VA Class:CN101

AHFS Class:

• Opioid Partial Agonists 28:08.12

Generic Name(s):

• Pentazocine Hydrochloride

• Pentazocine Lactate

• Naloxone Hydrochloride

• Pentazocine and Naloxone Hydrochlorides

Pentazocine is a synthetic opiate partial agonist analgesic.

Pentazocine is used as an analgesic for relief of moderate to severe pain. The drug has been used in the management of postoperative pain, including that associated with dental surgery, orthopedic pain, pain associated with cancer, and renal or biliary colic. Pentazocine also has been used parenterally (pentazocine lactate injection is no longer commercially available in the US) to provide preoperative sedation and analgesia, as an adjunct to surgical anesthesia, and for obstetrical analgesia during labor.

Although there have been many clinical studies comparing the analgesic effect of pentazocine with other analgesics, it is difficult to assess the relative efficacy of the drugs because of varying methodology and premedications used in these studies. Clear differences in analgesic efficacy between pentazocine and other opiate partial agonist analgesics such as butorphanol or nalbuphine have not been demonstrated. In general, usual parenteral doses of pentazocine are as effective in relieving moderate to severe pain as usual parenteral doses of morphine, meperidine, butorphanol, or nalbuphine. The duration of analgesia of IM pentazocine appears to be shorter than that of IM morphine. The analgesic activity of 50 mg of oral pentazocine is about equal to that of 60 mg of oral codeine or 600 mg or oral aspirin. Pentazocine hydrochloride and aspirin in combination for oral administration results in additive analgesic effects.

The oral dosage form of pentazocine was reformulated in the 1980s to contain a small amount of the opiate antagonist, naloxone hydrochloride. The reformulation, pentazocine and naloxone hydrochlorides tablets, potentially eliminates the misuse of the oral preparation in combination with the antihistamine, tripelennamine (no longer commercially available in the US); the combination, known as T's and blues, has been misused via parenteral injection by opiate addicts and drug abusers since its effect was purported to be similar to IV diacetylmorphine (heroin). Since naloxone is inactive when administered orally in the amount (0.5 mg) present in this formulation, its presence does not affect the efficacy of pentazocine when the tablets are administered orally; however, if the tablets are ground up and solubilized for parenteral administration, the naloxone will antagonize the effects of pentazocine and will precipitate withdrawal symptoms in drug abusers who are dependent on opiates. The reformulated preparation is still subject to misuse and abuse by the oral route.

Because it does not suppress the abstinence syndrome and may induce withdrawal in opiate-dependent patients, pentazocine cannot be substituted for opiates after physical dependence has been established without prior detoxification.

For further information on the role of opiate analgesics in the management of acute or chronic pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.

Administration

Pentazocine hydrochloride is administered orally; pentazocine lactate has been administered by IM, IV, or subcutaneous injection; however, a parenteral dosage form no longer is commercially available in the US.

Dosage

Dosage of pentazocine hydrochloride is expressed in terms of pentazocine. Pentazocine and naloxone hydrochlorides tablets are labeled in terms of the bases.100,101

Opiate analgesics should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.411,413,431,432,435 Dosage of pentazocine should be adjusted according to the severity of pain, physical status of the patient, and other drugs that the patient is receiving. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.700,703 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)

In the treatment of general pain states, the usual initial adult oral dosage of pentazocine recommended by the manufacturer is 50 mg every 3-4 hours. The dose may be increased to 100 mg when needed. The manufacturer recommends that total dosage not exceed 600 mg daily.

For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).411,433,434,435

When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily and avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate the dosage to such levels.411 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.423,431 Some states have set prescribing limits (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended).411,420,421,423

For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.

Dosage in Hepatic Impairment

In patients with impaired hepatic function (e.g., cirrhosis), doses and/or frequency of administration of pentazocine may need to be decreased, particularly when the drug is administered orally.144,145,155 (See Pharmacokinetics.)

