Chapter 186: Opioids

Opioids refers broadly to all compounds related to opium that possess analgesic and sedative properties. Opiate describes the opioid alkaloids found naturally in the opium poppy plant, Papaver somniferum. The term narcotic refers to a broader group of agents, predominantly used by law enforcement to designate a variety of controlled substances with abuse or addictive potential; use of this term in medical practice is discouraged.

Opioid abuse is a significant public health issue in the United States with a dramatic increase in prescription opioid use and abuse in the past 10 years.^1,2 Opioids most frequently involved in reported toxic drug exposures were, in order of number of cases recorded, tramadol, oxycodone, methadone, morphine, buprenorphine, and hydrocodone.³ Deaths were primarily associated with exposure to methadone, oxycodone, and morphine. The majority of prescription opioid overdose deaths were associated with diversion, doctor shopping, and nonmedical use.

Opioids modulate nociception in the terminals of afferent nerves in the CNS, peripheral nervous system, and GI tract. Opioids are agonists at the three primary opioid receptors: μ (mu), κ (kappa), and δ (delta). Opioid receptors are similar to other G protein–coupled receptors; they are transmembrane proteins that undergo conformational change when activated by external molecules, and this change then alters some aspect of intracellular function. Opioid receptors vary widely in morphology and distribution. Also, the specificity and affinity of an opioid for a particular receptor are variable. For example, tramadol possesses 1/6000 the affinity of morphine at the μ-receptor site.

Stimulation of the μ-receptors results in analgesia, sedation, miosis, respiratory depression, cough suppression, euphoria, and decreased GI motility. Stimulation of κ-receptors results in weaker analgesia, sedation, miosis, decreased intestinal motility, dysphoria, and hallucinations. Stimulation of the δ-receptors results in some analgesia and antidepressant effect. All currently available opioid agonists possess μ-receptor activity and result in some degree of respiratory depression.

There is interplay between opioid receptors and other transmembrane receptors found in the nervous system. One example is that opioid binding to μ-receptors in the nucleus accumbens results in the localized release of dopamine (the "dopamine pleasure pathway"). A second example is that the analgesic effect of morphine is enhanced in the presence of N-methyl-d-aspartate receptor blockers such as amantadine. A third example is the induction of mast cell histamine release by morphine and meperidine.

Opioids can be categorized as naturally occurring compounds (termed opiates), chemical modifications of natural compounds (semisynthetic), and completely artificial compounds (synthetic) (Table 186-1). Some opioids are agonists at all opioid receptors (e.g., morphine and hydromorphone), whereas others are partial agonists–antagonists (e.g., pentazocine, butorphanol, and nalbuphine) at the opioid receptors.

PHARMACOKINETICS

Opioids are readily absorbed, achieving peak blood levels 30 to 60 minutes after ingestion of standard oral formulations. Sustained-release forms take longer after ingestion to achieve peak blood levels; for example, morphine sulfate controlled-release tablets take about 90 minutes to reach peak blood levels compared with 30 minutes for standard morphine tablets. After GI absorption, most opioids undergo first-pass hepatic metabolism, so bioavailability can vary from as low as 10% to as high as 80% after PO administration. Thus, at equal doses, most opioids are more potent given parenterally than PO. The opioids with good oral bioavailability are codeine, oxycodone, methadone, hydromorphone, and tapentadol.

The metabolism of codeine, meperidine, methadone, morphine, oxycodone, and propoxyphene is mostly hepatic and subject to drug interactions and genetic variations. For example, antiretroviral medications can enhance the metabolism of methadone, which results in lower plasma methadone concentrations. As another example, codeine is metabolized to morphine via cytochrome P-450 isoenzyme 2D6, an enzyme with genotypic and phenotypic variability. Patients with rapid cytochrome P-450 enzyme 2D6 metabolism produce more morphine after a fixed dose of codeine.⁴ These interactions and genetic variations may influence the therapeutic effect of opioids (see chapter 35, "Acute Pain Management").

