AHFS Class:

• Opioid Partial Agonists 28:08.12

Brands:

Generic Name(s):

• Pentazocine Hydrochloride

• Naloxone Hydrochloride

Pentazocine hydrochloride and naloxone hydrochloride (pentazocine/naloxone) is a fixed combination of pentazocine (a partial opioid agonist) and naloxone (opioid antagonist).1

Pentazocine and naloxone has the following uses:

Pentazocine/naloxone is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.1

Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration, and persist over the course of therapy, reserve opioid analgesics, including pentazocine/naloxone for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.1

General

Pentazocine hydrochloride and naloxone hydrochloride is available in the following dosage form(s) and strength(s):

Tablets containing 50 mg of pentazocine and 0.5 mg of naloxone.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Dosage in Adults and Pediatric Patients 12 Years of Age

• Pentazocine/naloxone should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks.1
• Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. 1
• Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic.1 Clinical guidelines on opioid prescribing for some acute pain conditions are available.1
• There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors.1 Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse.1
• Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with pentazocine/naloxone.1 Consider this risk when selecting an initial dose and when making dose adjustments.1
• Recommended Dosage when Pentazocine/Naloxone is Used as the First Opioid Analgesic: Initiate treatment with pentazocine/naloxone in a dosing range of 1 tablet every 3 to 4 hours as needed for pain, at the lowest dose necessary to achieve adequate analgesia.1 Titrate the dose based upon the individual patient's response to their initial dose of pentazocine/naloxone.1 This may be increased to 2 tablets when needed.1 Total daily dosage should not exceed 12 tablets.1
• Recommended Dosage when Converting from Other Opioids to Pentazocine/Naloxone: There is inter-patient variability in the potency of opioid drugs and opioid formulations.1 Therefore, a conservative approach is advised when determining the total daily dosage of pentazocine/naloxone.1 It is safer to underestimate a patient's 24-hour pentazocine/naloxone dosage than to overestimate the 24-hour dosage and manage an adverse reaction due to overdose.1
• Individually titrate pentazocine/naloxone to a dose that provides adequate analgesia and minimizes adverse reactions.1 Continually reevaluate patients to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as assessing for the development of addiction, abuse, or misuse.1
• Do not rapidly reduce or abruptly discontinue pentazocine/naloxone in patients who may be physically dependent on opioids.1
• See Full Prescribing Information for additional details on administration.1

Contraindications

• Significant respiratory depression.1
• Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.1 Patients with known or suspected GI obstruction, including paralytic ileus.1
• Patients with hypersensitivity to either pentazocine, naloxone, or any of the formulation excipients (e.g., anaphylaxis).1

Warnings/Precautions

Addiction, Abuse, and Misuse

Pentazocine/naloxone contains pentazocine, a Schedule IV controlled substance.1 As an opioid, pentazocine/naloxone expose users to the risks of addiction, abuse, and misuse.1

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed pentazocine/naloxone.1 Addiction can occur at recommended dosages and if the drug is misused or abused.1 The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy.1 In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use.1

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing pentazocine/naloxone, and reassess all patients receiving the combination product for the development of these behaviors and conditions.1 Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression).1 The potential for these risks should not, however, prevent the proper management of pain in any given patient.1 Patients at increased risk may be prescribed opioids such as pentazocine/naloxone, but use in such patients necessitates intensive counseling about the risks and proper use of pentazocine/naloxone along with frequent reevaluation for signs of addiction, abuse, and misuse.1 Consider prescribing an opioid overdose reversal agent.1

Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use.1 Consider these risks when prescribing or dispensing pentazocine/naloxone.1 Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and proper disposal of unused drug.1

Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.1

Life-Threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended.1 Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death.1 Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status.1 Carbon dioxide (CO) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.1

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of pentazocine/naloxone, the risk is greatest during the initiation of therapy or following a dosage increase.1

To reduce the risk of respiratory depression, proper dosing and titration are essential.1 Overestimating the pentazocine/naloxone dosage when converting patients from another opioid product can result in a fatal overdose with the first dose.1 Accidental ingestion of even one dose of pentazocine/naloxone, especially by children, can result in respiratory depression and death due to an overdose of pentazocine.1 Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.1

Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose

Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene).1 Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.1 The presence of risk factors for overdose should not prevent the management of pain in any patient.1 Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).1 There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics.1 Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent.1 Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose.1 Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered.1

Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of pentazocine/naloxone with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non- benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids, other opioids).1 Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.1 Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone.1 Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics.1 If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use.1 In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response.1 If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.1 Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).1 If concomitant use is warranted, consider prescribing an opioid overdose reversal agent.1 Advise both patients and caregivers about the risks of respiratory depression and sedation when pentazocine/naloxone is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs).1 Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.1 Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs.1

Neonatal Opioid Withdrawal Syndrome NOWS

Use of pentazocine/naloxone for an extended period of time during pregnancy can result in withdrawal in the neonate.1 Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.1 Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.1 Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.1

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS)

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the FDA has required a Risk Evaluation and Mitigation Strategy (REMS) for these products.1 Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers.1 Healthcare providers are strongly encouraged to do all of the following:

• Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain.1
• Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed.1 The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG.1
• Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them.1
• Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities.1

To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 800-503-0784, or log on to www.opioidanalgesicrems.com.1 The FDA Blueprint can be found at [Web].1

Opioid Induced Hyperalgesia and Allodynia

Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain.1 This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect.1 Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia).1 These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.1

Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics.1 Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated.1 Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia.1 If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a different opioid moiety).1

Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients

The use of pentazocine/naloxone in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.1

P atients with Chronic Pulmonary Disease: Pentazocine/naloxone-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages.1

Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients.1

Regularly evaluate patients, particularly when initiating and titrating pentazocine/naloxone and when the fixed-combination preparation is given concomitantly with other drugs that depress respiration.1 Alternatively, consider the use of non-opioid analgesics in these patients.1

Adrenal Insufficiency

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use.1 Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.1 If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible.1 If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids.1 Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers.1 Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency.1 The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency.1

Severe Hypotension

Pentazocine/naloxone may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.1 There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics).1 Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of pentazocine/naloxone.1 In patients with circulatory shock, pentazocine/naloxone may cause vasodilation that can further reduce cardiac output and blood pressure.1 Avoid the use of pentazocine/naloxone in patients with circulatory shock.1

Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), pentazocine/naloxone may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure.1 Regularly evaluate such patients for signs of sedation and respiratory depression, particularly when initiating therapy with pentazocine/naloxone.1

Opioids may also obscure the clinical course in a patient with a head injury.1 Avoid the use of pentazocine/naloxone in patients with impaired consciousness or coma.1

Risk of GI Complications

Pentazocine/naloxone is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.1 The administration of pentazocine/naloxone or other opioids may obscure the diagnosis or clinical course in patients with acute abdominal conditions.1 Pentazocine/naloxone may cause spasm of the sphincter of Oddi.1 Opioids may cause increases in serum amylase.1 Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.1 Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids.1 The risk of OIED may increase as the dose and/or duration of opioids increases.1 Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain), and if necessary, adjust opioid therapy as clinically appropriate.1

Increased Risk of Seizures in Patients with Seizure Disorders

The pentazocine in pentazocine/naloxone may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.1 Regularly evaluate patients with a history of seizure disorders for worsened seizure control during pentazocine/naloxone therapy.1

Withdrawal

Do not abruptly discontinue pentazocine/naloxone in a patient physically dependent on opioids.1 When discontinuing therapy in a physically dependent patient, gradually taper the dosage.1 Rapid tapering of pentazocine/naloxone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain.1

Additionally, the use of pentazocine/naloxone, a mixed agonist/antagonist opioid analgesic, in patients who are receiving a full opioid agonist analgesic may reduce the analgesic effect and/or precipitate withdrawal symptoms.1 Avoid concomitant use of pentazocine/naloxone with a full opioid agonist analgesic.1

Risks of Driving and Operating Machinery

Pentazocine/naloxone may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.1 Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of pentazocine/naloxone and know how they will react to the medication.1

Acute CNS Manifestations

Patients receiving therapeutic doses of pentazocine/naloxone have experienced hallucinations (usually visual), disorientation, and confusion which have cleared spontaneously within a period of hours.1 The mechanism of this reaction is not known.1 Such patients should be very closely observed and vital signs checked.1 If the drug is reinstituted, it should be done with caution since these acute CNS manifestations may recur.1