Adverse effects of pentazocine are qualitatively similar to those of morphine and meperidine. Dizziness, lightheadedness, euphoria, sedation, and nausea occur most frequently. Vomiting occurs less frequently with pentazocine than with morphine.

Nervous System Effects

Dizziness, lightheadedness, euphoria, and sedation are among the most common adverse effects of pentazocine. Other adverse CNS effects of the drug include alteration of mood (nervousness, apprehension, depression, floating feeling), headache, weakness or faintness, disturbed dreams, insomnia, and syncope. Muscle tremor, irritability, and excitement have occurred rarely. Hallucinations (usually visual), disorientation, and confusion have occurred following therapeutic doses of pentazocine, but usually cleared spontaneously within several hours. The manufacturer recommends that patients experiencing such symptoms be observed closely and have their vital signs checked. Caution should be used if the drug is reinstated, since acute CNS reactions may recur. It has been suggested that psychotomimetic and dysphoric effects of the drug may result from agonist activity at Σ-receptors.142,164,185,186 Epileptiform EEG activity followed by seizures has been reported in anesthetized healthy adults given large IV doses of pentazocine (parenteral dosage form no longer commercially available in the US). Seizures have occurred following administration of the drug in a few seizure-prone patients. Although a causal relationship to pentazocine has not been established, the manufacturer recommends that the drug be used with caution in seizure-prone patients.

GI Effects

Nausea and vomiting are among the most common adverse effects of pentazocine. Other adverse GI effects which occur less frequently include constipation, and, rarely, abdominal distress, cramps, anorexia, and diarrhea.

Cardiovascular Effects

Adverse cardiovascular effects following parenteral administration of pentazocine include tachycardia, circulatory depression, shock, and increased blood pressure. IV administration of pentazocine in patients with acute myocardial infarction may increase systemic and pulmonary arterial pressure and systemic vascular resistance. Tachycardia and decreased blood pressure also have been reported following oral administration of pentazocine hydrochloride.

Dermatologic Effects

Dermatologic reactions to pentazocine include diaphoresis; flushed skin including plethora; rash; and pruritus. Allergic reactions including urticaria, edema of the face, and toxic epidermal necrolysis have been reported rarely.

Local Effects

Stinging, soft tissue induration, nodules, and cutaneous depression may occur at the site of pentazocine lactate injection. Ulceration and severe sclerosis of the skin, subcutaneous tissues, and underlying muscle have occurred following repeated injection of pentazocine lactate. Venous thrombosis in association with these local effects has been reported in at least one patient following chronic IM injection of the drug.146 Severe joint restriction and reduced range of motion secondary to fibrous myopathy have also occurred following chronic, repeated IM injections of pentazocine lactate.107,143,181,183

Hematologic Effects

Adverse hematologic effects of pentazocine include a rare depression of leukocytes (especially granulocytes), which is usually reversible,100,102,103,104,105 and moderate transient eosinophilia. Granulocytopenia has also occurred during combined abuse of pentazocine and tripelennamine (no longer commercially available in the US).119

Ocular Effects

Adverse ocular effects of pentazocine include blurred vision, focusing difficulty, nystagmus, diplopia, and miosis.

Genitourinary and Endocrine Effects

Urinary retention and dysuria have been reported in patients receiving pentazocine.

Adrenal insufficiency has been reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations of adrenal insufficiency are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400 The onset generally has occurred after at least 1 month of opiate agonist or partial agonist use, although the time to onset has ranged from within 1 day to more than 1 year.400 In many of the reported cases, patients required hospitalization.400 If adrenal insufficiency is suspected, appropriate laboratory testing should be performed promptly and physiologic (replacement) dosages of corticosteroids provided; therapy with the opiate agonist or partial agonist should be tapered and discontinued to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, follow-up assessment of adrenal function should be performed to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

Hypogonadism and androgen deficiency have been reported in patients receiving long-term opiate agonist or opiate partial agonist therapy,400,401,402,403,404 although a causal relationship has not been established.400 Patients receiving long-term opiate agonist or partial agonist therapy who present with manifestations of hypogonadism (e.g., decreased libido, impotence, erectile dysfunction, amenorrhea, infertility) should undergo laboratory evaluation.400

Other Adverse Effects

Other adverse effects of pentazocine include dry mouth, taste alteration, and, rarely, chills, paresthesia, and tinnitus.