In drug misuse, unconventional routes of administration (insufflating or injecting ground opioid tablets, heating fentanyl patches or applying more than one patch to the skin) may alter the drug's pharmacokinetics and often increase the rate of opioid absorption. Similarly, in cases of opioid overdose resulting in high plasma levels, the pharmacokinetics are altered due to enzymatic saturation. This may increase the severity of poisoning, delay the onset, and prolong the duration of action, as compared with the expected therapeutic actions.⁵

The full opioid intoxication toxidrome includes respiratory and mental status depression, analgesia, miosis, orthostatic hypotension, nausea and vomiting (especially in opioid-naïve patients), histamine release resulting in localized urticaria (Figure 186-1) and bronchospasm, ileus secondary to decreased GI motility, and urinary retention secondary to increased vesical sphincter tone.⁶ The depression in mental status can be profound. The respiratory depression is characterized by slow and shallow respirations that can produce hypercarbia, hypoxia, and cyanosis. Miosis is not universally present from intoxication with every opioid; normal or even enlarged pupils have been documented secondary to diphenoxylate, meperidine, morphine, pentazocine, and propoxyphene toxicity. Mydriasis may also signal severe cerebral hypoxia or result from co-ingestants. Other possible findings include pulmonary edema, hypothermia, rhabdomyolysis, compartment syndrome, myoglobinuric renal failure, and seizures associated with overdoses of tramadol, propoxyphene, and meperidine.

Opioid-induced acute lung injury, previously known as noncardiogenic pulmonary edema, is an uncommon complication associated with heroin overdose.^6,7 Acute lung injury can occur immediately or be delayed up to 24 hours after heroin overdose and presents with tachypnea, rales, decreased oxygen saturation, and bilateral pulmonary infiltrates with a normal cardiac silhouette on chest radiograph. The incidence of acute lung injury is 10% in patients with severe heroin overdose requiring naloxone.⁸ The pathophysiology of heroin-induced acute lung injury is poorly understood, but some degree of direct capillary injury is suspected. Treatment includes oxygen supplementation and ventilatory support, either noninvasive or invasive modalities, and positive end-expiratory pressure. Additional naloxone, diuretics, and digoxin are not indicated.

The combination of meperidine, tramadol, or dextromethorphan with monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, or linezolid can result in serotonin syndrome (see chapter 178, Atypical and Serotonergic Antidepressants).⁹ Serotonin syndrome is characterized by disorientation, hyperthermia, autonomic instability, hyperreflexia, and muscle rigidity, especially in the lower extremities. Although uncommon, deaths have been reported. Naloxone is not effective in treating opioid-induced serotonin syndrome.^9,10

The combination of coma, miosis, and respiratory depression strongly suggests opioid intoxication, and in many clinical scenarios, evidence of opioid use is present. The combination of a respiratory rate of <12 breaths/min, miosis, and circumstantial evidence of opioid use (drug paraphernalia, needle marks, presence of a tourniquet, bystander corroboration) was highly sensitive for opioid overdose.¹¹

Listen for auscultatory findings suggestive of pulmonary edema. Undress the patient completely and look for hidden opioids or drug-use paraphernalia, check for fentanyl patches on all parts of the body, including mucous cavities, and palpate muscle groups to detect signs of compartment syndrome.

The differential diagnosis of opioid intoxication includes toxicologic exposure to agents that produce similar findings, such as clonidine, organophosphates and carbamates, phenothiazines and atypical antipsychotic medications, sedative-hypnotic medications, and carbon monoxide. Clonidine overdoses are characterized by coma, bradycardia, hypotension, miosis, and periods of apnea that respond to tactile or auditory stimulation. Organophosphate and carbamate overdoses cause the cholinergic toxidrome: miosis, muscle fasciculations, profuse vomiting and diarrhea, and sweating. Phenothiazines, olanzapine, and risperidone cause neurologic depression and miosis from decreased adrenergic tone.¹² γ-Hydroxybutyrate intoxication is associated with profound CNS depression, bradypnea, and, occasionally, miosis. Sedative-hypnotic agents and carbon monoxide cause profound neurologic depression but are not usually associated with miosis. Hypoglycemia, hypoxia, CNS infections, postictal states, and pontine and intracranial hemorrhages should also be considered in the differential diagnosis.

