INTRODUCTION — Opiates, extracted from the poppy plant (Papaver somniferum), have been used recreationally and medicinally for millennia. Opiates belong to the larger class of drugs, opioids, which also include synthetic and semi-synthetic drugs. Abrupt cessation or reversal of opioids produce a withdrawal syndrome. Symptoms of withdrawal can be severe in some cases, and iatrogenic withdrawal (from a reversal agent such as naloxone or naltrexone) can produce sudden surges in catecholamines and hemodynamic instability that are occasionally life threatening.
This topic review will discuss the clinical features and management of opioid withdrawal in the emergency setting. A summary table to facilitate emergency management of withdrawal is provided (table 1). Discussions of opioid withdrawal during detoxification treatment, opioid intoxication, opioid withdrawal in neonates, and general management of the poisoned patient are found separately.
PHARMACOLOGY AND CELLULAR TOXICOLOGY — Repeated, regular use of opioids produces tolerance that predisposes an individual to withdrawal. Chronic opioid exposure causes adaptations that increase excitability in neurons in the locus ceruleus, the major noradrenergic center in the brain. The presence of opioids brings these neurons toward their normal firing rates .
KINETICS — The vast number of opioids precludes presenting pharmacokinetic data for each, although a few clinically important generalizations can be made. The majority of opioids have volumes of distribution of 1 to 10 L/kg, which makes removal of a significant quantity of drug by hemodialysis impossible. They have variable protein binding (from 89 percent for methadone to 7.1 percent for hydrocodone) and are renally eliminated. Many opioids are metabolized to active metabolites. Examples include hydrocodone (metabolized to hydromorphone) and codeine (metabolized to morphine), both by cytochrome 2D6. Cytochrome P polymorphisms cause variations in the clinical effects of many opioids. Morphine is also metabolized to an active metabolite (morphine-6-glucuronide), but not by cytochromes.
The most clinically important pharmacokinetic difference is a wide variation in serum half-life (table 2). The half-life data in these tables, taken from healthy subjects receiving therapeutic doses, should only serve as a rough guide to duration of clinical effect. Actual effects are influenced by dose, an individual's tolerance, and the presence of active metabolites.
EPIDEMIOLOGY — The Drug Abuse Warning Network in the United States estimated that there were 162,137 heroin-related emergency department (ED) visits and 37,007 unspecified opiate-related ED visits in 2004 . In addition to opioid overdose, a significant number of these visits were related to opioid withdrawal. The United States Centers for Disease Control and Prevention report that opioids were involved in 47,600 overdose deaths in 2017, about two-thirds of all drug overdose deaths . Problems related to opioid misuse and opioid use disorder have had a major impact on EDs. In 2014, there were approximately 20 opioid-related ED visits for each overdose death . More recent data reporting that 5.5 percent of patients who survive an opioid overdose die within one year emphasize the need for comprehensive longitudinal treatment options for these patients .
CLINICAL FEATURES OF OPIOID WITHDRAWAL — It is often (erroneously) asserted that opioid withdrawal is never life-threatening. While this conventional wisdom is usually true for "naturally occurring" withdrawal, iatrogenic withdrawal (from a reversal agent such as naloxone, naltrexone, or nalmefene as in the setting of ultrarapid opioid detoxification [UROD]) can produce sudden surges in catecholamines and hemodynamic instability that some patients may not tolerate.
History — In individuals with opioid dependance, opioid withdrawal begins almost immediately after receiving an antagonist and over a few hours after cessation of use. Partial agonists (eg, buprenorphine) and agonist-antagonists (eg, pentazocine) can also rapidly produce withdrawal, so for the purpose of this review, the term "antagonist" will be discussed in relation to these drugs as well.
Signs and symptoms of withdrawal begin as early as 4 to 12 hours after the last dose of a short-acting opioid and are often delayed 24 to 48 hours after cessation of a longer-acting opioid such as methadone. Withdrawal symptoms typically peak within 24 to 48 hours of onset and persist for several days with short-acting agents and up to two weeks with methadone.
Patients experiencing opioid withdrawal typically complain of the following:
●Craving for an opioid
●Dysphoria and restlessness
●Rhinorrhea and lacrimation
●Myalgias and arthralgias
●Nausea, vomiting, abdominal cramping, and diarrhea
Some or all of these symptoms may be present, and the severity depends on the individual's tolerance to opioids, the continued presence of opioid in the serum and end organs, and the duration of time over which the withdrawal has occurred. As an example, a person who is tolerant to 200 mg/day of methadone who was administered 2 mg of naloxone intravenously (IV) would experience much more severe symptoms than someone taking 10 mg of methadone daily who stopped abruptly one day earlier (ie, "cold turkey"). A thorough history should ascertain why the patient discontinued opioid use to ensure there is not another underlying medical condition that precluded them from obtaining the drug. In some patients, opioid metabolism is accelerated as a result of an interaction from a recently started medicine, and the patient experiences withdrawal despite continued use of their opioid.
