Drug and Alcohol Dependence, 14 (1985) 313-324 Elsevier Scientific Publishers Ireland Ltd.

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PENTAZOCINE

GEORGE GOLDSTEIN

Sterling Drug Co., 90 Park Avenue, New York, NY 10016 (U.S.A.)

SUMMARY

Published clinical studies and extensive experience has shown that penta- zocine, the first of the practical agonist/antagonist analgesics, is a potent analgesic with wide application in clinical medicine. It has been shown to have a spectrum of pharmacological activity which has qualitative differ- ences from pure opiate agonists and these have important implications in clinical medicine.

Pentazocine can provide analgesia as great as the opiates including mor- phine and meperidine, but does not have the same effect on mood. It is, therefore, less effective than the opiates in those situations where an anxio- lytic effect is desired. Conversely, it produces less CNS depression in partic- ular with regard to respiratory depression and nausea and vomiting. It also does not have the same potential for producing hypotension.

The parenteral administration of pentazocine produces rapid strong analgesia which is of less duration than with morphine or meperidine. The oral administration of pentazocine is less predictable with regard to response but in appropriate patients it is capable of providing a similar degree of analgesia to that achieved with parenteral pentazocine.

The dependence liability of pentazocine is substantially less than that with the opiates, and where abuse of parenteral pentazocine alone has taken place, it has usually been in medical and paramedical personnel seek- ing a support for inadequate personalities. Though physical and psychic dependence to parenteral pentazocine is undoubtedly possible, its incidence is extremely low with regard to the extent of the therapeutic use of penta- zocine.

Key words: Pentazocine - Pharmacological activity - Analgesia - Parenteral administration - Oral administration - Dependence liability - Therapeutic use

INTRODUCTION

It was a widely held view when in 1956 Schaumann [l] stated that strong analgesia and dependence liability were inseparable and probably

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part of the same pharmacological mechanism. Yet in the same year Isbell [2] found that nalorphine the opiate antagonist which had previously been shown to possess potent analgesic activity [3] could not substitute for morphine in morphine-dependent patients and was unable to induce a primary addiction in formerly dependent patients. Thus was the way laid open for the synthesis by Archer in 1962 of a series of opiate antagonists based on the benzomorphan nucleus [4]. Pharmacologically one of the most interesting of this series was pentazocine.

PHARMACOLOGY

The analgesic effect of opiate antagonists cannot be demonstrated by the usual animal assay procedures classically used to study opiate analgesics. In fact they antagonize the actions of opiates. However, it has been shown that these compounds can inhibit phenylquinone-induced writhing in mice and rats and that the potency of these drugs in decreasing writhing cor- responds with their estimated analgesic potency in man. In this test penta- zocine had approximately one-fifth the activity of morphine on a weight basis [ 51. The Flinch Jump test in rats has shown that pentazocine has one-fifth to one-quarter the analgesic potency of morphine [6]. The opiate antagonist activity was shown to be between one two-hundredth to one- sixth that of nalorphine [ 5,6].

These data together with other pharmacological information, indicated that pentazocine would have analgesic activity equivalent to that of mor- phine yet possessing weak opiate antagonistic activity which was likely to render it less liable to dependence than opiates.

CLINICAL PHARMACOLOGY

The mean plasma half-life following the administration of 30 mg of pentazocine i.v. is 135 min [ 71 with a peak blood level of about 200 ng per ml [8].

The peak plasma levels of pentazocine following the i.m. administration of 45 mg/70 kg body weight were loo-243 ng per ml at 15-60 min with a half-life of 120 min.

Peaks of 110-300 ng per ml were obtained between 60 and 180 min after the oral administration of 75 mg of pentazocine [9]. Considerable variation between patients of blood levels of pentazocine following oral administration indicates the variability of ‘first pass metabolism’ of penta- zocine [lo].

Thus pentazocine rapidly achieves effective blood levels following paren- teral administration with a half-life of approx. 2 h. Blood levels following oral adminstration of pentazocine are less predictable with a several fold variation between patients.

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Pentazocine is extensively metabolized to inactive metabolites which are mainly excreted by the kidneys. Pentazocine should therefore be ad- ministered with caution to patients with severely impaired renal or hepatic function.