OPIOID SCREENS

A qualitative urine opioid screen may aid in the diagnosis, but available tests have limitations. The assay in most commercially available urine opioid screens recognizes morphine.¹³ Therefore, morphine and those opioids that are metabolized to morphine, such as codeine and heroin, are readily detected. However, the semisynthetic opioids hydrocodone and oxycodone are usually not detected by urine opioid screens, and essentially all synthetic opioids also are not routinely detected. A specific urine assay is required to detect oxycodone or methadone.

Urine opioid screens can have false-positive results.¹³ Depending on the threshold level, ingestion of poppy seeds contained in baked goods can lead to a false-positive test result. Rifampin, rifampicin, quinine, diphenhydramine, and fluoroquinolones have been reported to cause false-positive urine opioid screen results, presumably by interfering with the immunoassay technique. An opioid analogue, dextromethorphan, can produce a positive result on the urine opioid screen. Prescription drugs reported to cause a false-positive result with the methadone urine drug screen include chlorpromazine, clomipramine, diphenhydramine, doxylamine, ibuprofen, quetiapine, thioridazine, and verapamil.

A urine opioid screen can be positive up to 2 to 3 days after a single use of codeine, morphine, or heroin. The methadone-specific screen can be positive up to 3 days after ingestion. Thus, detection of an opioid agent taken in the recent past may not correctly identify the toxicologic cause of the patient's current condition. Plasma acetaminophen concentration should be obtained in all suicidal ingestions and all cases of combination opioid-acetaminophen overdoses.

Airway protection and ventilatory maintenance are the most important treatment steps for opioid intoxications, because respiratory depression is the major morbidity and the cause of essentially all the mortality.⁶ Use bag-valve mask ventilatory support as needed to initially maintain adequate oxygenation and ventilation. After adequate ventilation is ensured, administer naloxone (Table 186-2). In fully awake patients or after the airway is protected with an endotracheal tube in unresponsive patients, administer single-dose activated charcoal, 1 gram/kg PO, if an opioid ingestion occurred within the hour. Endotracheal intubation is a therapeutic option in some cases of opioid overdose with severe respiratory depression unresponsive or poorly responsive to naloxone or in cases in which acute lung injury is suspected.⁶ Intubation offers the advantages of protection of the airway, easy access for suctioning, provision of an alternate route of administration for some medications, and total airway control. Rapid-sequence intubation, omitting anesthetic-sedative agents, is the preferred technique.

Under special circumstances, delayed and multiple doses of activated charcoal may be useful, as in diphenoxylate hydrochloride–atropine sulfate overdoses and in cases of large ingestions of sustained-release preparations.¹⁴

NALOXONE

Naloxone, a derivative of oxymorphone, is a pure competitive antagonist at all opioid receptors, with particular affinity for μ-receptors. Naloxone therefore fully reverses all the effects of opioids, including respiratory depression, CNS depression, miosis, and analgesia. Naloxone also antagonizes opioid-induced seizures, except those induced by meperidine, propoxyphene, or tramadol. The elimination half-life of naloxone is 60 to 90 minutes, but the duration of action is as short as 20 minutes if a large amount of opioid agonist is present.

