Opiates are a group of naturally occurring compounds derived from the juice of the poppy Papaver somniferum. Morphine and codeine are classic opiate derivatives used widely in medicine; heroin (diacetylmorphine) is a well-known semi-synthetic, highly addictive street narcotic. The term opioid refers to opiates and semi-synthetic derivatives of naturally occurring opium (eg, morphine, heroin, codeine, and hydrocodone) as well as new, totally synthetic opiate analogs (eg, fentanyl, butorphanol, meperidine, and methadone [Table II-45]). A wide variety of prescription medications contain opioids, often in combination with aspirin or acetaminophen. Dextromethorphan is an opioid derivative with potent antitussive but no analgesic or addictive properties. Tramadol is an analgesic that is unrelated chemically to the opiates but acts on mu-opioid receptors and blocks serotonin reuptake. Butorphanol is available as a nasal spray with rapid absorption. Buprenorphine is a partial opioid agonist that is approved for the treatment of opioid addiction. Suboxone is a sublingual tablet containing buprenorphine plus naloxone to reduce intravenous abuse. Tapentadol is a mu-opioid agonist that also inhibits the reuptake of norepinephrine. The alkaloid mitragynine is the active component of kratom found in the Southeast Asian tree Mitragyna speciosa Kroth; it has stimulant and opioid-like effects, and has been used for self-treatment of opioid withdrawal. Rates of overdose deaths involving synthetic opioids other than methadone are on the rise in the United States, likely due to the increasing availability of illicitly manufactured and highly potent fentanyl and fentanyl derivatives (eg, furanyl fentanyl, U47700). Fentanyl is increasingly found in counterfeit tablets (eg, alprazolam) and adulterated cocaine and methamphetamine, potentially producing lethal effects in unsuspecting users.

1. In general, opioids share the ability to stimulate a number of specific opiate receptors in the CNS, causing sedation and respiratory depression. Death results from respiratory failure, usually as a result of apnea or pulmonary aspiration of gastric contents. In addition, acute noncardiogenic pulmonary edema may occur by unknown mechanisms. In addition to its opioid-like effects, kratom may also stimulate postsynaptic alpha-2 adrenergic and serotonergic (5HT_2A) receptors.
2. Pharmacokinetics. Usually, peak effects occur within 2-3 hours, but absorption may be slowed by the pharmacologic effects of opioids on GI motility. Slow-release preparations may have a delayed onset of action and prolonged effects. With fentanyl patches, dermal absorption can continue even after removal. Smoking or ingesting fentanyl patches can result in rapid and high levels. Most of these drugs have large volumes of distribution (3-5 L/kg). The rate of elimination is highly variable, from 1-2 hours for fentanyl derivatives to 15-30 hours for methadone (see also Tables II-45 and II-63). Some patients have been found to be rapid metabolizers of codeine (to morphine through the hepatic enzyme CYP2D6), which may increase the risk for acute intoxication.

The toxic dose varies widely, depending on the specific compound, the route and rate of administration, and tolerance to the effects of the drug as a result of chronic use. Some newer fentanyl derivatives have potency up to 2,000 times that of morphine.