Precautions and Contraindications

Concomitant use of opiate agonists or opiate partial agonists and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiates, alcohol) may result in profound sedation, respiratory depression, coma, and death.416,417,418,700,701,702,703 Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703 Patients receiving pentazocine and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines, alcohol, or other CNS depressants.700,703 Concomitant use with alcohol should be avoided.700 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)

Respiratory depression (decreased rate and depth of respiration), dyspnea, and laryngospasm have occurred in patients receiving pentazocine. Because pentazocine potentially may elevate CSF pressure (as a result of vasodilation following carbon dioxide retention), the drug should be used only when it is essential, and with extreme caution in patients with head injury, other intracranial lesions, or increased intracranial pressure. In patients with head injury, the drug may also interfere with evaluation of CNS function. Pentazocine-induced respiratory depression can be reversed by naloxone.

Pentazocine should be administered with caution and in low doses to patients with impaired respiration caused by other drugs, uremia, or severe infection, and in patients with severely limited respiratory reserve, bronchial asthma or other obstructive respiratory conditions, or cyanosis.

Because of the potential for fatal respiratory depression following overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including pentazocine.750 Patients should be advised of the benefits of naloxone administration following an overdose and of their options for obtaining the drug.750 Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose)411,431,750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 Even if patients are not receiving an opiate analgesic, a naloxone prescription should be considered if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of opiate use disorder [OUD], those who have experienced a prior opiate overdose).750 (See Naloxone Hydrochloride 28:10.)

Oral pentazocine should be used with caution in patients with acute myocardial infarction accompanied by nausea and vomiting.

Pentazocine should be used with caution in patients about to undergo biliary tract surgery since the drug may cause spasm of Oddi's sphincter. The drug should be used with caution in patients who have been chronically receiving opiates, including methadone, because pentazocine does not suppress the abstinence syndrome in these patients and high doses may precipitate withdrawal symptoms because of opiate antagonistic effect. Pentazocine should be used with caution in patients with renal or hepatic dysfunction. Extensive liver disease may predispose a patient to a greater incidence or severity of adverse effects than would be expected from usual doses, probably as a result of decreased hepatic metabolism of the drug.

Because of possible adverse CNS effects such as drowsiness and dizziness, ambulatory patients receiving pentazocine should be cautioned against performing hazardous tasks requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle) and warned about possible additive effects with other drugs that cause CNS depression. (See Drug Interactions.) Although pentazocine appears to have a low physical dependence liability (see Chronic Toxicity), the drug should be prescribed cautiously for patients who are emotionally unstable or have a history of opiate abuse, and these patients should be closely supervised when more than 4 or 5 days of therapy are contemplated.

Pentazocine is contraindicated in patients with known hypersensitivity to the drug.

Pediatric Precautions

Safety and efficacy of pentazocine in children younger than 12 years of age have not been established.

Pregnancy and Lactation

Pregnancy

Animal reproduction studies to date using pentazocine have not shown teratogenic or embryotoxic effects. Safe use of pentazocine in pregnant women (except during labor) has not been established. The drug should not be administered to women who are pregnant unless the potential benefits outweigh the possible risks to the fetus. Alterations (usually increases) in the rate and strength of uterine contractions may occur following parenteral administration of pentazocine during labor. In addition, respiratory depression and transient apnea may occur in the neonate when pentazocine is administered during labor and delivery.

Rarely, there have been reports of possible abstinence (withdrawal) syndrome in neonates after prolonged maternal use of pentazocine during pregnancy.100,150,151,152,153,154 Signs and symptoms of withdrawal have also been reported in neonates born to women who abused the combination of pentazocine and tripelennamine (T's and blues).147,148 For information on the management of neonatal opiate abstinence syndrome, see Uses: Neonatal Opiate Withdrawal, in the Opiate Agonists General Statement 28:08.08.

