• DOI:10.2165/00003495-197305010-00002
• Corpus ID: 28014084

Pentazocine: A Review of its Pharmacological Properties, Therapeutic Efficacy and Dependence Liability

@article{Brogden2012PentazocineAR,
  title={Pentazocine: A Review of its Pharmacological Properties, Therapeutic Efficacy and Dependence Liability},
  author={Rex N. Brogden and Trevor M. Speight and Graeme S. Avery},
  journal={Drugs},
  year={2012},
  volume={5},
  pages={6-91}
}

• R. N. Brogden, T. Speight, G. Avery
• Published 2012
• Medicine, Biology
• Drugs

SummarySynopsis: Pentazocine2, the N-allyl derivative of the narcotic analgesic phenazocine, is a strong analgesic with weak narcotic antagonist activity. It is advocated for the relief of moderate to severe pain. Pentazocine has a low abuse potential and is not controlled by narcotic regulations. Therapeutic trials comparing pentazocine with other strong analgesics have shown it to possess a strong analgesic effect when given intramuscularly and a lesser analgesic effect when administered orally at a dose of 50 mg. There is evidence that a greater analgesic effect can be obtained with an oral dose of 100 mg. Pentazocine produces side-effects similar to those associated with the morphine-like analgesics, and as with these analgesics the effects are exaggerated in ambulatory patients. Unlike the narcotic antagonist nalorphine, pentazocine produces only occasional subjective psychotomimetic effects at usual therapeutic doses.Pharmacodynamic studies in animals have shown pentazocine to be a potent analgesic, but only a weak narcotic antagonist. In comparison with nalorphine, pentazocine was approximately one-fifth to one-sixth as potent as an analgesic (on a weight for weight basis), but only one-fiftieth to one two-hundredth as potent as a narcotic antagonist. As with nalorphine, the analgesic potency of pentazocine was able to be demonstrated in some laboratory procedures, but not others. Pentazocine was approximately one-quarter to one-fifth as active as morphine in the phenylquinone-writhing and flinch-jump tests in rats, but in contrast to morphine, the analgesic efficacy of pentazocine exhibited a relatively low ceiling effect. Whereas the efficacy of morphine (as well as that of pethidine) increased markedly with increasing dosage and was uninfluenced by the intensity of the pain stimulus, the efficacy of pentazocine was reduced when the intensity of stimulus was increased. This finding suggests that there may be a limit to the analgesia which pentazocine can provide, although such a phenomenon has not been demonstrated in man. As with other antagonists, the analgesic effect of pentazocine may be mediated, at least in part, by receptors distinct from those which mediate the effect of morphine.In man, the peak analgesic effect of pentazocine occurred within 1 hour after an intramuscular dose of 45 mg/70 kg and within 15 minutes after an intravenous dose of 20 mg/70 kg, but peak analgesia was more delayed after oral administration and did not occur until 1 to 3 hours after an oral dose of 75 mg. The duration of analgesia however, was more prolonged with oral administration than with parenteral administration. In comparison with morphine, the analgesic effect of pentazocine reached a higher initial peak, although it declined more rapidly. The analgesic efficacy of pentazocine was shown to reside mainly in its 1-isomer.The respiratory depressant effect of pentazocine in comparison with that of other strong analgesic drugs remains a disputed point, particularly as respiratory depression has not proved a significant problem with pentazocine in clinical practice. Although pentazocine is claimed to be relatively free from the severe respiratory depression associated with morphine, parenteral doses of 20 mg/70 kg pentazocine in healthy conscious subjects were shown to cause the same degree of respiratory depression as 10 mg/70 kg morphine. When this is compared with estimates of relative analgesic potency (vide infra), there can be no reason to suppose therefore, that pentazocine produces less respiratory depression than an equianalgesic dose of morphine. In terms of displacement of the carbon dioxide respiratory response curve, 21 mg of pentazocine was estimated to be equivalent to 10 mg morphine, but whilst pentazocine achieved a higher initial peak effect, it showed a more rapid decline than morphine. In a comparison of pentazocine and pethidine in conscious subjects, single intravenous doses of 15 mg/70 kg pentazocine produced a similar respiratory depressant effect to that of 50 mg/70 kg pethidine. However, in contrast to pethidine, pentazocine did not cause a cumulative respiratory depressant effect following repeated administration. Although nalorphine and levallorphan did not antagonise the effects of pentazocine, reversal of pentazocine-induced respiratory depression may be achieved by the administration of the analeptics methylphenidate and nikethamide, and also by the narcotic antagonist naloxone.Pentazocine differs in its cardiovascular effects from the classical morphine pattern of hypotension and bradycardia, in that most investigators have observed a slight rise in blood pressure and a slight increase in heart rate following its