The use of a validated scale, such as the Clinical Opioid Withdrawal Scale (COWS) (table 3) (calculator 1), facilitates diagnosis and evaluation of therapeutic response in patients in opioid withdrawal [6,7]. It also provides a clear context for medical documentation and decision-making.
Physical examination — Opioid withdrawal is characterized by the following signs:
●Mydriasis (pupillary dilation)
●Increased bowel sounds
●Piloerection (table 4)
Of these signs, interrater reliability was >0.75 for piloerection (0.94), yawning (0.93), mydriasis (0.9), perspiration (0.88), and rhinorrhea (0.87) .
If the patient is in severe distress, heart rate, blood pressure, and respiratory rate may be increased. Hypotension may be present in the setting of volume depletion from vomiting and diarrhea. Temperature is normal and, with the exception of very severe cases, mental status is preserved. The COWS (table 3) (calculator 1) or a similar instrument should be used to help determine the presence of symptoms and signs consistent with opioid withdrawal and the severity of withdrawal.
DIFFERENTIAL DIAGNOSIS — Opioid withdrawal may appear similar to other withdrawal or intoxication syndromes. Most patients in opioid withdrawal have good insight into their problem, so the diagnosis is usually established by history alone. When present, the findings of yawning, lacrimation, and piloerection are helpful because of their specificity.
Ethanol, sedative-hypnotic, and opioid withdrawal can all present with a broad spectrum of severity and vital sign abnormalities, but the first two syndromes are much more likely to cause significant hypertension and tachycardia. Many patients in opioid withdrawal have a pulse and blood pressure within normal limits. Although some patients in opioid withdrawal have a tachycardia that reflects their agitation, discomfort, or hypovolemia, only a small minority of patients manifest both hypertension and tachycardia. When present, these signs are almost always a result of a surge in catecholamines from iatrogenically-induced withdrawal. Conversely, in ethanol and sedative-hypnotic withdrawal, normal vital signs are the exception rather than the rule. Unlike opioid withdrawal in adults, ethanol and sedative-hypnotic withdrawal may produce seizures or hyperthermia. (See "Management of moderate and severe alcohol withdrawal syndromes" and "Alcohol withdrawal: Epidemiology, clinical manifestations, course, assessment, and diagnosis".)
Sympathomimetic toxicity produces mydriasis, agitation, diaphoresis, tachycardia, and hypertension, but these findings are usually much more severe than those that occur in opioid withdrawal.
Cholinergic (muscarinic) toxicity, which can cause diarrhea and vomiting, can be distinguished from opioid withdrawal syndrome by salivation, bradycardia, and altered level of consciousness. Also, when induced by organic phosphorus pesticides, nicotinic signs such as neuromuscular weakness or paralysis are expected in severe cases. (See "Organophosphate and carbamate poisoning".)
LABORATORY EVALUATION — Most patients with opioid intoxication and withdrawal can be managed without laboratory studies. If the patient presents with a history of significant vomiting or diarrhea, it is prudent to obtain a basic metabolic profile to help assess fluid and electrolyte abnormalities.
MANAGEMENT — Below, we discuss the management of acute opioid withdrawal in adults being cared for in the emergency setting. The general management of patients with opioid use disorder and opioid withdrawal are reviewed separately.
Withdrawal from interruption in opioid use
Opioid agonist therapy — A summary table to facilitate emergency management is provided (table 1). If withdrawal was produced by an interruption in opioid use, symptoms can be managed with either opioids or with non-opioid adjuncts (table 5). Whenever possible, we prefer to use a single class of agents for treatment. Methadone and buprenorphine (with or without naloxone) are good choices for opioid replacement therapy. Most experts agree that buprenorphine is the preferred choice for most patients. However, patients who have previously used methadone and those with a very high dependency tend to do better with methadone than with buprenorphine.
Buprenorphine — Four to eight mg of sublingual buprenorphine can be administered for acute opioid withdrawal . If symptoms persist 30 to 60 minutes later, a second dose is recommended . Subsequent doses should be given until there is a subjective improvement of symptoms or, if preferred, until a COWS score of <8 is achieved (table 3). Total daily doses should not exceed 24 mg. (See "Opioid use disorder: Pharmacologic management", section on 'Buprenorphine: Opioid agonist'.)