Lactation

Since it is not known if pentazocine is distributed into milk, the drug should be used with caution in nursing women.

Benzodiazepines and Other CNS Depressants

Concomitant use of opiate agonists or opiate partial agonists, including pentazocine, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiates, alcohol) may result in profound sedation, respiratory depression, hypotension, coma, and death.416,417,418,700,701,702,703,704 Opiate analgesics frequently are implicated as contributing to fatal overdoses involving benzodiazepines or other CNS depressants, and epidemiologic studies have shown that a substantial proportion of fatal opiate overdoses involve the concurrent use of benzodiazepines, alcohol, or other CNS depressants.416,417,418,435,700,701,702 Whenever possible, concomitant use of opiates and benzodiazepines should be avoided.410,411,415,435 Alcohol also should be avoided in patients receiving opiates.700 Concomitant use of opiate analgesics and benzodiazepines or other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703

If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving pentazocine, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700,703 In patients receiving a CNS depressant, pentazocine, if required, should be initiated at a reduced dosage and titrated based on clinical response.700,703 Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.411,431,750 (See Cautions: Precautions and Contraindications.)

Drugs Associated with Serotonin Syndrome

Serotonin syndrome may occur in patients receiving opiate partial agonists concomitantly with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort ( Hypericum perforatum ), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400

If concomitant use of other serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.400 If serotonin syndrome is suspected, treatment with pentazocine, other opiate agonist or partial agonist therapy, and/or any concurrently administered serotonergic agents should be discontinued.400

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Laboratory Test Interferences

In one patient, oral pentazocine hydrochloride has been reported to slightly decrease urinary 17-hydroxycorticosteroid determinations (Porter-Silber reaction); however, the clinical importance of this finding has not been established.

Acute Toxicity

Limited information is available on the acute toxicity of pentazocine.

Manifestations

Expected symptoms of pentazocine overdosage would be respiratory depression, cardiovascular effects, and other CNS effects.

Treatment

In acute pentazocine overdosage, the stomach should be emptied immediately by inducing emesis or by lavage. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of vomitus. Treatment of respiratory depression consists of parenteral administration of naloxone; repeated doses of naloxone may be necessary. Appropriate supportive measures such as administration of oxygen, IV fluids and vasopressors, and assisted or controlled respiration should also be used if necessary.

Chronic Toxicity

Tolerance and psychologic and physical dependence may occur in patients receiving pentazocine.100,109,124,125,126,127,128,129,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,186 These reactions have occurred mainly in patients with a history of opiate drug abuse. Unnecessary increases in dosage or frequency of administration and use of the drug in anticipation of pain should be avoided. The potential for abuse of pentazocine is reportedly less than that of codeine or propoxyphene. The oral dosage form of pentazocine was reformulated in the early 1980s to contain a small amount of the opiate antagonist, naloxone hydrochloride, in an attempt to reduce the parenteral abuse potential of the drug.100,114,161,186 If the tablets are ground up and solubilized for parenteral administration, the naloxone will antagonize the effects of pentazocine and can precipitate withdrawal in individuals physically dependent on opiates.100,106,161 However, since naloxone is inactive when administered orally in the amount present in the tablets, the tablets are still subject to misuse and abuse by the oral route.100