administration. These effects were shown to be associated with an increase in plasma catecholamine levels, suggesting that an increase in sympathetic activity may be the mechanism of pentazocine-induced circulatory changes. In patients with myocardial infarction, pentazocine unlike morphine, caused a rise in blood pressure and a decrease in the physiological dead space/tidal volume ratio and alveolar/arterial oxygen tension difference, but it also caused a significant increase in pulmonary artery pressure. As the latter finding may be due to an elevation of left ventricular end-diastolic pressure, pentazocine should be used with caution in patients with myocardial infarction, particularly in those with evidence of left ventricular failure.In other studies, pentazocine was shown to cause a delay in gastric emptying and a reduction in propulsive motility of the small intestine, but it had no significant effect on renal function or on pupillary constriction. Uterine activity was increased by pentazocine and the second stage of labour was slightly (but not significantly) shortened when compared with pethidine. In patients who were either undergoing intracranial operations or had severe head injuries, pentazocine did not cause a rise in intracranial pressure when respiration was controlled (and arterial Pco2 was kept at a constant level), but an increase in intracranial pressure was observed in spontaneously breathing patients when the arterial Pco2 level was raised.
Pharmacokinetic studies: The absorption, metabolism and excretion of pentazocine have been well studied. Pentazocine is well absorbed by all the common routes of administration, but the blood levels show considerable individual variation and a tendency to fluctuate in any one patient. Absorption is slower after oral administration than after parenteral administration, but the blood levels achieved correlate well with the onset, duration and intensity of analgesia in each case. Peak blood levels are reached within 15 to 60 minutes after intramuscular administration but not until after 1 to 3 hours following oral administration. Comparable blood levels are achieved by 75 mg orally and 40 mg intramuscularly. The plasma half-life of pentazocine is approximately 2 hours after intravenous or intramuscular administration.The intersubject variation in the blood levels reached is evidently due to individual differences in the rate of metabolism. Pentazocine is extensively metabolised in the liver and only 2 to 12 % of the administered dose is excreted as the unchanged drug. Due to the slower rate of absorption, pentazocine is more extensively metabolised when given orally than by the parenteral route; after oral administration, up to 25 % of the drug was present in the plasma as a metabolite, but after intramuscular administration, this metabolite was not detected. In man, hepatic biotransformation involves oxidation of the methyl groups to yield the ‘cis’-alcohol and ‘trans’-acid metabolites. Individual differences in the ability to metabolise pentazocine result in higher concentrations of unchanged drug in some subjects, and hence a greater and more intense pharmacological effect. This may account for individual differences in the therapeutic efficacy of the drug, and for differences in the incidence of side-effects.Pentazocine is mainly excreted in the urine, both as the unchanged drug and as the metabolised form. The excretion is rapid as most of the drug is excreted within the first 12 hours. Faecal excretion accounts for less than 2 % of the administered dose whether the drug is given orally, parenterally or rectally. Pentazocine crosses the placental barrier in man, but to a lesser extent than pethidine.
Therapeutic trials: There are many published reports involving a large number of patients, which have shown that parenteral or oral pentazocine is an effective analgesic for the relief of moderate to severe pain resulting from a wide range of surgical procedures and medical conditions. A 30 mg intramuscular dose has given adequate relief of moderate to severe pain in the majority of postoperative patients, but in some studies about one-fifth of patients have required higher doses (45 to 60 mg) for satisfactory relief of pain. Although many of the studies have been conducted under double-blind conditions and have been able to show that the analgesic activity of intramuscular or intravenous pentazocine is comparable with that of selected doses of morphine or pethidine, varying methodology and premedications (some of which employed strong analgesics), small numbers of patients and insensitive methods of evaluation have made it difficult to determine if equianalgesic doses have been used, except in a few well designed and carefully conducted trials. The better studies have employed more than one dosage level of pentazocine and a standard analgesic, and have attempted to select patients likely to have a similar need for analgesia, or have studied large numbers of patients. They have also attempted to standardise environmental factors, to determine equianalgesic doses from dose-response curves, or to distinguish between sedation and analgesia by the use of objective criteria.In one study involving over 1,000 patients with