Alternatively, 0.3 to 0.9 mg of intravenous (IV; given over 20 to 30 minutes) or intramuscular buprenorphine are reasonable first doses in patients with severe gastrointestinal distress. If any dose of buprenorphine precipitates opioid withdrawal, more buprenorphine (up to 16 mg by sublingual route) is recommended [11,12].
Like methadone, buprenorphine is used as substitution therapy to treat opioid dependence. It can be given daily or several times per week to patients as part of maintenance therapy. Buprenorphine is formulated alone for IV, transdermal, sublingual, and oral administration; and as an oral formulation combined with naloxone to discourage crushing and IV administration.
Buprenorphine is a partial agonist and therefore a theoretical ceiling exists for its potential to cause respiratory depression . This feature, combined with its long duration of action and high affinity for opioid receptors , is advantageous in the long-term management of opioid dependence. In addition, the initiation of buprenorphine treatment in the emergency department (ED) may increase the chance for future engagement with addiction treatment .
The complex pharmacology of buprenorphine creates problems that do not exist with methadone. First, as a partial agonist, buprenorphine will produce withdrawal in an opioid-intoxicated patient. This precipitated withdrawal may be overcome with more buprenorphine [11,12]. Second, the drug has a high affinity for opioid receptors, which may require a large dose of naloxone to overcome . However, respiratory depression is distinctly uncommon with buprenorphine, there are less significant drug interactions, and it does not alter the QT interval like methadone.
Methadone — In patients with opioid withdrawal, 20 mg of orally administered methadone or 10 mg of intramuscular methadone are usually sufficient to relieve withdrawal symptoms without producing opioid toxicity . We recommend the intramuscular route as the nauseated withdrawing patient may vomit after an oral dose. Decades of clinical experience have validated the use of methadone in the management of opioid withdrawal. The long duration of action of methadone protects against severe withdrawal symptoms for about one day. (See "Opioid use disorder: Pharmacologic management", section on 'Methadone: Opioid agonist'.)
We recommend against routine administration of a full daily methadone maintenance dose to an unfamiliar patient who has missed a single dose from their clinic. Some patients intentionally take reduced doses to save a portion so their prescribed dose may be sold or misused.
Withdrawal due to opioid antagonist and other circumstances not amenable to treatment with opioid agonist
Non-opioid adjunctive medications — A summary table to facilitate emergency management is provided (table 1).
While opioids are intuitively the ideal agents to treat opioid withdrawal, there are situations when their use is undesirable. As an example, when withdrawal is triggered by a full antagonist (such as naloxone, nalmefene, or naltrexone), it may be difficult to give enough opioid to overcome the antagonist, and rebound opioid intoxication could ensue following treatment with short-acting antagonists (naloxone and nalmefene). Another example would be an individual experiencing withdrawal after intentionally stopping use of opioids to treat an addiction. In such situations, non-opioid adjuncts are useful for managing symptoms.
In patients with normal or elevated blood pressure, an alpha-2 adrenergic agonist may be administered. Clonidine binds to a central alpha-2 adrenergic receptor that shares potassium channels with opioids and blunts symptoms of withdrawal . Lofexidine presumably exhibits the same mechanism of action. It is important to monitor heart rate and blood pressure while administering alpha-2 adrenergic agonists, and blood pressure should be taken prior to each dose of medication. If hypotension is present, then alpha-2 adrenergic agonist medication should not be used.
Clonidine may be administered orally, in a dose of 0.1 to 0.3 mg every hour until symptoms resolve [18-20]. Typically, the daily dose of clonidine does not exceed 0.8 mg, but the optimal maximum daily dose of clonidine in this setting is unknown. Some experts recommend no more than 1.2 mg per day.
Lofexidine dosing for acute withdrawal has not been established. However, based on the pharmacokinetics of the drug and dosing recommendations for medically supervised detoxification, an initial dose of 0.2 to 0.4 mg is reasonable. This may be followed by a repeat dose in four hours if needed to a maximum of 0.8 mg/day.
Although significant hypertension and tachycardia precipitated by a short-acting antagonist are expected to resolve after brief observation, hemodynamic instability induced by a long-acting drug (eg, naltrexone) requires pharmacologic management. The clinician should use clinical judgment to determine which patients require more intensive management. As an example, a young patient may tolerate a heart rate of 120, whereas an older patient with coronary artery disease should not be allowed to remain hypertensive and tachycardic for any prolonged period.
