Opioid Analgesics: Opioid Antagonists

Opioid Antagonists

Naloxone and naltrexone are pure opioid antagonists synthesized by relatively minor changes in the morphine structure. Alteration of the substituent on the piperidine nitrogen from a methyl group to a longer side chain changes the drug from an agonist to an antagonist.

Opioid antagonists bind to the opioid receptor with high affinity and have low efficacy. The pure antagonists block the effects of opioids at all opioid receptors. However, as previously discussed, the dose required for naloxone blockade of the μ-receptor versus the - opioid receptor is several times as much. All opioid an-tagonists will precipitate withdrawal in opioid-depend-ent patients.

Naloxone

Because of its fast onset (minutes), naloxone (Narcan) administered IV is used most frequently for the rever-sal of opioid overdose. However, it fails to block some side effects of the opioids that are mediated by the - receptor, such as hallucinations. The rapid offset of naloxone makes it necessary to administer the drug re-peatedly until the opioid agonist has cleared the system to prevent relapse into overdose. The half-life of nalox-one in plasma is 1 hour. It is rapidly metabolized viaglucuronidation in the liver and cleared by the kidney. Naloxone given orally has a large first-pass effect, which reduces its potency significantly. Often an overshoot will follow the administration of naloxone for overdose. The heart rate and blood pressure of the patient may rise significantly. The overshoot is thought to be due to precipitation of acute withdrawal signs by naloxone. Given alone to nonaddicts, naloxone produces no phar-macological effects.

Naloxone is approved for use in neonates to reverse respiratory depression induced by maternal opioid use. In addition, naloxone has been used to improve circula-tion in patients in shock, an effect related to blockade of endogenous opioids. Other experimental and less well documented uses for naloxone include reversal of coma in alcohol overdose, appetite suppression, and allevia-tion of dementia from schizophrenia. Side effects of naloxone are minor

Naltrexone

Naltrexone (Trexan) is three to five times as potent as naloxone and has a duration of action of 24 to 72 hours, depending on the dose. It is used orally in the treatment of opioid abstinence. Naltrexone exhibits a large first-pass effect in the liver. However, the major metabolite, 6- β-naltrexol, is also a pure opioid antagonist and con-tributes to the potency and duration of action of nal-trexone. Administration of naltrexone orally blocks the subjective effects of abused opioids and is used to de-crease the craving for opioids in highly motivated re-covering addicts. However, high doses of the opioids can overcome the naltrexone blockade and lead to seizures or respiratory depression and death. In addi-tion, it has been reported recently that naltrexone can reduce the craving for alcohol in alcoholic patients. Naltrexone also has been used with success in treating apneic episodes in children, an effect hypothesized to be due to blockade of -endorphin–induced respiratory depression.

Naltrexone can induce hepatotoxicity at doses only five times the therapeutic dose and should be used with care in patients with poor hepatic function or liver dam-age. Side effects of the use of naltrexone are more fre-quently observed than following naloxone administra-tion. Such side effects include headache, difficulty sleeping, lethargy, increased blood pressure, nausea, sneezing, delayed ejaculation, blurred vision, and in-creased appetite.

Nalmefene

Nalmefene (Revex) is a long-acting injectable pure opi-oid antagonist recently introduced in the United States. It binds all opioid receptors and reverses the effects of opioid agonists at those receptors. The onset of action is2 minutes after IV administration. Hepatic metabolism is slow and occurs via glucuronide conjugation to inac-tive metabolites. Its half-life of 11 hours is about 5 times that of naloxone. Indications include use in postopera-tive settings to reverse respiratory depression and in opioid overdose. Due to the long duration of action of nalmefene, however, naloxone may be preferred for treatment of overdose because it produces a shorter du-ration of withdrawal effects.