treatment of migraine. Eur Neurol. 1992;32(3):177-84.

Vinson DR, Migala AF, Quesenberry CP Jr. Slow infusion for the prevention of akathisia induced by prochlorperazine: a randomized controlled trial. J Emerg Med. 2001 Feb;20(2):113-9.

Vinson DR. Diphenhydramine in the treatment of akathisia induced by prochlorperazine. J Emerg Med. 2004 Apr;26(3):265-70.

Weaver CS, Jones JB, Chisholm CD, Foley MJ, Giles BK, Somerville GG, Brizendine EJ, Cordell WH. Droperidol vs prochlorperazine for the treatment of acute headache. J Emerg Med. 2004 Feb;26(2):145-50.

Weinman D, Nicastro O, Akala O, Friedman BW. Parenteral treatment of episodic tension-type headache: a systematic review. Headache. 2014 Feb;54(2):260-8.