Pentazocine has also been abused in combination with tripelennamine (no longer commercially available in the US) (T's and blues) via parenteral injection by opiate addicts and drug abusers in an attempt to provide effects similar to those of IV heroin (diacetylmorphine).106,109,110,111,112,113,114,115,116,117,118,119,130,186 Although the mechanism(s) of interaction between pentazocine and tripelennamine is not known, there is some evidence from in vitro and animal studies to suggest that tripelennamine, in a dose- and ratio-dependent manner, potentiates the opiate-like effects of pentazocine possibly by antagonizing pentazocine's effect at the Σ-receptor (mediates psychotomimetic effects of pentazocine)136,156,157 and/or by enhancing agonist activity at the µ-receptor (mediates analgesia, euphoria, physical dependence, and other effects of opiates).136 However, other mechanisms may be involved.158,159 There is also some evidence from animal studies that tripelennamine potentiates the lethality of pentazocine, with seizures preceding death.160 The combination of tripelennamine and pentazocine has been purported to produce an immediate rush, reportedly similar to that produced by heroin, within 5-10 minutes after IV injection.110,111,112,113,117 In most abusers, the rush is followed by dysphoria;110,111,117 repeated injections of the drugs may ultimately result in a euphoria110,111,112,116,117 which slowly subsides over 3-6 hours.111,112,117 As the effects of the combination dissipate, restlessness, irritability, malaise, and abdominal cramps often develop.111,112,117

Severe, potentially lethal effects, such as precipitation of acute withdrawal in opiate-dependent individuals, pulmonary emboli, vascular occlusion, and ulceration and abscesses, may result from parenteral misuse of pentazocine and naloxone hydrochlorides tablets alone or in combination with other drugs. These effects may result from excipients in the tablets (e.g., microcrystalline cellulose, starch, talc) and/or the lack of sterile technique.110,111,112,113,114,115,116,117,118,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135 Adverse local effects at the site of IV, IM, or subcutaneous injection frequently occur and have included abscesses110,112,113,116 and cellulitis,110,113,116 sometimes requiring surgery and/or anti-infective therapy;110,113,116 nodules;121 thrombophlebitis;110 burning and irritation along the vein;110,112,116 and severe cutaneous (e.g., ulceration), subcutaneous (e.g., induration), and muscle damage.111,112,113,130 Bacterial endocarditis (e.g., secondary to Pseudomonas aeruginosa ) has been reported in abusers of the combination.162,163 Pulmonary abnormalities resulting from parenteral misuse of the tablets include alterations in pulmonary function such as reduced carbon monoxide diffusing capacity and total lung capacity,114,121,122,126,129 decreased mean arterial oxygen tension,114,115,126 and increased mean alveolar-arterial oxygen gradient and mean dead space to tidal volume ratio;114,126 respiratory symptoms such as cough,114,115,126 sputum production,114,126 dyspnea at rest or exercise,114,115,121,122,124,125,126,127,130 tachypnea,113 orthopnea,123 and wheezing;113,115,121 and other changes such as pulmonary hypertension115,120,122,123,124 and occasional right-sided heart failure,120,123,124 and pulmonary edema.118,120,124,125 These changes are associated with pulmonary emboli, granulomas, interstitial fibrosis, vascular occlusion, and pulmonary arterial, arteriolar, and capillary thrombosis secondary to insoluble excipients (e.g., microcrystalline cellulose, starch, talc) from the tablet preparations.113,114,115,117,118,121,122,123,124,125,126,127,128,129 Renal granulomas and amyloidosis123,125,130 and cerebrovascular insufficiency (e.g., stroke)117 have also been reported following IV misuse of the tablets. Cerebrovascular insufficiency has also been reported following IV misuse of other tablet preparations.131 Following IV misuse of tablet preparations containing microcrystalline cellulose, starch, or talc, deposits have also been reported in other organs and tissues including the eye,128,132,133,134,135 liver,125,131 spleen,125,131 heart,125 brain,125 and pancreas.125

