Opioid Agonist-Antagonist Drugs in Acute and Chronic Pain States

Abstract

The agonist-antagonist opioid analgesics are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as codeine and morphine but with a limited effective dose range. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine-like. Meptazinol does not fit into either classification and occupies a separate category Pentazocine, butorphanol and nalbuphine are weak μ-antagonists and κ-partial-agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is slightly less potent than morphine, and butorphanol is 3.5 to 7 times as potent. The duration of analgesia is similar to that of morphine (3 to 4 hours). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol (acetaminophen) than the weak opioid analgesics such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation At usual therapeutic doses nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (though the duration of such effects with butorphanol may be longer). Unlike morphine there appears to be a ceiling to both the respiratory depression and the analgesic action All of these 3 drugs have a lower abuse potential than the pure agonist opioid analgesics such as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to Controlled Drug restrictions Buprenorphine is a potent partial agonist at the M-receptor, and by intramuscular injection is 30 times as potent as morphine. A ceiling to the analgesic effect of buprenorphine has been demonstrated in animals and it is also claimed in humans. However, there are no reliable data available to define the maximal dose of buprenorphine in humans. A practical ceiling exists for sublingual use in that the only available formulation is a 2/ug tablet and few patients will accept more than 3 or 4 of these in a single dose. The duration of analgesia is longer than that of morphine, at 6 to 9 hours There have been suggestions that buprenorphine causes less respiratory depression than morphine, but viewed overall it appears that in equianalgesic doses the 2 drugs have similar respiratory depressant effects. Naloxone is relatively ineffective in reversing serious respiratory depression caused by buprenorphine Buprenorphine has a lower abuse potential than morphine, but misuse of this drug has been a growing problem in some areas. Buprenorphine is now a controlled drug Meptazinol is a synthetic hexahydroazepine derivative with opioid agonist and antagonist properties, but is unlike either the nalorphine-type agonist-antagonists, or buprenorphine. Meptazinol has central cholinergic properties which may account at least in part for its analgesic effects. Receptor binding studies show it to be a specific μ₁-agonist. Meptazinol is one-tenth as potent as morphine by intramuscular injection and has a duration of action of about 4 hours. Adverse effects — nausea, vomiting, sweating, dizziness and psychotomimetic symptoms — have been more frequent in some studies than with morphine, though respiratory depression and constipation appear to be less When viewed overall the evidence indicates few significant advantages of this group of drugs over the strong opioid agonists in the treatment of acute pain. Buprenorphine has established a place in the treatment of postoperative pain, partly because until recently it was not subject to controlled drug regulations. The recent change in its legal status removes an important advantage in the postoperative situation. Nalbuphine is an effective analgesic in myocardial infarction pain and has an advantage over morphine in that it is still not subject to the same legal restrictions on its storage and use. This has facilitated its use for emergency administration, particularly outside the hospital setting The agonist-antagonist analgesics do not have a major role in the treatment of chronic pain. Buprenorphine is potentially the most useful member of the group because it is potent, long-acting and effective when given sublingually