The amount of naloxone present in pentazocine/naloxone (0.5 mg per tablet) has no action when taken orally and will not interfere with the pharmacologic action of pentazocine.1 However, this amount of naloxone given by injection has profound antagonistic action to narcotic analgesics.1

Severe, even lethal, consequences may result from misuse of tablets by injection either alone or in combination with other substances, such as pulmonary emboli, vascular occlusion, ulceration and abscesses, and withdrawal symptoms in narcotic dependent individuals.1

Porphyria

Particular caution should be exercised in administering pentazocine to patients with porphyria since it may provoke an acute attack in susceptible individuals. 1

Cardiovascular Disease

Pentazocine can elevate blood pressure, possibly through the release of endogenous catecholamines.1 Particular caution should be exercised in conditions where alterations in vascular resistance and blood pressure might be particularly undesirable, such as in the acute phase of myocardial infarction.1

Pentazocine/naloxone should be used with caution in patients with myocardial infarction who have nausea or vomiting.1

Impaired Renal or Hepatic Function

Decreased metabolism of pentazocine by the liver in extensive liver disease may predispose to accentuation of side effects.1 Although laboratory tests have not indicated that pentazocine causes or increases renal or hepatic impairment, the drug should be administered with caution to patients with such impairment. 1

Biliary Surgery

Narcotic drug products are generally considered to elevate biliary tract pressure for varying periods following their administration.1 Some evidence suggests that pentazocine may differ from other marketed narcotics in this respect (i.e., it causes little or no elevation in biliary tract pressures).1 The clinical significance of these findings, however, is not yet known. 1

Specific Populations

Pregnancy

Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome.1 There are no available data with pentazocine/naloxone in pregnant women to inform a drug-associated risk for major birth defects and miscarriage.1 In animal reproduction studies, pentazocine administered subcutaneously to pregnant hamsters during the early gestational period produced neural tube defects (i.e., exencephaly and cranioschisis) at 2.6 times the maximum daily dose (MDD).1 In pregnant rats administered pentazocine/naloxone during organogenesis, there were increased incidences of resorptions and extra ribs at 0.2 times the MDD.1 There was no evidence of malformations in rats or rabbits.1 Based on animal data, advise pregnant women of the potential risk to a fetus.1 The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.1 All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.1 In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.1

Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.1

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight.1 The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.1 Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly.1

Opioids cross the placenta and may produce respiratory depression and psycho physiologic effects in neonates.1 An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate.1 Pentazocine/naloxone is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate.1 Opioid analgesics, including pentazocine/naloxone, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions.1 However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor.1 Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression.1

Lactation

Pentazocine is excreted in human milk.1 Caution should be exercised when pentazocine/naloxone is administered to a nursing woman.1 The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pentazocine/naloxone and any potential adverse effects on the breastfed infant from the drugs or from the underlying maternal condition.1 Infants exposed to pentazocine/naloxone through breast milk should be monitored for excess sedation and respiratory depression.1 Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped.1

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.1

Geriatric Use

Elderly patients (aged 65 years or older) may have increased sensitivity to pentazocine/naloxone.1 In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.1

Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid tolerant or when opioids were co-administered with other agents that depress respiration.1 Titrate the dosage of pentazocine/naloxone slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression.1

Pentazocine and naloxone are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.1 Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.1

Common Adverse Effects

See Full Prescribing Information for a list of adverse reactions.1

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Benzodiazepines and Other Central Nervous System (CNS) Depressants: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, benzodiazepines and other sedative hypnotics, anxiolytics, and tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.1 Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.1 Limit dosages and durations to the minimum required.1 Inform patients and caregivers of this potential interaction, educate them on the signs and symptoms of respiratory depression (including sedation).1 If concomitant use is warranted, consider prescribing an opioid overdose reversal agent.1

Serotonergic Drugs: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system, such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone),monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue), has resulted in serotonin syndrome.1 If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment.1 Discontinue pentazocine/naloxone if serotonin syndrome is suspected. 1

Monoamine Oxidase Inhibitors (MAOIs): Concomitant use of monoamine oxidase inhibitors (MAOIs) with pentazocine/naloxone may cause CNS excitation and hypertension through their respective effects on catecholamines.1 Caution should therefore be observed in administering pentazocine/naloxone to patients who are currently receiving MAOIs or who have received them within the preceding 14 days. 1