Following abrupt discontinuance after prolonged use of pentazocine, withdrawal symptoms, including abdominal cramps, vomiting, increased temperature, sweating, chills, restlessness, anxiety, lethargy, rhinorrhea, sneezing, and lacrimation, have occurred.166,169,172,173,174,175,176,181,182,184,185 Opiates occasionally have been used in the management of pentazocine withdrawal;169,172,174,182,183 benzodiazepines (e.g., chlordiazepoxide, diazepam) have also been used in a limited number of individuals.181 Signs and symptoms of acute withdrawal following discontinuance of pentazocine and tripelennamine have included shaking,110,116 chills,110,116 nausea,110,112,116 vomiting,110,112,116 hallucinations,110,116 psychosis,110,116 restlessness,112 insomnia,112 and drug craving.112 Benzodiazepines,111,112 hydroxyzine,110 and/or pentazocine110,116 have occasionally been used in the management of acute withdrawal from the combination. The benefits of low-dose (i.e., 5-10 mg daily) methadone maintenance therapy in individuals dependent on the combination of pentazocine and tripelennamine have not been fully evaluated.111 In one individual with a history of parenteral misuse of pentazocine and tripelennamine who injected the pentazocine and naloxone hydrochlorides reformulation, the usual rush previously experienced with the combination did not occur and signs and symptoms of withdrawal, including nervousness, tremors, headache, nausea, vomiting, and palpitations, occurred shortly after injection.106 An acute hypertensive episode also occurred in this patient, but responded to three 0.1-mg oral doses of clonidine hydrochloride and the patient remained normotensive without additional hypotensive therapy.106

Pharmacology

Pentazocine has analgesic and very weak opiate antagonistic effects. The analgesic and respiratory depressant activity of the drug apparently result mainly from the l -isomer. The exact mechanisms of actions of the drug are not known. Pentazocine is believed to be a competitive antagonist at µ opiate receptors and an agonist at κ and Σ opiate receptors. Pentazocine has about 1/50 the antagonistic activity of nalorphine. Parenterally administered pentazocine (parenteral dosage form no longer commercially available in the US) has been estimated to be one-half to one-sixth as potent as morphine in patients with postoperative pain and chronic pain resulting from cancer or other causes. Estimates of oral potency have varied, but in one well-designed study, oral pentazocine was found to be one-third to one-fourth as potent as IM pentazocine. Pentazocine does not antagonize morphine-induced respiratory depression, but it may precipitate opiate withdrawal symptoms in patients who have been receiving opiates regularly. In patients not tolerant to opiates, the analgesic effect of pentazocine and morphine may be additive, but in patients tolerant to opiates, pentazocine may produce a dose-related reduction in the analgesic effect of morphine.

Pentazocine produces respiratory depression, sedation, miosis, and antitussive effects. In one study in healthy adults, a single 20 mg/70 kg IM dose of pentazocine decreased respiration to the same degree as a 10 mg/70 kg IM dose of morphine sulfate, although the duration of respiratory depression induced by pentazocine was shorter than that induced by morphine. In another study, administration of a 30-mg IV dose of pentazocine 10 minutes after an initial 30-mg dose of the drug did not produce proportional increases in respiratory depression. Doses in excess of 30 mg do not usually produce proportionate increases in respiratory depression; however, at doses of 60-90 mg, nalorphine-like dysphoric and psychotomimetic effects may occur which can be antagonized by naloxone. Pentazocine's psychotomimetic and dysphoric effects are thought to result from agonist activity at Σ-receptors.142,164,185,186

In one study, 1.2 mg/kg of IV pentazocine resulted in an increase in blood pressure and heart rate in patients who did not have heart disease. These effects were attributed to a pentazocine-induced rise in plasma catecholamine concentration. In patients with coronary artery disease, IV pentazocine elevates mean aortic pressure, left ventricular end-diastolic pressure (LVEDP), and mean pulmonary artery pressure, and causes an increase in cardiac work. In patients with acute myocardial infarction, IV pentazocine increases systemic and pulmonary arterial pressure and systemic vascular resistance.

In low doses (15 mg IM), pentazocine inhibits GI motility and slows the rate of gastric emptying. Higher doses (30-45 mg) reportedly increase intestinal transit time and produce less elevation of biliary pressure than equianalgesic doses of morphine. In one study, pentazocine (30 mg IV) but not buprenorphine (0.3 mg IV) prolonged the duration of contractions of Oddi's sphincter and increased pressures during contraction and relaxation.108

In dermal tests, pentazocine had no effect on systemic histamine release. In one study in healthy adults, pentazocine decreased effective renal plasma flow, but had no effect on urinary volume. No evidence of antidiuretic effects such as those associated with morphine has been published to date.

