xerostomia
Ultracet Adverse Reactions
NOTE: This monograph discusses the use of the acetaminophen; tramadol combination product for the management of pain. Clinicians may wish to consult the individual monographs for more information about the specific adverse reactions of each agent.
The more common adverse effects noted over 5 days treatment with acetaminophen; tramadol include: anorexia (3%), constipation (6%), diaphoresis (4%), dizziness (3%), diarrhea (3%), insomnia (2%), nausea (3%), prostatic disorder (2%), pruritus (2%), somnolence or drowsiness (6%) and xerostomia or dry mouth (2%). Abdominal pain, anxiety, asthenia, confusion, dyspepsia, euphoria, flatulence, flushing, hot flushes, nausea/vomiting, nervousness, and tremor were other adverse events noted at an incidence of at least 1%. Emotional lability, hallucinations, and visual impairment were reported in < 1% of patients in Ultracet® trials, but in 1 - 7% of patients in tramadol trials. Lower doses of acetaminophen; tramadol may be associated with less adverse effects than that seen with higher doses (i.e., nausea and vomiting). Single agent tramadol has been reported to cause less constipation than equipotent doses of acetaminophen and codeine.
Seizures have been reported with tramadol use in humans; patients with an existing seizure disorder are at greatest risk. Seizures have occurred at recommended doses as well as at high doses. Concomitant treatment with drugs that lower the seizure threshold including certain antidepressants (TCAs, and other tricyclic compounds), other opiate agonists, MAOIs, anoretics, or neuroleptics may increase the risk of seizures.[1784] The combination of SSRIs and tramadol has been associated with serotonin syndrome and an increased risk of seizures. One case report details a fatal seizure reaction in an alcoholic adult concomitantly taking tramadol with acetaminophen and several other drugs that increase this risk.[3347] Serotonin syndrome symptoms may include mental status changes, hyperreflexia, elevated temperature, shivering, tremors, agitation, excessive sweating and seizures. In overdose situations, tramadol ‘s neurotoxicity due to monoamine uptake inhibition appears to be a major problem as opposed to the opioid effects.
Tramadol produces less respiratory depression than morphine. At recommended doses of acetaminophen; tramadol, respiratory depression is not likely to be significant. However, in patients at risk for respiratory depression, alternative non-opioid analgesics should be selected. In tramadol overdose or in combination with anesthetic agents or ethanol, significant respiratory depression may occur. In a prospective case study of reports made to poison control centers of tramadol overdose, the lowest dose of tramadol associated with coma or respiratory depression was 800 mg.[2544]
A case of acquired purpura fulminans developed in a 32 year old woman who was instructed to take acetaminophen 1000 mg every 4 - 6 hours as needed for pain.[4443] The patient noted rapidly spreading purpuric lesions and edema. Her lesions were nonblanchable and enlarging, and she had multiple purplish-black hemorrhagic and necrotic areas. Purpura fulminans is usually associated with disseminated intravascular coagulation and can occur in patients with inherited or acquired deficiencies of the protein C anticoagulant pathway. The patient developed acquired protein C deficiency from alcohol-induced hepatotoxicity. Fibrin thrombi in the dermal blood vessels, a characteristic finding of purpura fulminans, were present. Discontinuation of alcohol and acetaminophen and administration of vitamin K, heparin, and a systemic antibiotic led to almost complete purpuric lesion and hepatotoxicity resolution in 6 days.
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving initial doses of single agent tramadol. Patients with an allergy to codeine are at increased risk. Other allergic manifestations of tramadol include angioedema, urticaria, pruritus, bronchospasm, rash (unspecified), Stevens-Johnson syndrome, and toxic epidermal necrolysis. Hypersensitivity reactions to acetaminophen may be manifested by urticaria, erythema, generalized pruritus, rash (unspecified), maculopapular rash, and fever. Anaphylactic shock, angioedema, and anaphylactoid reactions have been rarely reported with acetaminophen. Toxic epidermal necrolysis (TEN) occurred in a 7 year old girl after she took 3 doses of acetaminophen 10 mg/kg.[4442] Twelve hours after the last dose, an erythematous rash appeared, which became generalized over the next few hours. The patient developed a fever, low blood pressure and an elevated erythrocyte sedimentation rate and liver function tests. A skin biopsy showed subepidermal blister formation with full-thickness necrolysis of the epidermis and a sparse upper dermal lymphocytic infiltrate. On rechallenge with 10 mg/kg given orally, fever, low blood pressure, and diffuse urticaria and erythema developed 30 minutes after acetaminophen ingestion. In addition to the case of TEN, 4 cases of allergic contact dermatitis (delayed hypersensitivity type) have been reported in the literature.[4444] [4445] Various reactions including generalized pruriginous micropapular eruption, facial edema, generalized pruriginous exanthem, exfoliative dermatitis, and generalized exanthema occurred within several hours after acetaminophen ingestion. Acetaminophen has also been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly, is associated with fever above 38?°C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. Drugs are the main cause of AGEP. A period of 2 - 3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, pruritus, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome.[4446]
Physiological dependence (drug craving, drug seeking behavior), psychological dependence, tolerance and withdrawal reactions have been reported during tramadol therapy. Withdrawal reactions have been reported in patients receiving tramadol following naloxone administration. Tramadol can reinitiate physical dependence in patients who have been previously dependent or chronically taking opiate agonists. In patients with a tendency towards drug abuse, a history of drug dependence, or who are taking chronic opiate agonists, treatment with acetaminophen; tramadol is not recommended.