Naloxone has poor oral bioavailability but is well absorbed when given by injection (IV, SC, or IM), inhaled, or deposited on mucosa (intratracheally or intranasally, but not sublingual). Inhaled naloxone by nebulization is reasonably effective in reversing depressed mental status and respirations in opioid toxicity, with about 10% requiring additional rescue parenteral naloxone.^15,16,17 Intranasally administered naloxone provides a pharmacokinetic profile similar to that of IM or SC naloxone and is used by EMS personnel and in bystander naloxone administration programs.^18,19,20

Naloxone effectiveness is dependent on the dose administered and the amount of opioid that needs to be reversed. A small starting dose of naloxone, 0.1 milligram IV, is recommended in opioid-dependent patients who present with mental status depression but with minimal respiratory depression, because larger doses can induce opioid withdrawal symptoms in opioid-dependent patients. An initial dose of naloxone, 0.4 milligram IV, is recommended in non–opioid-dependent patients who present with mental status depression but with minimal respiratory depression. Subsequent doses of naloxone of 0.1 to 0.4 milligram IV are administered until the desired effect is reached. Incremental dosing of naloxone mitigates the precipitation of acute opioid withdrawal.²¹

An initial dose of naloxone, 2 milligrams IV, should be administered to patients presenting with apnea or near-apnea and cyanosis, regardless of drug use history. Repeated doses of 2 milligrams IV every 3 minutes are recommended until a maximum of 10 milligrams IV is reached or respiratory depression is reversed. Exposures to synthetic opioids, such as propoxyphene, fentanyl, pentazocine, or dextromethorphan, and to sustained-release preparations may require these larger-than-ordinary doses. Toxicity from leaking opioid-containing packets in the intestinal tract (i.e., in "body packers") can be extremely severe, and such patients require large and sustained naloxone doses until the drug-containing packets are expelled or removed.

The duration of action of naloxone is often shorter than that of the offending opioid, so naloxone infusions are occasionally required to support respiration over several hours as the opioid is metabolized. This is especially true for certain long-acting opioids, such as buprenorphine, methadone, and propoxyphene; for exposures to sustained-release preparations; and for ingestions of dermal patches. A continuous infusion should be considered only if the patient responded to the initial naloxone bolus and subsequently required repeat administration. To calculate the naloxone continuous infusion dose, determine the "wake-up dose" and administer two thirds of that dose per hour by IV infusion. Adjustments may be required if the patient develops respiratory depression (by repeating a bolus and increasing infusion rates) or withdrawal symptoms (by decreasing infusion rates). It is recommended that patients on naloxone infusions be admitted to a monitored unit.

Naloxone has a remarkable safety profile. Although adverse effects are seen in about one third of patients who receive it for a suspected opioid overdose, serious complications are rare.²² The most common adverse effects associated with naloxone are anxiety, nausea, vomiting, diarrhea, abdominal cramps, piloerection, yawning, and rhinorrhea, related to the precipitation of the opioid withdrawal syndrome. Careful dosing of naloxone can prevent the precipitation of opioid withdrawal symptoms.^21,23

Naltrexone, an oral opioid antagonist, is primarily used to maintain opioid abstinence after detoxification. Naltrexone may be useful in preventing delayed respiratory depression in opioid-naïve methadone-intoxicated patients in resource-limited locations.²⁴ The elimination half-life for the two major active metabolites of naltrexone is 10 to 13 hours, but the duration of action is dose-dependent and longer.

Nalmefene, both an oral and parenteral opioid antagonist, has not been available in the United States since August 2008. The elimination half-life is about 11 hours. In the suspected opioid-dependent adult with mental status and respiratory depression, the initial nalmefene dose is 0.1 milligram IV. If no withdrawal occurs, a dose of 0.5 milligram is given, followed by 1 milligram in 2 to 5 minutes if mental status or respirations are still depressed.

The optimal observation period after an opioid intoxication is determined by the history and clinical picture. Naloxone-responsive injection drug users with presumed heroin intoxication can be safely discharged 1 to 2 hours after administration of naloxone if they have independent mobility, oxygen saturation on room air >92%, respiratory rate >10 breaths/min, pulse rate >50 beats/min, normal temperature, and a Glasgow coma scale score of 15.²⁵

In cases of exposure to opioids other than heroin, an observation period of 4 to 6 hours in the ED is recommended after the last naloxone administration. In long-acting opioid overdose, observation should be extended for a minimum of 8 hours.⁴ Moderate to severely symptomatic patients usually require hospital admission to monitored settings and may require continued administration of naloxone. A behavioral health evaluation is needed in cases with suicidal intent.

