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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.
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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.
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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
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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.
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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 QTc 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 QTc 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
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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
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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.
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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
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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
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MIXED AGONISTS-ANTAGONISTS
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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
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DIPHENOXYLATE HYDROCHLORIDE–ATROPINE SULFATE
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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.
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MIXED DRUGS AND CONTAMINANTS
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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
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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
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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