Opioids With Mixed Receptor Actions

OPIOIDS WITH MIXED RECEPTOR ACTIONS

Care should be taken not to administer any partial agonist or drug with mixed opioid receptor actions to patients receiving pure ago-nist drugs because of the unpredictability of both drugs’ effects; reduction of analgesia or precipitation of an explosive abstinence syndrome may result.

Phenanthrenes

Nalbuphine is a strongκ-receptoragonistand aμ-receptorantagonist; it is given parenterally. At higher doses there seems tobe a definite ceiling—not noted with morphine—to the respira-tory depressant effect. Unfortunately, when respiratory depression does occur, it may be relatively resistant to naloxone reversal.

Buprenorphine is a potent and long-acting phenanthrenederivative that is a partial μ-receptor agonist and a κ–receptor antagonist. Administration by the sublingual route is preferred to avoid significant first-pass effect. Its long duration of action is due to its slow dissociation from μ receptors. This property renders its effects resistant to naloxone reversal. Its clinical applications are much like those of nalbuphine. In addition, studies continue to suggest that buprenorphine is as effective as methadone in the detoxification and maintenance of heroin abusers. Buprenorphine was approved by the FDA in 2002 for the management of opioid dependence. In contrast to methadone, high-dose administration of buprenorphine results in a μ-opioid antagonist action, limiting its properties of analgesia and respiratory depression. Moreover, buprenorphine is also available combined with a pure μ-opioid antagonist (Suboxone) to help prevent its diversion for illicit intra-venous abuse. A slow-release transdermal patch preparation that releases drug over a 1-week period is also available.

Morphinans

Butorphanol produces analgesia equivalent to nalbuphine andbuprenorphine but appears to produce more sedation at equianal-gesic 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.

Benzomorphans

Pentazocine is aκagonist with weakμ-antagonist or partial ago-nist 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.

MISCELLANEOUS

Tramadol is a centrally acting analgesic whose mechanism of actionis predominantly based on blockade of serotonin reuptake. Tramadol has also been found to inhibit norepinephrine transporter function. Because it is only partially antagonized by naloxone, it is believed to be only a weak μ-receptor agonist. The recommended dosage is 50–100 mg orally four times daily. Toxicity includes association with seizures; the drug is relatively contraindicated in patients with a history of epilepsy and for use with other drugs that lower the seizure threshold. Another serious risk is the development of sero-tonin syndrome, especially if selective serotonin reuptake inhibitor (SSRI) antidepressants are being administered . Other side effects include nausea and dizziness, but these symptoms typically abate after several days of therapy. It is surprising that no clinically significant effects on respiration or the cardiovascular sys-tem have thus far been reported. Given the fact that the analgesic action of tramadol is largely independent of μ-receptor action, tra-madol may serve as an adjunct with pure opioid agonists in the treatment of chronic neuropathic pain.

Tapentadol is a newer analgesic with modestμ-opioid receptoraffinity and significant norepinephrine reuptake-inhibiting action. In animal models, its analgesic effects were only moderately reduced by naloxone but strongly reduced by an α₂-adrenoceptor antagonist. Furthermore, its binding to the norepinephrine trans-porter (NET) was stronger than that of tramadol, whereas its binding to the serotonin transporter (SERT) was less than that of tramadol. Tapentadol was approved in 2008 and hasbeen shown to be as effective as oxycodone in the treatment of moderate to severe pain but with a reduced profile of gastrointesti-nal complaints such as nausea. Tapentadol carries risk for seizures in patients with seizure disorders and for the development of sero-tonin syndrome. It is unknown how tapentadol compares in clini-cal utility to tramadol or other analgesics whose mechanism of action is not based primarily on opioid receptor pharmacology.