AGONIST-ANTAGONIST OPIOID COMPOUNDS
Nalorphine, the first agonist-antagonist opioid, was successfully
synthesized by Weijland and Erickson in 1942 and was found to be strongly antagonistic
to almost all the properties of morphine. Although nalorphine was found to possess
strong analgesic actions, it was unsuitable for clinical uses because of its psychotomimetic
effects. Nalorphine was used in lower doses as an opioid antagonist.
Agonist-antagonist opioids are usually produced by alkylation
of the piperidine nitrogen and addition of a three-carbon side chain such as a propyl,
allyl, or methyl allyl to morphine. Buprenorphine is a partial agonist at the μ-receptor.
The other compounds are μ-antagonists and full or partial agonists at the κ-receptors.
Agonist-antagonist opioids are less prone (but not immune) to abuse because they
cause less euphoria and are associated with less drug-seeking behavior and physical
dependence.
Dosing data for these compounds are shown in Table
11-10
. The agonist-antagonist compounds depress respiration similar to
morphine, but ceiling effects exist ( Table
11-11
). Effects on the cardiovascular system differ among these compounds
( Table 11-12
).
TABLE 11-11 -- Respiratory depressant effects of agonist-antagonists compared with morphine
*
|
Drug |
Correlation of Respiratory Depression with
Dose |
|
Morphine |
Increases proportionally with dose |
|
Buprenorphine |
Ceiling effect at 0.15–1.2 mg in adults |
|
Butorphanol |
Ceiling effect at 30–60 µg • kg-1
|
|
Nalbuphine |
Ceiling effect at 30 mg in adults |
|
Pentazocine |
Ceiling effect suggested, but difficult to study because of psychotomimetic
effects |
|
From Zola EM, McLeod DC: Comparative effects of analgesic
efficacy of the agonist-antagonist opioids. Drug Intell Clin Pharm 17:411, 1983. |
*
Low or moderate naloxone doses readily reverse the respiratory effects produced by
therapeutic doses of all drugs listed, except buprenorphine.
Pentazocine
Analgesia produced by pentazocine is primarily related to κ-receptor
stimulation. Pentazocine is one half to one fourth as potent as morphine. Ceilings
to both analgesia and respiratory depression occur after 30 to 70 mg of pentazocine.
Although the potential for abuse is less than with morphine, prolonged use of pentazocine
can lead to physical dependence. Nalorphine-like dysphoric side effects are common,
especially after high doses (>60 mg) of pentazocine in the elderly. The dysphoric
effects of pentazocine can be reversed with naloxone. Pentazocine depresses myocardial
contractility and increases arterial blood pressure, heart rate, systemic vascular
resistance, pulmonary artery pressure, and left ventricular work index. Pentazocine
also increases blood catecholamine levels.
Pentazocine inhibits gastric emptying and gastrointestinal transit
in rats, whereas U50488H, a pure κ-receptor agonist, did not significantly
inhibit either.[476]
Therefore, it is speculated
that pentazocine may affect gastrointestinal function through a mechanism other than
the opioid receptors. Because pentazocine is associated with a high incidence of
postoperative nausea and vomiting, it provides limited analgesia. It partially antagonizes
other opioids, and it can produce undesirable cardiovascular and psychotomimetic
effects.