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Mixed agonist/antagonist and partial agonist opioid analgesics such as butorphanol, nalbuphine, pentazocine, buprenorphine, may reduce the analgesic effect of pentazocine/naloxone and/or precipitate withdrawal symptoms.1 Avoid concomitant use of these drugs.1

Muscle relaxants: The concomitant use of opioids and muscle relaxants may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.1 Because respiratory depression may be greater than otherwise expected, decrease the dosage of pentazocine/naloxone and/or the muscle relaxant as necessary.1 Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing an opioid overdose reversal agent.1

Diuretics: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.1 Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.1

Anticholinergic drugs: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.1 Evaluate patients for signs of urinary retention or reduced gastric motility when pentazocine/naloxone is used concomitantly with anticholinergic drugs.1

Tobacco: Smoking tobacco could enhance the metabolic clearance rate of pentazocine reducing the clinical effectiveness of a standard dose of pentazocine.1

Actions

Mechanism of Action

Pentazocine is a mixed agonist-antagonist at opioid receptors.1 Pentazocine is a partial agonist at the mu opioid receptor and an agonist at the kappa opioid receptor.1

Naloxone is an opioid antagonist.1

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Medication Guide).1
• Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store pentazocine/naloxone securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.1 Inform patients that leaving pentazocine/naloxone unsecured can pose a deadly risk to others in the home.1
• Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly.1 Expired, unwanted, or unused pentazocine/naloxone should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available.1 Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines.1
• Inform patients that the use of pentazocine/naloxone, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death.1 Instruct patients not to share pentazocine/naloxone with others and to take steps to protect pentazocine/naloxone from theft or misuse.1
• Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting pentazocine/naloxone or when the dosage is increased, and that it can occur even at recommended dosages.1 Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.1
• Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose.1
• Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death.1
• Inform patients and caregivers that potentially fatal additive effects may occur if pentazocine/naloxone is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these drugs concomitantly unless supervised by a healthcare provider.1
• Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene).1 Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.1 Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).1 Educate patients and caregivers on how to recognize the signs and symptoms of an overdose.1
• Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered.1
• Advise patients and caregivers how to treat with the overdose reversal agent in the event of an opioid overdose; to tell family and friends about the opioid overdose reversal agent, and to keep it in a place where family and friends can access it in an emergency; and to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent.1 Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do.1
• Inform patients and caregivers not to increase opioid dosage without first consulting a clinician.1 Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain.1
• Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs.1 Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop.1 Instruct patients to inform their healthcare provider if they are taking, or plan to take serotonergic medications.1
• Advise patients not to adjust the dose of pentazocine/naloxone without consulting with a physician or other healthcare professional.1
• If patients have been receiving treatment with pentazocine/naloxone for more than a few weeks and cessation of therapy is indicated, counsel them on the importance of safely tapering the dose as abruptly discontinuation of the medication could precipitate withdrawal symptoms.1 Provide a dose schedule to accomplish a gradual discontinuation of the medication.1
• In order to avoid developing withdrawal symptoms, instruct patients not to discontinue pentazocine/naloxone without first discussing a tapering plan with the prescriber.1
• Inform patients that pentazocine/naloxone may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery.1 Advise patients not to perform such tasks until they know how they will react to the medication.1
• Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.1
• Inform patients that opioids could cause adrenal insufficiency, a potentially life threatening condition.1 Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.1 Advise patients to seek medical attention if they experience a constellation of these symptoms.1
• Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).1
• Inform patients that anaphylaxis have been reported with ingredients contained in pentazocine/naloxone.1 Advise patients how to recognize such a reaction and when to seek medical attention.1
• Inform female patients of reproductive potential that use of pentazocine/naloxone for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.1
• Inform female patients of reproductive potential that pentazocine/naloxone can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy.1
• Advise nursing mothers to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness.1 Instruct nursing mothers to seek immediate medical care if they notice these signs.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1
• Inform patients of other important precautionary information.1

Additional Information

AHFS first Release^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Lupin Pharmaceuticals,Inc. PENTAZOCINE HYDROCHLORIDE AND NALOXONE HYDROCHLORIDE^® (pentazocine hydrochloride and naloxone hydrochloride) ORAL prescribing information. 2025 Aug. [Web]