Pentazocine Acetaminophen

Mechanism of Action

Pentazocine: Opioid agonist; inhibits ascending pain pathways, which causes alteration in response to pain; produces analgesia, respiratory depression, and sedation  

Acetaminophen: Nonopiate, nonsalicylate analgesic: may work peripherally to block pain impulse generation; acts on hypothalamus to produce antipyresis

BOXED WARNING
Hepatotoxicity
Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product.

Clinical experience with pentazocine and acetaminophen tablets has been insufficient to define all possible adverse reactions with this combination. However, reactions reported after oral administration of pentazocine in 50 mg dosage include the following:

Cardiovascular: hypertension, hypotension, circulatory depression, tachycardia. 

Respiratory: rarely respiratory depression,

Acute CNS Manifestations: Hallucinations (usually visual), disorientation, and confusion

Other CNS effects: grand mal convulsions, increase in intracranial pressure, dizziness, lightheadedness, hallucinations, sedation, euphoria, headache, confusion, disorientation; infrequently weakness, disturbed dreams, insomnia, syncope, and depression; and rarely tremor, irritability, excitement, tinnitus.

Autonomic: sweating; infrequently flushing; and rarely chills.

Gastrointestinal:  nausea, vomiting, constipation; diarrhea, anorexia, dry mouth, Biliary tract spasm, and rarely abdominal distress.

Allergic: edema of the face, anaphylactic shock, dermatitis including pruritus, flushed skin including plethora, infrequently rash; and rarely urticaria.

Ophthalmic: visual blurring and focusing difficulty, miosis.

Hematologic: depression of white blood cells (especially granulocytes) with rare cases of agranulocytosis, which is usually reversible, moderate transient eosinophilia.

Dependence and Withdrawal Symptoms: (See WARNINGS , PRECAUTIONS , and DRUG ABUSE AND DEPENDENCE  Sections).

Other:  urinary retention, paresthesia, serious skin reactions, including erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, and alterations in rate or strength of uterine contractions during labor.

A few cases of hypersensitivity to acetaminophen have been reported, as manifested by anaphylaxis, angioneurotic edema, thrombocytopenic purpura, skin rashes, and rarely hemolytic anemia and agranulocytosis.  Occasionally individuals respond to ordinary doses with nausea and vomiting and diarrhea.

Signs and Symptoms

For pentazocine alone in single doses above 60 mg there have been reports of the occurrence of nalorphine-like psychotomimetic effects such as anxiety, nightmares, strange thoughts, and hallucinations.  Somnolence, marked respiratory depression associated with increased blood pressure and tachycardia have also resulted as have seizures, hypotension, dizziness, nausea, vomiting, lethargy, and paresthesias.  The respiratory depression is antagonized by naloxone (see Treatment). Circulatory failure and deepening coma may occur in more severe cases, particularly in patients who have also ingested other CNS depressants such as alcohol, sedative/hypnotics, or antihistamines.

In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48-72 hours post-ingestion.

Treatment

Adequate measures to maintain ventilation and general circulatory support should be employed. Assisted or controlled ventilation, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Consideration should be given to gastric lavage and gastric aspiration to reduce drug absorption.

Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For respiratory depression due to overdosage or unusual sensitivity to pentazocine and acetaminophen tablets, parenteral naloxone is a specific and effective antagonist.

Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less then 4 hours post-ingestion may be misleading.  To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected.  Intravenous NAC may be administered when circumstances preclude oral administration.

Vigorous supportive therapy is required in severe intoxication.  Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

Applies to acetaminophen / pentazocine: oral tablet

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Hard stools (constipation).
• Dizziness.
• Feeling sleepy.
• Upset stomach.
• Sweating a lot.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Applies to acetaminophen / pentazocine: oral tablet

General

In general, acetaminophen is well tolerated when administered in therapeutic doses.[Ref]

Cardiovascular

Two cases of hypotension have been reported following the administration of acetaminophen. Both patients experienced significant decreases in blood pressure. One of the two patients required pressor agents to maintain adequate mean arterial pressures. Neither episode was associated with symptoms of anaphylaxis. Neither patient was rechallenged after resolution of the initial episode.[Ref]

Cardiovascular side effects associated with acetaminophen have included at least two cases of hypotension. Hypertension, hypotension, circulatory depression, and tachycardia have been reported with pentazocine.[Ref]

Nervous system

Nervous system side effects associated with pentazocine have included grand mal convulsions, increased intracranial pressure, dizziness, lightheadedness, hallucinations, sedation, headache, confusion, disorientation, weakness, insomnia, syncope, tremor, excitement, tinnitus, and paresthesia. Acute central nervous system side effects associated with pentazocine have also included hallucinations (usually visual), confusion, and disorientation.[Ref]

Dermatologic

Dermatologic side effects associated with acetaminophen have included general erythematous skin rashes (rare). Cases of bullous erythema and purpura fulminans associated with acetaminophen have been reported. Acetaminophen has been associated with a risk of rare but potentially fatal serious skin reactions know as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP). Serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with pentazocine.[Ref]

Gastrointestinal

One study has suggested that acetaminophen may precipitate acute biliary pain and cholestasis. The mechanism of this effect may be related to inhibition of prostaglandin and alterations in the regulation of the sphincter of Oddi.[Ref]

Gastrointestinal side effects associated with acetaminophen were rare except in alcoholics and after overdose. Nausea, vomiting, and diarrhea have been reported with ordinary doses of acetaminophen. Acetaminophen may precipitate acute biliary pain and cholestasis. Cases of acute pancreatitis have been reported rarely. Nausea, vomiting, constipation, abdominal distress, anorexia, dry mouth, biliary tract spasm, and diarrhea have been reported with pentazocine.[Ref]

Hepatic

Hepatotoxicity may be increased by thyroid drugs, zidovudine, fasting, or alcohol use.