IV administration of naloxone hydrochloride 0.008-0.016 mg/kg reverses the respiratory depressant effects of 40-60 mg of IV pentazocine. Naloxone also reverses the psychotomimetic and dysphoric effects of pentazocine.

Pharmacokinetics

Absorption

Pentazocine salts are well absorbed from the GI tract and from IM and subcutaneous injection sites. Orally administered pentazocine hydrochloride undergoes first-pass metabolism in the liver and less than 20% of a dose reaches systemic circulation unchanged; however, there is considerable interindividual variability in metabolism and oral bioavailability. Oral bioavailability of the drug may be substantially increased in individuals with hepatic dysfunction; about 60-70% of an oral dose is reportedly absorbed unchanged in individuals with cirrhosis.144,145

Following oral administration of a single 75-mg dose of pentazocine to women postoperatively, peak plasma concentrations of 160 ng/mL were achieved within 1-3 hours in one study; as much as 25% of the drug in plasma was in the form of metabolites. In the same study, peak plasma pentazocine concentrations of approximately 140 ng/mL occurred within 15-60 minutes after IM administration of a single pentazocine dose of 45 mg/70 kg. Peak plasma drug concentrations occur almost immediately after a single IV dose.

The onset and duration of analgesia and the time to peak analgesia may vary according to the dose and route of administration. In general, after oral administration of pentazocine, the onset of analgesia occurs within 15-30 minutes, peak analgesia occurs within 1-3 hours, and the duration of analgesia is about 3 hours or longer. Following IM or subcutaneous injection of pentazocine, the onset of analgesia occurs within 15-20 minutes. After IM administration of the drug, peak analgesia occurs within about 1 hour, and the duration of action is about 2 hours. Following IV administration of pentazocine, the onset of analgesia occurs within 2-3 minutes, peak analgesia occurs within 15 minutes, and the duration of analgesia is about 1 hour.

Distribution

Animal studies have shown that pentazocine is widely distributed in the body. The drug crosses the placenta, and neonatal serum concentrations have been reported to average about 65% of maternal concentrations at delivery. It is not known if pentazocine is distributed into milk.

About 60% of pentazocine is reportedly bound to plasma proteins.

Elimination

The plasma half-life of pentazocine after IV administration has been reported to be 2-3 hours. Plasma clearance of the drug may be decreased and the elimination half-life prolonged in individuals with impaired hepatic function.144,145,155

Pentazocine is metabolized in the liver, mainly by oxidation of the terminal methyl groups of the dimethyl alkyl side chain to form alcoholic and carboxylic acid metabolites; glucuronide conjugation also occurs. There is considerable interindividual variation in the rate of metabolism and in the cumulative urinary excretion of the drug following oral administration. In one study in healthy adults, about 70% of a 20-mg IM dose of radiolabeled pentazocine was excreted in urine as unchanged drug and metabolites within 24-48 hours. In another study, following IV administration of the drug, less than 13% of a dose was excreted unchanged in urine; less unchanged drug was excreted after oral administration of pentazocine hydrochloride than after IV administration of pentazocine. Very small amounts of the drug are excreted in feces following oral or parenteral administration.

Chemistry and Stability

Chemistry

Pentazocine is a synthetic opiate partial agonist analgesic that is pharmacologically similar to butorphanol and nalbuphine. Pentazocine is commercially available as the hydrochloride salt in a tablet formulation (also containing naloxone hydrochloride). Pentazocine hydrochloride occurs as a white, crystalline powder and is sparingly soluble in water and freely soluble in alcohol.

Stability

Pentazocine and naloxone hydrochlorides tablets should be stored in tight, light-resistant containers at a temperature less than 40°C, preferably between 15-30°C.

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