BUPRENORPHINE

Buprenorphine is a partial agonist at μ-receptors, with decreased intrinsic activity that causes its clinical effects to plateau at higher dosages.²⁶ Buprenorphine has high affinity for and slow dissociation from the μ-receptor, which results in a long duration of action. Furthermore, other opioid agonists (such as heroin) or antagonists (such as naloxone) cannot easily displace buprenorphine from the μ-receptor. Buprenorphine has poor oral bioavailability because of extensive first-pass metabolism and is therefore administered SL or parenterally. The most frequently prescribed SL buprenorphine formulation is in combination with naloxone in a 4:1 ratio. Because naloxone has poor bioavailability from PO or SL administration, it was introduced into the preparation to discourage and limit parenteral abuse of the buprenorphine portion while not interfering with therapeutic use in the form of the SL tablet.

Buprenorphine can be associated with three distinct clinical scenarios. First, the opioid-naïve patient who overdoses on buprenorphine will experience mental status depression, nausea, vomiting, miosis, and respiratory depression (usually with a plateau). In this situation, naloxone may not be fully effective in reversing mental status and respiratory depression.²⁷ Because of the long duration of action of buprenorphine, readministration of naloxone and naloxone infusions is frequent, and admission to the hospital is necessary in symptomatic patients. The second possible scenario is buprenorphine exposure in the opioid-dependent patient still under the influence of the opioid agonist. In this case, buprenorphine will precipitate opioid withdrawal symptoms, because the partial agonist buprenorphine behaves like an antagonist in the presence of an agonist. Buprenorphine-induced withdrawal is best managed with symptom-driven therapy, including antiemetics, nonopioid analgesics, antidiarrheals, and nonbenzodiazepine sedatives for insomnia. The third possible clinical scenario is buprenorphine exposure in the opioid-dependent patient undergoing withdrawal, in whom buprenorphine will act as a partial agonist and alleviate the symptoms of opioid withdrawal. This forms the basis for buprenorphine detoxification and maintenance therapy. Thus, buprenorphine is unique in that it can both induce and treat opioid withdrawal, depending on the timing of its administration.

METHADONE

Methadone is synthetic opioid used as replacement therapy in opioid-dependence and for chronic pain. The initial analgesic duration is 4 to 8 hours with an elimination half-life of 12 to 18 hours. With repetitive dosing, analgesic action duration and elimination half-life increase to about 22 to 36 hours and up to 59 hours, respectively. The long duration of activity enables once-a-day dosing during chronic therapy. Methadone has a higher risk for overdose-related deaths than other opioids, often with co-ingestants.^28,29

Methadone has several drug–drug interactions that can precipitate toxicity or withdrawal in patients on chronic therapy.³⁰ Interactions between methadone and human immunodeficiency virus medications are common and complex, creating potential for both increased toxicity and withdrawal. The relevant interactions for emergency physicians include ciprofloxacin, fluconazole, ketoconazole, and omeprazole, which can increase toxicity. Drug–methadone interactions that have potential to precipitate withdrawal include macrolide (especially clarithromycin), phenobarbital, phenytoin, spironolactone, and verapamil.