Alcoholic patients may develop hepatotoxicity after even modest doses of acetaminophen. In healthy patients, approximately 15 grams of acetaminophen is necessary to deplete liver glutathione stores by 70% in a 70 kg person. Hepatotoxicity has been reported following smaller doses. Glutathione concentrations may be repleted by the antidote N-acetylcysteine. One case report has suggested that hypothermia may also be beneficial in decreasing liver damage during overdose.

In a recent retrospective study of 306 patients admitted for acetaminophen overdose, 6.9% had severe liver injury but all recovered. None of the 306 patients died.

A 19-year-old female developed hepatotoxicity, reactive plasmacytosis, and agranulocytosis followed by a leukemoid reaction after acute acetaminophen toxicity.[Ref]

Hepatic side effects associated with acetaminophen have included hepatic dysfunction which may occur after overdose. In this setting, severe and sometimes fatal dose-dependent hepatitis has been reported. Several cases of hepatotoxicity from chronic acetaminophen therapy at therapeutic doses have also been reported despite a lack of risk factors for toxicity. Hepatotoxicity, reactive plasmacytosis, and agranulocytosis followed by a leukemoid reaction have been reported after acute acetaminophen toxicity.[Ref]

Hematologic

Hematologic side effects associated with acetaminophen have included rare cases of thrombocytopenia. Methemoglobinemia with resulting cyanosis has also been observed in the setting of acute overdose. Hepatotoxicity, reactive plasmacytosis, and agranulocytosis followed by a leukemoid reaction have been reported after acute acetaminophen toxicity. Depression of white blood cells (especially granulocytes) with rare cases of agranulocytosis, which is usually reversible, and moderate transient eosinophilia have been reported with pentazocine.[Ref]

A 19-year-old female developed hepatotoxicity, reactive plasmacytosis, and agranulocytosis followed by a leukemoid reaction after acute acetaminophen toxicity.[Ref]

Hypersensitivity

Hypersensitivity side effects associated with acetaminophen have included rare reports of anaphylaxis and fixed drug eruptions. A few cases of acetaminophen hypersensitivity (as manifested by anaphylaxis, angioneurotic edema, skin rashes, thrombocytopenic purpura, and rarely hemolytic anemia and agranulocytosis) have been reported. Rash, urticaria, edema of the face, anaphylactic shock, dermatitis including pruritus, flushed skin including plethora, and in at least one case, an apparent anaphylactic reaction have been reported with pentazocine.[Ref]

Renal

Renal side effects associated with acetaminophen have been reported rarely and have included acute tubular necrosis and interstitial nephritis. Additional adverse renal effects were most often observed after overdose, after chronic abuse (often with multiple analgesics), or in association with acetaminophen-related hepatotoxicity. A possible increased risk of renal cell carcinoma has been associated with chronic acetaminophen use. A recent case-control study of patients with end-stage renal disease suggested that long term consumption of acetaminophen may significantly increase the risk of end-stage renal disease, particularly in patients taking more than two tablets per day.[Ref]

Acetaminophen-related acute tubular necrosis usually occurred in conjunction with liver failure, but has been observed as an isolated finding in rare cases.[Ref]

Respiratory

Respiratory side effects associated with acetaminophen have included a case of eosinophilic pneumonia. Respiratory depression has been reported with pentazocine.[Ref]

Psychiatric

Psychiatric side effects associated with pentazocine have included euphoria, depression, irritability, and disturbed dreams. Dependence and withdrawal symptoms have been reported with pentazocine.[Ref]

Other

Other side effects associated with pentazocine have included sweating, flushing, and chills.[Ref]

Genitourinary

Genitourinary side effects associated with pentazocine have included urinary retention and alterations in rate or strength of uterine contractions during labor.[Ref]

Ocular

Ocular side effects associated with pentazocine have included miosis, visual blurring, and focusing difficulty.[Ref]

Some side effects of acetaminophen / pentazocine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Pentazocine can cross the placental barrier and cause central nervous system depression in the neonate, and if used regularly during pregnancy, may lead to withdrawal symptoms in the newborn.

Acetaminophen-pentazocine has been assigned to pregnancy category C by the FDA. Animal studies have not been reported with the combination of acetaminophen and pentazocine. Animal studies have revealed evidence of teratogenicity with pentazocine. There are no controlled data in human pregnancy. Frequent acetaminophen use (defined as most days or daily use) in late pregnancy may be associated with increased risk of persistent wheezing in the infant which may persist into childhood. Possible abstinence syndromes in newborns following prolonged use of pentazocine during pregnancy have been reported rarely. Acetaminophen-pentazocine is only recommended for use during pregnancy when benefit outweighs risk.