Analgesic activity Pentazocine is capable of producing the same level of analgesia as mor-

phine. It is, however, not possible to describe an exact dosage equivalence hecause of the varying duration of activity between the two analgesics. Thus, in a study of over 1000 surgical patients, it was found that 40 mg pentazocine administered i.m. produced a higher peak analgesic effect than 10 mg morphine, but that its effect declined more rapidly [ 111. When comparing peak analgesic effects, 27 mg pentazocine was equiv- alent to 10 mg morphine; while on the basis of total pain relief over a period of 4 h, the equivalent dose was 36 mg: Similar conclusions are reached with regard to the analgesic equivalence of pentazocine with meperidine. The approximate analgesic equivalence following i.m. injection is 40 mg penta- zocine and 100 mg meperidine [ 121.

The onset, duration and intensity of analgesia correlate with plasma concentrations of pentazocine following i.m. administration. Peak analgesic effect is achieved within 1 h and analgesia lasts for 2-3 h. After iv. adminis- tration peak, analgesia occurs within 15 min with the duration depending on the dosage used [ 91.

An oral dose of 50 mg pentazocine is an effective analgesic being on average about one-third as potent as an i.m. dose on the basis of intensity and duration of effect, and about one-quarter as effective on the basis of peak effect [ 131.

Effect on mood and alertness One of the traditional features of strong analgesics is that they sedate

the patient in severe pain and introduce a level of mood elevation such as to lessen the anxiety associated with the severely painful condition. Sedation and its consequences are very dependent on the environmental circum- stances of the moment. It is, therefore, very difficult to establish the relative incidence of sedation following drug therapy. Thus, for example, one study noted that the incidence of sedation with pentazocine varied from 12.8% to 80% in five hospitals all following the same treatment protocol [ 111. One feature, however, which does appear with pentazocine, is that patients who become drowsy or who sleep after receiving the analgesic are easily aroused [ 13,141 and when awakened are alert and cooperative [ 151.

The patient on morphine attains a state in which analgesia is attended by dissociation, euphoria and also mental clouding characterized by drowsi- ness and inability to concentrate, difficult in mentation, apathy, lessened physical activity, reduced visual acuity and lethargy. It has been described as a pleasurable state of detachment.

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Although pentazocine can effectively disconnect the patient from the realities of the pain situation it evidently still leaves him in a state from which he can easily be roused. It would appear that there is less overall dissociation than after opiates with a consequently less tranquilizing effect and, for the same reason, a lesser impairment of consciousness and aware- ness [16]. Unlike with morphine, patients receiving pentazocine retain their capacity for lucid thought and on the whole are brighter and experi- ence less detachment [ 17,181.

The sensations of floating, dreaming detachment and dissociation pro- duced by the opiates may have some bearing on their overall euphoric potential. Although the subjective effects produced by therapeutic doses of pentazocine resemble those produced by morphine [ 181 and may thus on occasion give rise to euphoria, increasing the dose of pentazocine pro- duces subjective effects which more nearly resemble those seen with nalor- phine.

Thus pentazocine produces a more pure form of analgesia compared with opiates and therapeutic significance of this depends upon the clinical situation and the desirability of concomitant sedation or of tranquilization. Where the latter are desirable features pentazocine will be regarded as a less useful therapeutic agent and this may have led to the belief that penta- zocine is a less effective analgesic than the opiates.

Effect on respiration Pentazocine shares with the opiates a capacity for depressing respiration.

However, the outstanding difference between them was demonstrated by Davie et al. [ 191 who compared the effect of i.v. doses of 30 mg of penta- zocine or meperidine repeated after 10 min. It was found that both the compounds had a significant effect on respiration but the meperidine show- ed accumulative action with repeated dosage; whereas, a second dose of pentazocine had little additional effect.

It has been postulated that the respiratory depressant effect of penta- zocine reaches a maximum with doses in the region of 40 mg and that thereafter, additional amounts of the drug have little or no effect on respira- tion [20].

Respiratory depression following the administration of pentazocine is thus considered not to be of major clinical significance. Where depression is induced, for example in a situation or overdosage, the ‘pure’ narcotic antagonist naloxone will effectively reverse such respiratory depression

[=I.

Cardiovascular and haemodynamic effects Heart rate. In conscious patients the majority of clinical studies have

shown that pentazocine causes a small increase in heart rate sometimes preceded by a decrease. The increase in pulse rate is dependent on the dose of pentazocine with tachycardia occurring with i.v. doses in excess of 2 mg/kg body weight [22].