Headache was reported in at least 1% of patients receiving acetaminophen; tramadol. Overuse of combination analgesics such as acetaminophen; tramadol products by headache-prone patients frequently produces drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance (refractoriness to prophylactic medication), and withdrawal symptoms. In this case, overuse of acetaminophen; tramadol products has been defined as taking 3 or more doses per day more often than 2 days per week.[4043] The frequency of use may be more important than the dose. Features of a rebound headache include morning headache, end-of-dosing interval headache, or headache improvement with discontinuation of overused medication. Stopping the symptomatic medication may result in a period of increased headache and then headache improvement. Analgesic overuse may be responsible for the transformation of episodic migraine or episodic tension headache into daily headache and may perpetuate the syndrome.[4043]
Neonatal abstinence syndrome, fetal death, and still birth have been reported with tramadol in post-marketing reports.
Urinary effects reported in < 1% of patients receiving acetaminophen; tramadol include urinary retention, albuminuria, oliguria, and micturition disorder.
Overdose with acetaminophen; tramadol is a serious and life-threatening event due to toxicity of both the respiratory and hepatic systems. Treatment of tramadol overdose with naloxone is only partially effective and may increase the risk of seizures. Treatment of acetaminophen overdose is with prompt oral administration of N-acetylcysteine. Sinus tachycardia, confusion, and hypertension suggestive of a serotonin syndrome have been reported with overdoses. Respiratory depression may lead to death with tramadol overdose. Acute overdose and excessive chronic use of acetaminophen can lead to hepatotoxicity, manifest as hepatic necrosis, jaundice, bleeding and encephalopathy. After acute acetaminophen overdose, 2 or 3 days pass before maximum liver damage becomes apparent. Nausea/vomiting, anorexia, diaphoresis and abdominal pain usually occur within 2 - 3 hours after ingestion of toxic doses. Elevated hepatic enzymes, hypoprothrombinemia, and GI bleeding may occur. Agents which affect cytochrome P450 function and ethanol may affect the severity of acetaminophen-induced hepatotoxicity.
The incidence of adverse cardiovascular events with acetaminophen; tramadol is low. Less than 1% of patients developed hypotension, hypertension, or sinus tachycardia.
Acetaminophen can cause acute renal tubular necrosis and chronic analgesic nephropathy, which is characterized by interstitial nephritis and renal papillary necrosis, in patients receiving high doses (e.g., 2.5 - 10 g/day) chronically or after acute overdose. Acute renal failure may occur in 25 - 30% of patients secondary to liver dysfunction. Rarely, acute renal failure (unspecified) may occur without severe hepatic toxicity. The risk of renal complications appears to be higher in patients with alcoholism. Chronic acetaminophen use has been implicated as a contributing factor in the decline of renal function in patients with underlying renal disease, including diabetic nephropathy.[541]
Methemoglobinemia can occur after acute overdoses of acetaminophen and can lead to hemolysis thereby causing hemolytic anemia. This can result in cyanosis of the fingernails, skin, and mucosa. Children develop methemoglobinemia more readily than do adults. Other hematologic reactions reported with acetaminophen include agranulocytosis, neutropenia, thrombocytopenia, thrombocytosis, and pancytopenia. Acetaminophen sulfate, a metabolite of acetaminophen, may cause immune-mediated thrombocytopenia. Two adults had improvement in their platelet counts from 45 - 50 x109/L to 165 - 325 x109/L within 7 - 10 days of acetaminophen discontinuation. The sera from each patient had antibodies against platelets in the presence of acetaminophen sulfate.[8205] Agranulocytosis, thrombocytosis, and pancytopenia have only been documented in the literature after acetaminophen overdose. Symptoms such as unusual tiredness or weakness, unusual bleeding or bruising, and unexplained sore throat or fever should be investigated promptly.
[ Last revised: 8/26/2005 9:55:00 PM ]
References
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1784. Jick H, Derby LE, Vasilakis C et al. The risk of seizures associated with tramadol. Pharmacotherapy 1998;18:607 - 11.
2544. Spiller HA, Gorman SE, Villalobos D, et al. Prospective multicenter evaluation of tramadol exposure. J Toxicol Clin Toxicol 1997;35:361 - 4.
3347. Ripple MG, Pestaner JP, Levine BS et al. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol 2000;21:370 - 4.
4043. Silberstein SD. Drug-induced headache. Neuro Clinic N America 1998;16:107 - 23.
4442. Halevi A, Ben-Amitai D, Garty BZ. Toxic epidermal necrolysis associated with acetaminophen ingestion. Ann Pharmacother 2000;34:32 - 4.
4443. Guccione JL, Zemtsov A, Cobos E, et al. Acquired purpura fulminans induced by alcohol and acetaminophen. Successful treatment with heparin and vitamin K. Arch Dermatol 1993;129:1267 - 9.
4444. Irion R, Gall, H, Werful T, et al. Delayed-type hypersensitivity rash from paracetamol. Contact Dermatitis 2000;43:60 - 1.
4445. Ibanez MD, Alonso E, Munoz MC, et al. Delayed hypersensitivity reaction to paracetamol. Allergy 1996;51:121 - 3.
4446. Beylot C, Doutre M, Beylot-Barry M. Acute generalized exanthematous pustulosis. Semin Cutan Med Surg 1996;15:244 - 9.
8205. Bougie D, Aster R. Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen. Blood 2001;97:3846 - 50.
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