As noted above, buprenorphine is a potent and long-acting phenanthrene derivative that is a partial μ-receptor agonist (low intrinsic activity) and an antagonist at the δ and κ receptors and is therefore referred to as a mixed agonist-antagonist. Although buprenorphine is used as an analgesic, it can antagonize the action of more potent μ agonists such as morphine. Buprenorphine also binds to ORL1, the orphanin receptor. Whether this property also participates in opposing μ receptor function is under study. Administration by the sublingual route is preferred to avoid significant first-pass effect. Buprenorphine’s long duration of action is due to its slow dissociation from μ receptors. This property renders its effects resistant to naloxone reversal. Buprenorphine was approved by the FDA in 2002 for the management of opioid dependence, and studies suggest it is as effective as methadone for the management of opioid withdrawal and detoxification in programs that include counseling, psychosocial support, and direction by physicians qualified under the Drug Addiction Treatment Act. In the USA, a special Drug Enforcement Administration (DEA) license and training are needed to legally prescribe buprenorphine for addiction. In contrast to methadone, high-dose administration of buprenorphine results in a μ-opioid antagonist action, limiting its properties of analgesia and respiratory depression. However, buprenorphine formulations can still cause serious respiratory depression and death, particularly when extracted and injected intravenously in combination with benzodiazepines or used with other CNS depressants (ie, sedatives, antipsychotics, or alcohol). Buprenorphine is also available combined with naloxone, a pure μ-opioid antagonist (as Suboxone), to help prevent its diversion for illicit intravenous misuse. A slow-release transdermal patch preparation that releases drug over a 1-week period is also available (Butrans). Most recently, the FDA approved an implanted buprenorphine rod (Probuphine) that lasts for 6 months and is meant to deter misuse. Psychotomimetic effects, with hallucinations, nightmares, and anxiety, have been reported after use of drugs with mixed agonist-antagonist actions.
Pentazocine (a benzomorphan) and nalbuphine are other examples of opioid analgesics with mixed agonist-antagonist properties. Nalbuphine is a strong κ-receptor agonist and a partial μ-receptor antagonist; it is given parenterally. At higher doses there seems to be a definite ceiling—not noted with morphine—to the respiratory depressant effect. Unfortunately, when respiratory depression does occur, it may be relatively resistant to naloxone reversal due to its greater affinity for the receptor than naloxone. Nalbuphine is equipotent to morphine for analgesia and, at lower doses, can be effective for pruritus for opioid and nonopioid etiologies.
Butorphanol produces analgesia equivalent to nalbuphine but appears to produce more sedation at equianalgesic doses. Butorphanol is considered to be predominantly a κ agonist. However, it may also act as a partial agonist or antagonist at the μ receptor.
Pentazocine is a κ agonist with weak μ-antagonist or partial agonist properties. It is the oldest mixed agent available. It may be used orally or parenterally. However, because of its irritant properties, the injection of pentazocine subcutaneously is not recommended.