In anesthetized patients, pentazocine has a different effect. It has shown that five doses of 0.6 mg per kg of pentazocine administered at lo-min intervals produced a reduction of 20-25s in heart rate in patients under- going elective surgery [23]. A possible explanation for this difference in response to pentazocine is that the tachycardia seen in conscious patients may be a manifestation of the central sympathetic stimulation which penta- zocine produces in conscious patients and which is blocked in those who are anesthetized.

Arterial pressure. In contrast to opiates, pentazocine usually produces an increase in blood pressure which, as with the pulse rate, is dose depen- dent. In contrast to the effect on the pulse rate, anesthetized patients respond in a similar manner to those who are conscious. The effect of pentazocine on arterial pressure is probably secondary to an increase in catecholamine levels. It has been reported that a maximum increase of 70% in epinephrine and norepinephrine levels can occur after the adminis- tration of 1.2 mg/kg i.v. which coincides with the increase in blood pressure and heart rate [ 241.

Pulmonary circulation. In patients with heart disease i.v. pentazocine has been reported to bring about an increase in systolic and diastolic and mean pulmonary arterial pressure [ 251. It was thought that the in- crease in pulmonary artery pressure may be due to a pulmonary vasocon- strictor effect of pentazocine rather than to any impairment of left ventri- cular function. However, this has not been conclusively proved.

Effect on the nervous system Tests of the Flicker Fusion Threshold show that oral doses of 50 mg

pentazocine have a sedative action and subjectively produce drowsiness and relaxation.

Pentazocine shares with the opiates and their antagonists the ability at high doses to produce electrocortical arrhythmias [ 261.

Effects on the gastrointestinal tract Pentazocine slows gastric emptying and delays propulsive motility in the

small intestine [ 27,281. Pentazocine depresses colonic motility in normal subjects [29] and it

has been shown to decrease intraluminal pressure in patients with irritable colon syndrome or diverticular disease [ 301. However, constipation is not a significant side effect of the use of pentazocine.

Pentazocine only has a small effect on smooth muscle sphincters with doses of 30-45 mg of pentazocine causing a minimal rise in biliary pres- sure compared with much greater rises following 10 mg morphine [31].

Other effects Minor effects of pentazocine of little clinical significance have been

reported involving renal function, the uterus, lungs, the eye and the cough center.

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CLINICAL EXPERIENCE

Pentazocine has been established as a widely used general analgesic for the treatment of moderate and severe pain in a wide variety of conditions for almost 20 years. Parenteral administration can produce analgesia equiv- alent to that of parenteral morphine or meperidine while its oral adminis- tration variety of situations of acute and chronic pain in place of parenteral morphine or meperidine or when aspirin or acetaminophen alone are in- adequate. Clinical trials in many conditions have confirmed this activity of pentazocine.

Surgical uses Pre-anesthetic medication. Opioids are frequently used as medication

prior to the induction of anesthesia. Their efficacy lies in their analgesic effect and their ability to calm the patient either by inducing a state of tranquility or by their sedation effect.

Pentazocine has been extensively evaluated in adults and children for this indication and has been shown to be an effective alternative to the opiates [ 321.

In cases where a greater anxiolytic effect is required than can be pro- duced by pentazocine alone, an excellent result may be obtained by giving a tranquilizer concurrently. Thus it was found that the parenteral adminis- tration of 30 mg pentazocine or 10 mg diazepam separately produced ‘good’ to ‘fair’ sedation in 68-70% of subjects, but when the same drugs were given together, the proportion increased to 87%, without any signi- ficant alteration in the cardio-respiratory response [ 331.

Anesthetic supplement. Supplementary strong,analgesics allow greater flexibility in the use of anesthetic agents and thus quick, uneventful re- covery. However, both anesthetic and analgesic agents can adversely affect respiration and the cardiovascular system.

Pentazocine has been reported to cause little additional effect on respira- tion or the circulation when combined with general anesthetics, unless halothane is used when the latter’s respiratory depression and circulatory effects may be increased [ 351.

When pentazocine is used as an anesthetic supplement satisfactory anal- gesia often persists in the postoperative period with a few untoward sequlea and patients have been reported to be detected, but cooperative, rather than sedated [ 351.

Neuroleptanalgesia, Neuroleptanalgesia involves the administration of an analgesic with a neuroleptic agent to render the patient tranquil, catatonic and pain-free but cooperative. Pentazocine has been shown to be as effective as phenoperidine, fentanyl and dextromoramide when used with droperidol [34,36,37].

Pentazocine has been effectively used in conjunction with diazepam in a number of procedures such as endoscopic examination, gynecological procedures and minor cardiovascular surgery [ 381.