Methadone prolongs the QT interval prolongation in acute overdose or during long-term methadone treatment, providing the substrate for cardiac dysrhythmias, such as torsade de pointes.³¹ In patients with acute methadone overdose resulting in QT interval prolongation, serum electrolyte imbalances should be corrected and the patient should be admitted to a monitored bed until the condition resolves. Patients on long-term methadone therapy who develop a QT_c interval of >450 milliseconds but <500 milliseconds do not require a dosage adjustment, but electrolyte imbalances should be corrected if present, and patients should be followed on an outpatient basis with frequent ECGs. In patients on long-term methadone therapy who develop a QT_c interval of >500 milliseconds, any electrolyte imbalances should be corrected, methadone dosage reduction or discontinuation should be considered, and other contributing factors should be eliminated.³²

Acute methadone overdoses present similar to other opioid intoxications, but the duration can be much longer.³³ Naloxone infusions are often required with close neurologic and respiratory monitoring, or oral naltrexone can be used in resource-limited circumstances.²⁴

PROPOXYPHENE

Propoxyphene and its metabolite, norpropoxyphene, are cardiotoxic and neurotoxic.³⁴ Propoxyphene overdoses produce sodium channel blockade, causing QRS interval prolongation, atrioventricular conduction block with bradycardia, prolonged QT interval, and ventricular bigeminy. Seizures have been reported in about 10% of overdoses. Propoxyphene is usually combined with acetaminophen or salicylates, so levels of those drugs should be checked in an overdose.

As in other overdoses that involve sodium channel blockade, propoxyphene-induced QRS interval prolongation should be treated with sodium bicarbonate, 1 mEq/kg IV.³⁵ Seizures should be treated with benzodiazepine or phenobarbital. Naloxone will not reliably reverse the cardiotoxicity or terminate propoxyphene-induced seizures.³⁶

TRAMADOL

Tramadol overdoses are associated with lethargy, nausea, tachycardia, and seizures.^37,38 At doses exceeding 500 milligrams, coma, hypertension, respiratory depression, and apnea are seen.^10,39 Features consistent with serotonin syndrome have been seen in isolated tramadol overdoses.⁴⁰ Tramadol-induced seizures are common, and naloxone is ineffective in preventing them. Fortunately, tramadol-induced seizures are usually single and anticonvulsants are not necessary.^41,42 Dependence during chronic therapy and withdrawal symptoms upon discontinuation have been reported with tramadol.⁴³

MIXED AGONISTS-ANTAGONISTS

The mixed agonists-antagonists include pentazocine, butorphanol, and nalbuphine. These agents have variable but mostly antagonist activity at the μ-receptor. They may cause significant respiratory depression in overdose, and naloxone will reverse this respiratory depression. Mixed agonists-antagonists usually precipitate withdrawal when taken by an opioid-dependent individual, which reduces their potential for abuse. Pentazocine overdose can cause seizures.⁴⁴

DIPHENOXYLATE HYDROCHLORIDE–ATROPINE SULFATE

Diphenoxylate hydrochloride–atropine sulfate is a frequently prescribed antidiarrheal agent. The medication is formulated as a combination tablet or liquid, containing diphenoxylate, 2.5 milligrams, and atropine, 0.025 milligram, in each tablet or 5 mL of liquid. In an overdose, initially the anticholinergic toxidrome dominates the clinical picture (see chapter 202, "Anticholinergics"). The second phase of intoxication is characterized by the opioid toxidrome. Children <6 years of age can be symptomatic after ingestion of a single tablet. In pediatric patients, absorption can be delayed up to 6 to 12 hours in some cases because of the effect of atropine on GI motility. Current recommendations are that all children <6 years of age be admitted to the hospital and be closely observed for 24 hours after ingestion of a combination tablet of diphenoxylate and atropine. Older children and adults should be observed in the ED for 6 hours. Administration of activated charcoal is recommended unless contraindicated.