Benzodiazepines are a good supplement to clonidine therapy because they have an excellent safety profile and clinicians are familiar with their dosing and administration. While not studied well in humans, other gamma-aminobutyric acid (GABA)-ergic drugs reduce catecholamine release during severe withdrawal, and the benzodiazepines themselves have been shown to improve withdrawal in animal models [21,22]. In addition to clonidine, we typically use diazepam, in 10- to 20-mg IV aliquots, given every 5 to 10 minutes until adequate sedation and hemodynamic stability are achieved. Alternative benzodiazepines include lorazepam 1 to 2 mg IV every 10 minutes, or less frequently midazolam 2 mg IV every 5 to 10 minutes. Benzodiazepines may also be helpful in suppressing muscle cramping.
Treatment of symptoms — Other symptoms associated with acute opioid withdrawal can be addressed specifically. Suitable medications are summarized in the accompanying table (table 5). Antiemetics can be given as needed to control nausea and vomiting. Promethazine, 25 mg intramuscularly or IV, may be a good choice because of its anticholinergic properties. Loperamide, 4 mg orally, or octreotide, 50 mcg subcutaneously, may help with diarrhea.
Risk of QT interval prolongation — It is important to recognize the risk of QT interval prolongation when multiple medications (methadone, ondansetron, loperamide, etc) that prolong the QT interval are given sequentially to patients who might also have electrolyte abnormalities that resulted from vomiting and/or diarrhea. A baseline electrocardiogram and close cardiac monitoring with special attention paid to the QT interval are recommended in patients at risk for QT interval prolongation. Drugs that can prolong the QT interval are included in the following table (table 6).
Ultrarapid opioid detoxification — Ultrarapid opioid detoxification (UROD) has been promoted as a faster, more comfortable means of stopping opioid use. The procedure is controversial because it exposes people to the risks of general anesthesia, as well as seizures and hemodynamic instability, without a clear benefit. For these reasons, we recommend against its use. (See "Opioid withdrawal: Medically supervised withdrawal during treatment for opioid use disorder".)
In this practice, opioid antagonists are administered under general anesthesia or heavy sedation with the intent of producing withdrawal. In theory, after emerging from anesthesia, the patient has already "slept" through the most difficult period of withdrawal symptoms. "Induction" may be a better term than detoxification as the intent of the procedure is not an immediate cure of opioid dependence, but rather a rapid transition to naltrexone maintenance therapy . Immediately after the procedure, the patient will still experience withdrawal symptoms, and anxiety and depression may last for weeks to months. Often, patients are prescribed agents such as baclofen, octreotide, clonidine, and antiemetics to help control withdrawal symptoms at home.
Generally, a patient presenting with symptoms of withdrawal following UROD can be treated like any other patient in withdrawal. Because these individuals are usually given naltrexone, it may be difficult to treat them with opioid agonists.
NEONATAL AND PEDIATRIC CONSIDERATIONS
Neonatal withdrawal — Neonatal abstinence syndrome (NAS) is the term used to describe neonatal withdrawal from substances they were exposed to in utero. Symptoms of NAS include autonomic (sweating, low-grade fever), neurologic (irritability, high-pitched cry, decreased sleeping, myoclonus, tremors, hyperreflexia, yawning, seizures), and gastrointestinal (vomiting, diarrhea, poor feeding) features. NAS typically begins within 48 to 72 hours of birth. Pharmacologic treatment of NAS should be conducted in close consultation with an experienced neonatologist. Possibly more important than the choice of agent is the consistent use of an effective clinical scoring tool to guide treatment. A detailed discussion of NAS is found elsewhere. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)
Children receiving intensive care — Critically ill children are often given continuous infusion of opioids to treat pain and can develop tolerance after prolonged therapy. Patients who receive continuous opioid infusions for longer than five days warrant careful weaning of opioids under the direction of a pediatric pain specialist (eg, pediatric critical care specialist or pediatric anesthesiologist) guided by the duration and dose of opioid analgesic therapy [24,25]. Whenever weaning is anticipated to require more than five to seven days, conversion of continuous opioid infusions to oral methadone is usually performed. During the transition, the clinician must ensure equianalgesic dosing. Subsequently, the oral dose is tapered to avoid withdrawal. Evidence regarding the best regimen (degree of daily dose reduction and duration of oral weaning for methadone) is limited. Examples of methadone regimens are provided in the references [24,25].
Adolescents — As with younger children, critically ill adolescents may receive opioids for analgesia. Adolescents who receive opioid therapy in the hospital and are at risk for developing tolerance are managed in a manner comparable to that described immediately above for children. However, opioid misuse and opioid use disorder are also serious problems among adolescents. The management of adolescents withdrawing from opioids is discussed separately. (See "Opioid withdrawal in adolescents".)
Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)
Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment of acute poisoning caused by recreational drug or alcohol use" and "Society guideline links: Poisoning prevention".)
SUMMARY AND RECOMMENDATIONS
●Emergency management table – A summary table to facilitate emergency management is provided (table 1).
●Possible dangers of withdrawal – Repeated, regular use of opioids produces tolerance that predisposes an individual toward withdrawal. It is often (erroneously) asserted that opioid withdrawal is never life threatening. While usually true for "naturally occurring" withdrawal (opioid user abruptly stops), iatrogenic withdrawal (caused by a reversal agent; eg, naloxone, nalmefene, or naltrexone) can produce sudden surges in catecholamines and hemodynamic instability that can endanger patients. (See 'Clinical features of opioid withdrawal' above.)
●Clinical presentation – Signs and symptoms of withdrawal may begin 4 to 12 hours after the last dose of a short-acting opioid and 24 to 48 hours after cessation of methadone. Withdrawal symptoms typically peak within 24 to 48 hours of onset but may persist for several days with short-acting agents and up to two weeks with methadone. (See 'History' above.)
Patients experiencing opioid withdrawal usually complain of the following:
•Craving for an opioid
•Dysphoria and restlessness
•Rhinorrhea and lacrimation
•Myalgias and arthralgias
•Nausea, vomiting, abdominal cramping, and diarrhea
Some or all of these symptoms may be present. Severity depends upon the individual's tolerance to opioids, the presence of opioid in the serum and end organs, and the period over which withdrawal developed. (See 'History' above.)
Opioid withdrawal is characterized by mydriasis, yawning, increased bowel sounds, and piloerection (table 4). If the patient is in severe distress, heart rate, blood pressure, and respiratory rate may be increased. Hypotension may be present in the setting of volume depletion from vomiting and diarrhea. Temperature is normal and, with the exception of severe cases, mental status is preserved. The use of a validated scale, such as the Clinical Opioid Withdrawal Scale (table 3) (calculator 1), facilitates diagnosis and evaluation of therapeutic response. (See 'Physical examination' above.)
●Differential diagnosis – Unlike opioid withdrawal, ethanol and sedative-hypnotic withdrawal may produce seizures and hyperthermia. Ethanol, sedative-hypnotic, and opioid withdrawal can all present with a broad spectrum of severity and vital sign abnormalities, but the first two syndromes are much more likely to cause significant hypertension and tachycardia. (See 'Differential diagnosis' above.)
●Treatment if withdrawal is caused by interruption in use – If withdrawal was produced by an interruption in opioid use, symptoms can be managed with either opioids or with non-opioid adjuncts (table 5). We suggest buprenorphine or methadone be used for treatment in this setting (Grade 2C). The starting dose of sublingual buprenorphine is 4 to 8 mg. If symptoms persist after 30 to 60 minutes, additional doses can be given (maximum total daily dose 24 mg). Twenty mg of orally administered methadone or 10 mg of intramuscular methadone are usually sufficient to relieve symptoms without producing opioid intoxication. We prefer the intramuscular route as the withdrawing patient may vomit. (See 'Withdrawal from interruption in opioid use' above.)
●Treatment if withdrawal is caused by opioid antagonist, intentional cessation, and other circumstances – When the use of opioids (ie, buprenorphine or methadone) is undesirable, nonopioid adjuncts may be used to manage symptoms. Examples of such situations include withdrawal triggered by an opioid antagonist and withdrawal after intentionally stopping use of opioids to treat an addiction. In patients with normal or elevated blood pressure, we suggest treatment with clonidine (Grade 2C). While monitoring heart rate and blood pressure, the clinician can give clonidine 0.1 to 0.3 mg orally every hour until symptoms resolve, to a maximum total daily dose of 0.7 mg. (See 'Withdrawal due to opioid antagonist and other circumstances not amenable to treatment with opioid agonist' above.)
●Treatment of hemodynamic instability from long-acting antagonist – Significant hypertension and tachycardia precipitated by a short-acting antagonist should resolve after brief observation, but hemodynamic instability induced by a long-acting drug (eg, naltrexone) requires pharmacologic management. Patients who may require more intensive management include older adults and those with cardiovascular disease. Benzodiazepines are a good supplement to clonidine therapy. We typically use diazepam in 10 to 20 mg intravenous (IV) aliquots, given every 5 to 10 minutes, until adequate sedation and hemodynamic stability are achieved. Midazolam or lorazepam in equivalent doses is equally efficacious.
●Neonatal abstinence syndrome – A detailed discussion of neonatal abstinence syndrome is found separately. (See "Prenatal substance exposure and neonatal abstinence syndrome (NAS): Management and outcomes".)
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