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Postoperative analgesia. Pentazocine has been widely and successfully used to alleviate postoperative pain of most types. It has been shown to be comparable with morphine, meperidine and other strong analgesics [ 391. A particular advantage of pentazocine in this situation is a lower incidence of nausea and vomiting [ 401.

In one study, the effect of pentazocine was compared with buprenor- phine as postoperative on demand analgesics. Both compounds provided good analgesia. In 24 h the mean quantity of buprenorphine demanded was 1.68 mg and the corresponding dose for pentazocine was 382 mg 1411.

It has been noted that with pentazocine, patients are less sedated, not euphoric and are generally more alert, but at the same time calm. The fact that patients are much more cooperative and better able to move around may contribute to a lowering of the incident of thromboembolism and chest complications.

Obstetrics Parenteral analgesics are a convenient, frequently used method of allevi-

ating pain during childbirth. In several studies, i.v. pentazocine has been shown to provide adequate analgesia in a majority of patients. It is slightly shorter acting than meperidine but is associated with less nausea and vomit- ing at equi-analgesic doses [ 42,431.

Pentazocine does not significantly effect normal maternal blood pressure or pulse rate, fetal heart rate or Apgar scores. In patients with pre-eclamptic toxemia, the administration of pentazocine resulted in a sustained rise in systolic blood pressure [ 441.

Use in trauma The acute pain of trauma requires a rapidly acting potent analgesic with

minimal adverse effects. Pentazocine comes close to filling the needs of the ideal analgesic and is widely and successfully used in the treatment of acute trauma. It has been reported to provide more effective pain relief with shorter onset than many other commonly used analgesics and is useful in controlling the pain during the movement of such patients. It has been recommended that pentazocine should be included in emergency packs for use in accidents [45].

Cardiology In acute myocardial infarction 30 mg pentazocine intravenously has

been shown to produce a degree of analgesia comparable with the com- monly used opiates [ 461 and 40 mg pentazocine intramuscularly produced the same relief of pain as 100 mg meperidine but with less nausea and vomiting [47].

Pentazocine has been shown to increase pulmonary artery pressure prob- ably by increasing pulmonary vascular resistance. This together with the increases in cardiac muscle oxygen demand. These effects are unlikely to be a problem with modest doses of pentazocine but caution should be

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exercised whenever administering pentazocine intravenously to patients with acute myocardial infarction, accompanied by hypertension, or left ventricular failure.

General medical analgesia Pentazocine has been extensively used as a strong analgesic in a number

of general medical conditions. These have included acute and chronic pain in such conditions as neoplasia, including bone metastases, neurological diseases, musculoskeletal pain and severe ischemic limb pain [ 48-501.

Pentazocine does not possess the antidiuretic action of morphine nor does it affect voiding. In one double blind study in patients with either renal colic or undergoing neurological surgery, it was found that 40 mg of pentazocine and 100 mg meperidine produced comparable analgesia though the duration of action for pentazocine was somewhat less [ 511.

Geriatrics Many of the trials carried out to study the value of pentazocine in anes-

thetic practice, postoperative pain or general medicine have included elderly patients. A review of the results suggests pentazocine has a number of advantages over the opiates in geriatric practice.

Elderly patients often have sluggish intestinal function and here, penta- zocine has the advantage of not causing constipation problems even during long-term administration. The relatively minor effect of pentazocine on the cardiovascular system and on bladder function and its limited effect on respiration, point to pentazocine being a suitable analgesic for geriatric use. It is well tolerated by elderly patients and in one study, doses of 15- 60 mg intramuscularly every 3-4 h in 210 patients following orthopedic surgery, resulted in good pain relief and no significant adverse reactions

]521.

Side effects Sedation. Sedation is the most commonly reported side effect to the

administration of pentazocine as an analgesic. However, as previously noted, sedation and its consequences are very dependent on the environmental circumstances of the moment. Furthermore, sedation in some circumstances is a desired consequence of the administration of a strong analgesic, while in other circumstances it may be a hindrance. Sedation associated with the administration of pentazocine is not as complete as after opiates, in that patients are easily aroused and when awakened are alert and cooperative.

Psychotomimetic effects. The administration of pentazocine is associated with changes in mood. The subjective effects produced by therapeutic doses resembled those produced by morphine and may thus, on occasion, give rise to euphoria. Increasing the dose of pentazocine produces subjective effects which more nearly resemble those seen with nalorphine [ 181. A survey of hospital inpatients treated with oral doses of 50-100 mg or i.m.

