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
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.
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.
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
Volume of Distribution: 2.6 L/kg
Metabolism: Hepatic metabolism via CYP3A4 and CYP2D6 to hydromorphone
Elimination T1/2: Adults 4 hr
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
- NYC DOHMH ED Opioid Guidelines
- CDC Guideline for Opioid Prescribing for Chronic Pain
Adverse Effects and Management
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.
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 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.
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.
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 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)
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).
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 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.
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.
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.
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.
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)
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.
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 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.
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.