Kaplan + Sadock's Synopsis of Psychiatry, 11e

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29.25 Opioid Receptor Antagonists: Naltrexone, Nalmefene, and Naloxone

Table 29.25-1 Naloxone (Narcan) Challenge Test

in the United States. Nalmefene (Revex) is an opioid receptor antagonist that is sometimes used in the management of alcohol dependence. Pharmacological Actions Oral opioid receptor antagonists are rapidly absorbed from the gastrointestinal (GI) tract, but because of first-pass hepatic metabolism, only 60 percent of a dose of naltrexone and 40 to 50 percent of a dose of nalmefene reach the systemic circula- tion unchanged. Peak concentrations of naltrexone and its active metabolite, 6- b -naltrexol, are achieved within 1 hour of ingestion. The half-life of naltrexone is 1 to 3 hours and the half-life of 6- b -naltrexol is 13 hours. Peak concentrations of nalmefene are achieved in about 1 to 2 hours, and the half-life is 8 to 10 hours. Clinically, a single dose of naltrexone effectively blocks the rewarding effects of opioids for 72 hours. Traces of 6- b -naltrexol may linger for up to 125 hours after a single dose. Naltrexone and nalmefene are competitive antagonists of opioid receptors. Understanding the pharmacology of opioid receptors can explain the difference in adverse effects caused by naltrexone and nalmefene. Opioid receptors in the body are typed pharmacologically as m , k , or d . Whereas activa- tion of the k - and d -receptors is thought to reinforce opioid and alcohol consumption centrally, activation of m -receptors is more closely associated with central and peripheral antiemetic effects. Because naltrexone is a relatively weak antagonist of k - and d -receptors and a potent m -receptor antagonist, dosages of naltrexone that effectively reduce opioid and alcohol consump- tion also strongly block m -receptors and therefore may cause nausea. Nalmefene, in contrast, is an equally potent antagonist of all three opioid receptor types, and dosages of nalmefene that effectively reduce opioid and alcohol consumption have no particularly increased effect on m -receptors. Thus, nalmefene is associated clinically with few GI adverse effects. Naloxone has the highest affinity for the m -receptor but is a competitive antagonist at the m -, k -, and d -receptors. Whereas the effects of opioid receptor antagonists on opioid use are easily understood in terms of competitive inhibition of opioid receptors, the effects of opioid receptor antagonists on alcohol dependence are less straightforward and probably relate to the fact that the desire for and the effects of alcohol consump- tion appear to be regulated by several neurotransmitter systems, both opioid and nonopioid. Therapeutic Indications The combination of a cognitive-behavioral program plus use of opioid receptor antagonists is more successful than either the cognitive-behavioral program or use of opioid receptor antago- nists alone. Naltrexone is used as a screening test to ensure that the patient is opioid-free before the induction of therapy with naltrexone (see “Naloxone Challenge Test” in Table 29.25-1). Opioid Dependence Patients in detoxification programs are usually weaned from potent opioid agonists such as heroin over a period of days to weeks, during which emergent adrenergic withdrawal effects are treated as needed with clonidine (Catapres). A serial protocol is

sometimes used in which potent agonists are gradually replaced by weaker agonists followed by mixed agonist–antagonists and then finally by pure antagonists. For example, an abuser of the potent agonist heroin would switch first to the weaker agonist methadone (Dolophine), then to the partial agonist buprenor- phine (Buprenex) or levomethadyl acetate (ORLAAM)—commonly called LAAM—and finally, after a 7- to 10-day washout period, to a pure antagonist, such as naltrexone or nalmefene. However, even with gradual detoxification, some persons continue to experience mild adverse effects or opioid withdrawal symptoms for the first several weeks of treatment with naltrexone. As the opioid receptor agonist potency diminishes, so do the adverse consequences of discontinuing the drug. Thus, because there are no pharmacological barriers to discontinuation of pure opioid receptor antagonists, the social environment and frequent cognitive-behavioral intervention become extremely important factors supporting continued opioid abstinence. Because of poorly tolerated adverse symptoms, most persons not simulta- neously enrolled in a cognitive-behavioral program stop taking opioid receptor antagonists within 3 months. Compliance with the administration of an opioid receptor antagonist regimen can also be increased with participation in a well-conceived voucher program. The naloxone challenge test should not be performed in a patient showing clinical signs or symptoms of opioid withdrawal or in a patient whose urine contains opioids. The naloxone challenge test may be administered by either the intravenous (IV) or the subcutaneous route. IV challenge: After appropriate screening of the patient, 0.8 mg of naloxone should be drawn into a sterile syringe. If the IV route of administration is selected, 0.2 mg of naloxone should be injected, and while the needle is still in the patient’s vein, the patient should be observed for 30 seconds for evidence of withdrawal signs or symptoms. If there is no evidence of withdrawal, the remaining 0.6 mg of naloxone should be injected and the patient observed for an additional 20 minutes for signs and symptoms of withdrawal. Subcutaneous challenge: If the subcutaneous route is selected, 0.8 mg should be administered subcutaneously and the patient observed for signs and symptoms of withdrawal for 20 minutes. Conditions and technique for observation of patient: During the appropriate period of observation, the patient’s vital signs should be monitored, and the patient should be monitored for signs of withdrawal. It is also important to question the patient carefully. The signs and symptoms of opioid withdrawal include, but are not limited to, the following: Withdrawal signs: Stuffiness or running nose, tearing, yawning, sweating, tremor, vomiting, or piloerection Withdrawal symptoms: Feeling of temperature change, joint or bone and muscle pain, abdominal cramps, and formication (feeling of bugs crawling under skin) Interpretation of the challenge: Warning —the elicitation of the enumerated signs or symptoms indicates a potential risk for the subject, and naltrexone should not be administered. If no signs or symptoms of withdrawal are observed, elicited, or reported, naltrexone may be administered. If there is any doubt in the observer’s mind that the patient is not in an opioid-free state or is in continuing withdrawal, naltrexone should be withheld for 24 hours and the challenge repeated.