Pentazocine: A Review of its Pharmacological Properties, Therapeutic Efficacy and Dependence Liability
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- Brogden, R.N., Speight, T.M. & Avery, G.S. Drugs (1973) 5: 6. doi:10.2165/00003495-197305010-00002
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Synopsis: 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 postoperative pain, the peak analgesic effect of intramuscular pentazocine 27 mg was comparable with that of 10 mg morphine given by the same route, but when total analgesia over a period of about 4 hours was compared, 36 mg of pentazocine was required to produce an effect equal to that of morphine 10 mg. Although pentazocine achieved a higher level of analgesia initially, its effect declined more rapidly than after morphine. This was even more pronounced in studies involving patients with chronic pain due to cancer, in which 60 mg of pentazocine provided total analgesia similar to that of morphine 10 mg. In a double-blind placebo-controlled study which evaluated the analgesic efficacy of two dose levels of pentazocine and 12 other intramuscular analgesics (3 at 2 dose levels) in relieving pain resulting from abdominal surgery, and which was designed to favour drugs which provided pain relief with minimal depression of consciousness, only levorphanol 2 mg proved superior to pethidine 100 mg (used as the standard for comparison). Oxycodone 10 mg, pentazocine 20 mg and a combination of morphine 10 mg and cyclizine 50 mg were the most successful of the remaining drugs when based on all recorded criteria. In another study, whereas an average intravenous dose of 33 mg of pethidine provided slightly better analgesia and a greater degree of sedation than an average intravenous dose of 19 mg of pentazocine, other workers found 40 mg of pentazocine given intramuscularly to be superior to pethidine 100 or 50 mg, or to pentazocine 20 mg in relieving postoperative pain. However, in this study no difference between the analgesic efficacy of the two doses of pethidine could be demonstrated.
Evaluations of the sedative effect of pentazocine when used as a pre-operative medication have also yielded variable findings. Whereas in one study the sedative effect of pentazocine 60 mg was slightly less than that of morphine 10 mg and pethidine 100 mg 60 to 90 minutes after intramuscular injection, other workers were unable to distinguish between the sedative effect of morphine and pentazocine used in the ratio of 1:2 to 1:4. These differences may have been related to the time after injection that evaluations were performed.
As a supplement to nitrous oxide-oxygen anaesthesia, intravenous pentazocine was unsatisfactory in some ‘poor risk’ patients in whom pentazocine alone was the only supplement to anaesthesia, but in other studies it had provided satisfactory analgesia during major surgery when preceded by premedication with promethazine, and was considered a satisfactory replacement for phenoperidine in neuroleptanalgesia.
When used during active labour, 30 to 60 mg pentazocine intramuscularly provided some degree of analgesia in the majority of patients without noticeably influencing the maternal blood pressure or heart-rate, or the progress of normal labour. Neonatal distress could be related to pentazocine only when an interval of less than 2 hours was allowed between injection and delivery or between consecutive doses. The incidence of nausea and vomiting has generally been lower after pentazocine than after approximately equianalgesic doses of pethidine.
Pentazocine 30 mg intravenously or 60 mg intramuscularly has provided some relief of pain in most patients with myocardial infarction or acute coronary insufficiency. It has been suggested that the tendency for pentazocine to cause slight elevation of blood pressure rather than the hypotension associated with the use of other analgesics such as morphine, may make pentazocine a more suitable analgesic than morphine for the treatment of pain in myocardial infarction. However, observed rises in pulmonary artery pressure following the administration of analgesic doses of pentazocine in such patients, indicate the need for further study.
There are few reports on the use of oral pentazocine, which has been shown to be about one-third as potent (weight for weight) as the intramuscular form in terms of total analgesic effect (i.e. 60 mg orally equivalent to 20 mg intramuscularly) in patients with chronic cancer pain. The peak analgesic effect of oral pentazocine occurs later and is lower than that of equianalgesic doses of intramuscular pentazocine, but the duration of effect is longer. There appears to be a linear trend to better analgesia with increasing oral dosage.
As in studies of intramuscular pentazocine, there have been variable findings regarding the relative analgesic potency of oral pentazocine. Although in all studies it has been superior to placebo, in one study the analgesic efficacy of oral pentazocine was indistinguishable from that of oral codeine 60 mg and superior to that of aspirin 600 mg in relieving postoperative pain, whilst in patients with chronic pain, no statistically significant difference could be detected between pentazocine 50 mg, aspirin 650 mg, codeine 65 mg, mefenamic acid 250 mg, or 650 mg of either paracetamol or phenacetin. These variations in results may be due to differences in the nature of chronic and postoperative pain and/or differences in methodology and patient selection.
Side-Effects: Pentazocine produces side-effects similar to those associated with morphine-like analgesics. In equianalgesic doses pentazocine generally produces almost as much nausea, vomiting and sleepiness, and at least as much dizziness, sweating, euphoria and other minor subjective complaints as do morphine-like analgesics. These minor side-effects are exaggerated in ambulatory patients, as they are with all morphine-like analgesics. Dizziness is the most troublesome. Tolerance to side-effects usually develops during the first few days of treatment. Although it is characteristic of the narcotic antagonists as analgesics that bizarre, subjective, psychotomimetic effects may be produced, they occur only occasionally with usual therapeutic doses of pentazocine, but occur more frequently if parenteral doses above the usual therapeutic level are used.
Respiratory depression has not proved to be a significant problem in clinical practice, but neither has it with the other strong analgesics at the dosages used in the same studies. Constipation and other gastro-intestinal effects, urinary retention and dry mouth may occur less frequently with pentazocine than with morphine.
Precautions: Pentazocine should be used with caution in patients with increased intracranial pressure, impaired renal or hepatic function, and in pregnancy.
Dependence and abuse: Pentazocine appears to have a low abuse potential and is not controlled by narcotic regulations. Recent studies have nevertheless shown that pentazocine is not devoid of actions which could lead to abuse, and there have been isolated reports of prolonged use of the drug resulting in both psychological and physical dependence. So far however, pentazocine has exhibited a much lower abuse liability than pethidine or other well known morphine-like analgesics. To date, nearly all people who have become dependent upon pentazocine have abused the parenteral form of the drug and most have previously abused or been dependent upon other drugs. The withdrawal syndrome described in patients dependent on pentazocine has usually been milder than that occurring on withdrawal of morphine, and discontinuance has been achieved without great difficulty. A recent report stated that nearly all pentazocine diverted for abuse had been obtained as a result of over prescribing, over filling of prescriptions and inadequate control of institutional drug supplies, and that the greatest potential for abuse is within a ‘medical-medicine context’. Thus, despite the fact that no form of narcotics control is recommended at the present time, physicians should exercise care in prescribing for chronic pain and watch for patient tendency to continue or increase the dose. Use of the drug in anticipation of pain should be avoided.
Dosage: The usually recommended dosage in adults and in children over 12 years of age is 30 mg parenterally, or 50 mg orally every 3 or 4 hours. An intramuscular dose of 40 to 60 mg may be necessary in some patients with severe pain. A single intramuscular 30 mg dose has been used most commonly during labour.
In children aged between 1 and 12 years, the maximum single dose of parenteral pentazocine is 1 mg/kg body weight by intramuscular or subcutaneous injection, and 0.5 mg/kg body weight intravenously.