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doses of 30-90 mg of pentazocine concluded that perceptual alterations occurred in 7-10% of patients receiving normal therapeutic doses, and that the incidence was not dependent on the route of administration [ 531.

The clinical impression may be that there is a greater frequency of un- pleasant subjective effects associated with pentazocine than opiates and it is possible that this is due to the greater awareness of patients receiving pentazocine than those receiving opiates. In one controlled clinical study the incidence of postoperative dreaming and other manifestations of bizarre behavior after pentazocine was not significantly different from that after morphine [ 541.

Mild reversible psychotomimetic effects would not appear to be more frequent with pentazocine than with opiates, although there may be a greater awareness of them when they occur because of the greater alert- ness of the patients. However, the occasional patient develops frank hallu- cinations. These occasionally are auditory but most often are visual. On those rare occasions where hallucinations develop, it is distressing for the patient and creates some notoriety among nursing staff. Their incidence and importance can thereby become exaggerated. In fact, the rarity of these events is such as to warrant no particular action with regard to the use of pentazocine in therapeutics, and the effect is so unpredictable that pentazocine in no way can be compared with those hallucinogens which are subject to abuse.

Gastrointestinal effects. The tendency for opiates to produce nausea and vomiting through a centrally acting mechanism is well recognized. Penta- zocine is similar to the opiates in this regard but the incidence is significant- ly less than with either morphine or meperidine [ 441.

Ambulant patients used to have a higher incidence of nausea and vomiting with centrally acting analgesics than those confined to bed and this has been confirmed with pentazocine in those studies concerned with evaluating oral pentazocine. The co-administration of an anti-emetic such as cyclizine will reduce the incidence of these gastrointestinal effects.

Dermatological effects. Some patients who have abused parenteral penta- zocine or who have received frequent injections over a long period have shown local reactions consisting of soft tissue induration, or inflammatory nodules, or fibrosis and irregular ulcers, which are painless and surrounded by an area of hyperpigmentation. In some cases, a myopathy may lead to contractures and interfere with normal movement and occasionally the changes may not be limited to the injection sites [ 55-571.

The precise cause of these reactions has not been established. Vaso- constriction with tissue ischemia’has been proposed as has inflammatory reaction to precipitated pentazocine.

Other side effects. The usual range of other side effects associated with a centrally acting analgesic has been reported with pentazocine and are of no particular clinical significance.

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DEPENDENCE LIABILITY

The early clinical evaluation along with the specific studies into the dependence liability of pentazocine indicated that the potential for physical and psychic dependence was extremely small. Since those early days when pentazocine was considered to have a lower abuse potential than morphine, codeine or propoxyphene, pentazocine has been marketed in more than 100 countries throughout the world. The experience with the drug indicates that since 1967 more than 250 million patients have been treated with approx. 2.8 billion doses of pentazocine. From this experience it is possible to conclude that the abuse of parenterally-administered pentazocine does occur and will produce physical and psychic dependence. The risk, however, is small and the abuse of pentazocine alone has largely been confined to medical and paramedical personnel rather than to street abuse. Narcotic- type abuse or orally administered pentazocine does not appear to occur, although, there have been isolated incidents of abuse which is more typical of the abuse of peripherally acting analgesics.

The overall conclusion of the abuse of pentazocine is that it is directed at enabling inadequate personalities to cope with the stress of life rather than for the creation of an artificial world of pleasure, as with opiate abuse.

A more recent peculiar form of abuse of pentazocine has been the paren- teral administration of a mixture of the antihistamine tripelennamine with pentazocine derived from the tablets. Such abuse has been confined to the U.S.A. where there has been evidence of street abuse in various cities. Most attention seems to have been paid to the part that pentazocine has played in this combination, apparently overlooking the evidence of abuse that has existed for over 20 years concerning the antihistamine tripelennamine. It is apparent that the addition of parenteral pentazocine to the parenteral administration of this antihistamine is capable of producing a significant euphoric effect.

One of the actions taken to combat this abuse has been to re-formulate oral pentazocine with the opiate antagonist naloxone, so that while in oral dosage it will have no pharmacological action, when administered paren- terally in conjunction with pentazocine after dissolving the pentazocine tablets, the naloxone is capable of antagonizing the central effects of penta- zocine. Evidence to date indicates that this measure appears to be having a significant influence on reducing the extent of this abuse of pentazocine with tripelennamine.

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