Pure Opioid Antagonists

PURE OPIOID ANTAGONISTS

Naloxone

It is N-alyl-noroxymorphone and a competitive antagonist on all types of opioid receptors. However, it blocks μ receptors at much lower doses than those needed to block κ or δ receptors. It is devoid of any kind of agonistic activity even at high doses (20 times μ blocking dose). No subjective or autonomic effects are produced in individuals who have not received an opioid. No physical/psychological dependence or abstinence syndrome has been observed.

Injected intravenously (0.4–0.8 mg) it promptly antagonizes all actions of morphine: analgesia is gone, respiration is not only normalized but stimulated—probably due to sudden sensitization of respiratory centre to retained CO₂, or it is a manifestation of acute withdrawal, pupils dilate. However, sedation is less completely reversed.

At 4–10 mg dose it also antagonizes the agonistic actions of nalorphine, pentazocine, etc., but the dysphoric and psychotomimetic effects of some of them are incompletely suppressed: the naloxone insensitive component is believed to be mediated through σ receptors.

Actions of buprenorphine are prevented but not effectively reversed by naloxone, because it fails to displace buprenorphine that has already bound to the opioid receptors.

Naloxone 0.4 mg i.v. precipitates morphine withdrawal in dependent subjects: the syndrome lasts for 2–3 hours; 5 mg or more is required to precipitate nalorphine and pentazocine withdrawal.

Naloxone also blocks the actions of endogenous opioid peptides (see below). These peptides have been implicated in a variety of physiological functions; it is surprizing that naloxone does not produce hyperalgesia or other effects in normal individuals. However, it has been found to render those individuals more susceptible to pain who normally have high tolerance. It blocks placebo, acupuncture and stress induced analgesia: showing involvement of endogenous opioid peptides in these. Naloxone partly antagonizes respiratory depression produced by certain nonopioids also, e.g. N₂O, diazepam.

Naloxone is inactive orally because of high first pass metabolism in liver. Injected i.v. it acts in 2–3 min. The primary pathway of metabolism is glucuronidation. Plasma t½ is 1 hour in adults and 3 hours in newborns.

Adverse effects of naloxone are uncommon; may include rise in BP and pulmonary edema.

NARCOTAN 0.4 mg in 1 ml (adult) and 0.04 mg in 2 ml (infant) amps; NALOX, NEX 0.4 mg inj.

Use

Naloxone is the drug of choice for morphine poisoning (0.4–0.8 mg i.v. every 2–3 min: max 10 mg) and for reversing neonatal asphyxia due to opioid use during labour (10 μg/kg in the cord). It is also used to treat overdose with other opioids and agonist-antagonists (except buprenorphine).

Other possible clinical applications of naloxone are:

ü To reverse respiratory depression due to intraoperative use of opioids: 0.1–0.2 mg i.v. (this dose usually preserves analgesia in the postoperative period).

ü It has also been tried as an adjunct to intraspinal opioid analgesia: reverses respiratory depression without abolishing pain relief.

ü Diagnosis of opioid dependence—precipitates withdrawal in dependent subjects.

ü It also partially reverses alcohol intoxication.

ü Naloxone has been found to elevate BP in endotoxic or hypovolaemic shock, stroke and spinal injury. In these conditions injection of morphine worsens cardiovascular status and opioid peptides are believed to be involved in the pathogenesis. However, the value of naloxone compared to conventional therapy is uncertain.

Naltrexone

It is chemically related to naloxone and is another pure opioid antagonist, that is devoid of subjective and other agonistic effects, but very high doses have caused unpleasant feelings in some individuals. It is more potent than naloxone. Naltrexone differs from naloxone in being orally active and having a long duration of action (1–2 days) which makes it suitable for ‘opioid blockade’ therapy of post-addicts: 50 mg/ day is given orally so that if the subject takes his/ her usual shot of the opioid, no subjective effects are produced and the craving subsides. Alcohol craving is also reduced by naltrexone; it is being used to prevent relapse of heavy drinking. Side effects are nausea and headache; high doses can cause hepatotoxicity.

NALTIMA 50 mg tab.

Nalmefene

This pure opioid antagonist lacks hepatotoxicity of naltrexone, has higher oral bioavailability and is longer acting.