11/27/13

Opioid Toxicity

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Opioid Toxicity
Author: Everett Stephens, MD; Chief Editor: Asim Tarabar, MD more... Updated: Oct 23, 2012

Background
Pain is arguably the most common reason why patients seek treatment, especially in the ED. The modern physician wields many tools to relieve pain, the most potent of which are opioids. The term narcotic specifically refers to any substance that induces sleep, insensibility, or stupor, and it is used to refer to opioids or opioid derivatives. It is derived from the Greek "narke" that means "numbness or torpor." It is common, however inaccurate, that the public uses the term narcotics for any illicit psychoactive substance. In cultivation since approximately 1500 BC, pure opium is a mixture of alkaloids extracted from the sap of unripened seedpods of Papaver somniferum (poppy). Opiates, such as heroin, codeine, or morphine, are natural derivatives of these alkaloids. The term opiate is often used (albeit slightly incorrectly) to refer to synthetic opiate derivatives, such as oxycodone, as well as true opiates. Although opioids constitute a relatively small percentage of total overdoses encountered in the ED, they merit particular attention because of the potential mortality/morbidity they cause when unrecognized and untreated, as well as the relative ease of reversing their effects. The notable prevalence of opioids in current prescribing patterns, as well as recreational uses, mandates that physicians maintain a high index of suspicion when treating the patient who is unconscious for unknown reasons. Opioid use and abuse have been reported as increasing in frequency in the past few years, a trend that has been blamed in increasing utilization of opioids by medical personnel as well as illicit drug abuse.[1] While increased availability certainly plays a role in opioid abuse, the link between legitimate use and abuse is not well proven.[2, 3] The increasing use and abuse of opioids has received increasing attention in recentyears.[4, 5] The medical profession, licensing agencies, and federal enforcement have been increasingly focusing on prescribing practices for short- and long-term use of narcotic substances. Some states have enacted sweeping legislation to require more oversight in the use of narcotics (eg, Kentucky HB1). Such legislation affects the prescribing practices of providers in an attempt to reduce diversion of legitimate opiate prescriptions. Statewide registers of controlled substances are available in many states and can help providers track use patterns among patients in an effort to identify those at high risk of abuse or diversion.

Pathophysiology
Activation of opioid receptors results in inhibition of synaptic neurotransmission in the central nervous system (CNS) and peripheral nervous system (PNS). Opioids bind to and enhance neurotransmission at 3 major classes of opioid receptors. It is also recognized that several poorly defined classes of opioid receptors exist with relatively minor effects. The physiological effects of opioids are mediated principally through mu and kappa receptors in the CNS and periphery. Mu receptor effects include analgesia, euphoria, respiratory depression, and miosis. Kappa receptor effects include analgesia, miosis, respiratory depression, and sedation. Two other opiate receptors that mediate the effects of certain opiates include sigma and delta sites. Sigma receptors mediate dysphoria, hallucinations, and psychosis; delta receptor agonism results in euphoria, analgesia, and seizures. The opiate antagonists (eg, naloxone, nalmefene, naltrexone) antagonize the effects at all 4 opiate receptors. Common classifications divide the opioids into agonist, partial agonist, or agonist-antagonist agents and natural, semisynthetic, or synthetic. Opioids decrease the perception of pain, rather than eliminate or reduce the painful stimulus. Inducing slight euphoria, opioid agonists reduce the sensitivity to exogenous stimuli. The GI tract and
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the respiratory mucosa provide easy absorption for most opioids. Peak effects generally are reached in 10 minutes with the intravenous route, 10-15 minutes after nasal insufflation (eg, butorphanol, heroin), 30-45 minutes with the intramuscular route, 90 minutes with the oral route, and 2-4 hours after dermal application (ie, fentanyl). Following therapeutic doses, most absorption occurs in the small intestine. Toxic doses may have delayed absorption because of delayed gastric emptying and slowed gut motility. Most opioids are metabolized by hepatic conjugation to inactive compounds that are excreted readily in the urine. Certain opioids (eg, propoxyphene, fentanyl, buprenorphine) are more lipid soluble and can be stored in the fatty tissues of the body. All opioids have a prolonged duration of action in patients with liver disease (eg, cirrhosis) because of impaired hepatic metabolism. This may lead to drug accumulation and opioid toxicity . Opiate metabolites are excreted in the urine. Impaired renal function can lead to toxic effects from accumulated drug or active metabolites (eg, normeperidine).

Epidemiology
Frequency
United States Opioids are prescribed widely, often in concert with other analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs) or muscle relaxants. Given all toxicologic presentations, pure opioid ingestions are generally a small proportion of ED overdose cases. The etiology of overdoses presenting to an ED often reflects local prescribing tendencies. Polypharmacy overdoses that include opioids can be a challenge for even the most experienced clinician. Fortunately, pharmacologic reversal of the opioid component can assist in the diagnosis of these potentially complex cases. Data from the Drug Abuse Warning Network (DAWN) from 1990-1996 indicated that the abuse of opioid analgesics (as recorded from the number of hospital ED visits) is low; compared with the abuse of other drugs, the abuse of opioid analgesics accounts for 3.8-5.1% of ED presentations. In 1998, a total of 36,848 opiate exposures (pure and mixed preparations) were reported to US poison control centers, of which 1227 (3.3%) resulted in major toxicity and 161 (0.4%) resulted in death. The CDC reports that methadone contributed to 31.4% of opioid-related deaths in the United States from 19992010. Methadone also accounted for 39.8% of all single-drug opioid-related deaths. The overdose death rate associated with methadone was significantly higher than that associated with other opioid-related deaths among multidrug and single-drug deaths.[6]

Mortality/Morbidity
The predominant cause of morbidity and mortality from pure opioid overdoses is respiratory compromise. Less commonly, acute lung injury, status epilepticus, and cardiotoxicity occur in the overdose setting. Case reports of increased incidence of mortality have been documented in patients with coexistent stenosing lesions of the upper airway.[7] Morbidities due to co-ingestants must be considered in polypharmacy overdoses, and they vary depending on the co-ingestant. Intent of the overdose also plays a role; the addition of suicidal intent is linked to increased emergency department usage,[8] and such intent could suggest higher dosages of narcotics or co-ingestants.

Contributor Information and Disclosures

Author Everett Stephens, MD Assistant Clinical Professor, Department of Emergency Medicine, University of Louisville Everett Stephens, MD is a member of the following medical societies: American Academy of Emergency Medicine Disclosure: Nothing to disclose. Specialty Editor Board Mark Louden, MD Assistant Professor of Clinical Medicine, Division of Emergency Medicine, Department of Medicine, University of Miami, Leonard M Miller School of Medicine
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Mark Louden, MD is a member of the following medical societies: American Academy of Emergency Medicine and American College of Emergency Physicians Disclosure: Nothing to disclose. John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals John T VanDeVoort, PharmD is a member of the following medical societies: American Society of HealthSystem Pharmacists Disclosure: Nothing to disclose. Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. John D Halamka, MD, MS Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine Disclosure: Nothing to disclose. Chief Editor Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital Disclosure: Nothing to disclose.

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