1. With mild or moderate overdose, lethargy is common. The pupils are usually small, often of “pinpoint” size. Blood pressure and pulse rate are decreased, bowel sounds are diminished, and the muscles are usually flaccid.
2. With higher doses, coma is accompanied by respiratory depression, and apnea often results in sudden death. Noncardiogenic pulmonary edema may occur, often after resuscitation and administration of the opiate antagonist naloxone.
3. Seizures are not common after opioid overdose but occur occasionally with certain compounds (eg, codeine, dextromethorphan, kratom, meperidine, methadone, propoxyphene, and tramadol). Seizures may occur in patients with renal compromise who receive repeated doses of meperidine owing to accumulation of the metabolite normeperidine.
4. A leukoencephalopathy with typical magnetic resonance imaging (MRI) changes has been reported in some heroin smokers (“chasing the dragon”).
5. Cardiotoxicity similar to that seen with tricyclic antidepressants and quinidine can occur in patients with severe propoxyphene intoxication. Prolonged QTc intervals and torsade de pointes have been reported with methadone and may account for some of the sudden deaths associated with its use. The R-enantiomer of methadone is apparently more active at the mu receptor and less likely to affect the hERG channel (and thus the QTc interval) compared with the S-enantiomer.
6. Some newer synthetic opioids have mixed agonist and antagonist effects, with unpredictable results in overdose. Buprenorphine causes less maximal opioid effect than morphine does, and because of strong binding to opioid receptors it can cause acute withdrawal symptoms in persons on high doses of conventional opioids.
7. Opioid withdrawal syndrome can cause anxiety, piloerection (goose bumps), heightened sensation of pain, abdominal cramps and diarrhea, and insomnia.

Is simple when typical manifestations of opiate intoxication are present (pinpoint pupils and respiratory and CNS depression) and is confirmed when the patient quickly awakens after administration of naloxone. Signs of intravenous drug use (eg, needle track marks) may be present.

1. Specific levels are not usually performed because of poor correlation with clinical effects. Qualitative screening of the urine is an effective way to confirm recent use of many opiates (eg, codeine, heroin, morphine, hydrocodone, hydromorphone), but many synthetic opioids are not detected on routine immunoassays (eg, fentanyl, methadone, oxycodone, tramadol). Separate specific immunoassays are available for oxycodone/oxymorphone, fentanyl, methadone, and 6-acetylmorphine (heroin-specific metabolite).
2. Other useful laboratory studies include electrolytes, glucose, arterial blood gases or oximetry, chest radiography, and stat serum acetaminophen or salicylate levels (if the ingested overdose was of a combination product).
3. Genetic polymorphisms. Individuals who are ultra-rapid metabolizers for CYP2D6 (eg, *1 gene duplication) are at risk for morphine toxicity at therapeutic codeine doses, while poor metabolizers (eg, *4, *10) can experience a reduced analgesic effect. CYP2D6 tests are available through reference laboratories.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Treat coma, seizures, hypotension, ventricular arrhythmias, and noncardiogenic pulmonary edema if they occur.
2. Specific drugs and antidotes
   1. Naloxone is a specific opioid antagonist with no agonist properties of its own; large doses may be given safely.
      1. As little as 0.2-0.4 mg IV or IM is usually effective for heroin overdose. Repeat doses every 2-3 minutes if there is no response, up to a total dose of 10-20 mg if an opioid overdose is strongly suspected. Intranasal naloxone is also an effective route of administration in the prehospital setting.
      2. Caution: The duration of effect of naloxone (1-2 hours) is shorter than that of many opioids. Therefore, do not release a patient who has awakened after naloxone treatment until at least 2-3 hours have passed since the last dose of naloxone. In general, if naloxone was required to reverse opioid-induced coma, it is safer to admit the patient for at least 6-12 hours of observation.
   2. Nalmefene is an opioid antagonist with a longer duration of effect (3-5 hours).
      1. Nalmefene may be given in doses of 0.1-2 mg IV, with repeated doses of up to 10-20 mg if an opioid overdose is strongly suspected.
      2. Caution: Although the duration of effect of nalmefene is longer than that of naloxone, it is still much shorter than that of methadone. If a methadone overdose is suspected, the patient should be observed for at least 8-12 hours after the last dose of nalmefene.
   3. Sodium bicarbonate may be effective for QRS-interval prolongation or hypotension associated with propoxyphene poisoning.
3. Decontamination . Administer activated charcoal orally if conditions are appropriate (see Table I-37,). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. Consider whole-bowel irrigation after ingestion of sustained-release products.
4. Enhanced elimination. Because of the very large volumes of distribution of the opioids and the availability of an effective antidotal treatment, there is no role for enhanced elimination procedures.