Dezocine

Summary

Synopsis

Dezocine is an analgesic agent with opioid agonist and antagonist activity. After parenteral administration of therapeutic doses it is approximately equipotent with morphine, and has proved at least as effective an analgesic as morphine, pethidine (meperidine) and butorphanol in moderate to severe postoperative pain. However, preliminary pharmacodynamic data indicate that the ceiling of analgesic activity of dezocine occurs at a higher level of analgesia than that of reference agonist/antagonist agents. Also, the drug exhibited a morphine-like degree of anaesthetic-sparing activity in animals.

Although long term data are very limited, single doses of dezocine are well tolerated, with mild and transient sedation and gastrointestinal upset the principal adverse effects. As with some other agonist/antagonist analgesics, a ‘ceiling’ effect to dezocine-induced respiratory depression occurs with increasing dosage, beyond which further depression has not been observed. In single analgesic doses, however, dezocine is a slightly more potent respiratory depressant than morphine. Clinically important haemodynamic changes have not been observed with usual analgesic doses of dezocine.

As an agonist/antagonist opioid, the dependence liability of dezocine would be expected to be lower than that of pure agonist opioids, but extended clinical use is required before more definitive conclusions can be drawn in this regard. Unlike older drugs of its type, dezocine produced opiate-like subjective effects and was identified as morphine-like by drug abusers.

Thus, provided the promising conclusions of currently available clinical studies are confirmed with its wider use, dezocine should be a useful additional agent for the treatment of moderate to severe postoperative pain.

Pharmacodynamic Properties

The opioid agonist activity of dezocine has been demonstrated in tests of analgesia in rodents and monkeys, in which the drug proved substantially more potent than standard centrally acting analgesics such as morphine, codeine and pentazocine. In animal behavioural tests, dezocine acted as a positive reinforcer, and shared discriminative stimulus properties with morphine and etorphine, but not ethylketazocine. As with several other drugs of this class, dezocine proved relatively resistant to reversal by classic opioid antagonists in animal models. However, its effects are fully reversible with naloxone in humans. Successive intravenous doses of dezocine 0.15 mg/kg in healthy volunteers produced a ceiling or plateau in the analgesic effect at 0.30 mg/kg, with further doses failing to increase the level of analgesia. In clinical studies of postoperative pain, dezocine provided dose-dependent analgesia with parenteral doses of 5 to 20mg. Dezocine is estimated to be 5 to 9 times more potent than pethidine (meperidine), of similar potency to morphine (although there are minor differences in the time course of analgesia with the 2 agents), and one-fifth as potent as butorphanol. The anaesthetic-sparing effect of dezocine in animals is much greater than that of older agonist-antagonist opioids such as butorphanol and nalbuphine, and approaches that of morphine and fentanyl.

Typical opioid antagonistic activity exhibited by dezocine includes dose-related reversai of morphine-induced loss of righting reflex, body rigidity and respiratory depression. In contrast to nalorphine, dezocine did not induce the jumping response in morphine-treated rodents, but did produce a severe abstinence syndrome in morphine-dependent monkeys.

At therapeutic doses in humans (e.g. 10 mg/70kg), dezocine is a more potent respiratory depressant than morphine during the first hour after administration. However, unlike the dose-dependent respiratory effects of morphine, dezocine-induced respiratory depression reached a ceiling at a dose of approximately 0.30 to 0.40 mg/kg. The ceiling respiratory and analgesic activities of dezocine occurred at the same dosage, and both maximal responses were greater than similar plateau effects previously reported for nalbuphine. The administration of dezocine to morphine-treated volunteers produced an additive analgesic effect, but the respiratory depression associated with the combination given in this order did not exceed that normally associated with dezocine alone.

Dezocine has not been associated with clinically significant haemodynamic changes following administration to patients with postoperative or other pain, or those undergoing diagnostic cardiac catheterisation. Unlike morphine, dezocine did not cause hypotension in the latter group of patients. The limited information available indicates that, as with other agonist/antagonists, the dependence liability of dezocine is likely to be much lower than that of the classic opiates such as morphine. Long term administration of dezocine did not produce addiction in monkeys, but it was equipotent with morphine in producing opiate-like effects, including euphoria, and was consistently identified as ‘dope’ when administered to drug abusers. In this latter regard dezocine differs from other agonist/antagonist drugs such as nalbuphine, pentazocine and cyclazocine, which produce a profile of signs and symptoms readily distinguishable from those of morphine.

Pharmacokinetic Properties

Only very limited data are available concerning the pharmacokinetic disposition of dezocine in humans. Following intravenous administration to healthy male volunteers, dezocine underwent biphasic elimination, with a rapid initial distribution phase. The elimination half-life was approximately 2.5 hours in these subjects. The mean peak serum dezocine concentration of 19 μg/L occurred 35 minutes after a 10mg intramuscular dose in healthy males, while a mean peak concentration of 11 μg/L occurred 1.2 hours after the same dose administered subcutaneously. Animal studies indicate extensive distribution of dezocine, with drug concentrations in highly perfused tissues exceeding that of plasma. The very high systemic clearance of 14C-dezocine in healthy volunteers and animals indicates biliary secretion to be a significant route of elimination of the parent drug and its metabolites.

Therapeutic Trials

Dezocine, usually administered in single intravenous or intramuscular doses, has been compared with the established opioid analgesics morphine, pethidine and butorphanol, and with placebo in patients with moderate to severe pain. The majority of these patients were suffering from postoperative pain, although patients with renal colic and severe cancer pain have also been treated with dezocine. Single doses of dezocine 5 to 15mg produced dose-dependent analgesia in each pain state. The onset and duration of action and magnitude of peak analgesic effect were similar after 10mg doses of dezocine and morphine. However, patient and physician evaluations consistently favoured dezocine. In postoperative pain studies, dezocine was estimated to be 5 to 9 times more potent than pethidine, and approximately one-fifth as potent as butorphanol; once again, at similar analgesic doses patients’ and physicians’ overall impressions usually favoured dezocine over the alternative agent.

In 1 study multiple-dose administration of dezocine for up to 7 days was found to be superior to butorphanol. In contrast to the increasing toxicity of butorphanol, which usually led to its discontinuation, multiple doses of dezocine did not result in either tolerance or limiting adverse effects.

Adverse Effects

Dezocine is at least as well tolerated as morphine, pethidine and butorphanol after single-dose parenteral administration. Overall, the adverse effects of dezocine have been mild, transient events of dose-dependent incidence. The most frequent adverse effects are nausea/vomiting and somnolence, each with a variable incidence of up to 20%. Effects such as dizziness, anxiety, sweating and tachycardia have also been reported, usually at an incidence of less than 5%. In therapeutic doses dezocine does not produce clinically significant respiratory depression. Further information is required to more fully establish the drug’s adverse effect profile during long term use.

Dosage

In most situations of moderate to severe pain, the effective adult dose of dezocine will be in the range 10 to 15mg, administered intravenously or intramuscularly, repeated 2- to 4-hourly as required. Dezocine has not been evaluated in children, and caution should be observed in patients with renal and especially hepatic dysfunction, and those with compromised respiratory or cardiovascular status.