MIXED DRUGS AND CONTAMINANTS

Illicitly obtained heroin is often mixed with other compounds, such as cocaine, scopolamine, clenbuterol, and fentanyl, which may contribute to heroin overdose toxicity. Adulterants found in illicit heroin may include strychnine, quinine, lactose, and talc. Scopolamine is an antimuscarinic agent that produces the anticholinergic toxidrome. Clenbuterol is a long-acting β-adrenergic agonist similar to albuterol and is used in veterinary medicine. Heroin-fentanyl mixtures (colloquially called China-white) resulted in hundreds of deaths among injection drug users in metropolitan areas of the United States during 2007.⁴⁵ A potent neurotoxin, 1-methyl-4-phenyl-1,2,3,-tetrahydropyridine, has been used as a meperidine adulterant, producing parkinsonism in users.⁴⁶

Starting in Russia in 2010, episodes of deaths and gangrene were reported associated with intravenous desomorphine or "Crokodile," a synthetic alternative to heroin crudely made from codeine tablets with a high concentration of tissue-toxic impurities. The colloquial name is derived from the appearance of the skin after it is injected.⁴⁷

KRATOM

Kratom (Mitragyna speciosa) has mitragynine as its principal alkaloid, with stimulating effects at low doses (cocaine-like effect) and sedative effects (opioid-like effect) at high doses.⁴⁸ Regular kratom use can lead to dependence, craving, and withdrawal symptoms.^49,50 Kratom can produce serious toxicity or even death, often associated with interaction with other drugs, such as nasal decongestants, over-the-counter drugs, and benzodiazepines.⁵¹ Krypton, a combination containing kratom, desmethyltramadol, and caffeine has been associated with fatalities.⁵² Kratom is available in smoke shops and on the Internet.⁵³ Kratom preparations are used as self-management of chronic pain, as replacement therapy for opioid analgesics, and for opioid and alcohol withdrawal symptoms.⁵⁴

Downregulation of endogenous endorphins, dynorphins, and opioid receptors occurs with long-term use of opioids. Abrupt cessation of opioid use does not allow time for upregulation of receptors and results in increased neuronal firing and the opioid withdrawal syndrome.

Opioid withdrawal usually starts with feelings of anxiety, yawning, lacrimation, diaphoresis, rhinorrhea, and diffuse myalgias (Table 186-3),⁵⁵ progressing to piloerection, mydriasis, nausea, profuse vomiting, diarrhea, and abdominal cramping. Opioid withdrawal reactions are very uncomforTable but are not life-threatening and rarely fatal. Vomiting and aspiration of gastric contents can cause pneumonitis and dehydration. Onset of withdrawal is usually within 6 to 12 hours of last heroin use and within 30 hours of last methadone exposure. It can be precipitated by the administration of antagonists such as naloxone or naltrexone or the administration of partial agonists such as buprenorphine. Opioid withdrawal symptoms usually peak on the third day of abstinence and resolve by the fifth or sixth day. Subjective and objective opiate withdrawal scales can be used to monitor the severity of symptoms and signs and guide therapy.⁵⁶

Symptoms of opioid withdrawal can be rendered more tolerable by the administration of the central α₂-agonist clonidine, antiemetics, and antidiarrheal agents.⁵⁷ Clonidine may be used at a dose of 5 micrograms/kg PO if the blood pressure is >90 mm Hg systolic. Multidrug regimens are sometimes used in ambulatory detoxification programs to control withdrawal symptoms.^58,59

The management of opioid-dependent individuals hospitalized for medical or surgical reasons remains controversial. Detoxification from opioids during the course of an acute medical illness is usually unsuccessful, and alleviation of withdrawal symptoms with opioid replacement is generally the goal. Daily administration of a verified dose of methadone PO (or half the verified dose IM if the patient cannot take oral medications) is recommended to inhibit withdrawal symptoms and reduce craving. This applies only to individuals who are enrolled in a methadone treatment program and in whom the dose can be verified. A habitual user who is not receiving methadone maintenance therapy can be given methadone 20 milligrams PO or 10 milligrams IM. These doses should inhibit withdrawal symptoms but not induce euphoria. Buprenorphine, 0.3 to 1.2 milligrams IV or IM every 6 hours, can safely be administered to a medically ill opioid-dependent patient experiencing withdrawal who will be admitted to the hospital.⁶⁰ No methadone or buprenorphine should be administered to an opioid-dependent patient until withdrawal symptoms appear.