Acetaminophen; Codeine Adverse Reactions
- abdominal pain
- acute generalized exanthematous pustulosis (AGEP)
- agranulocytosis
- anaphylactic shock
- anaphylactoid reactions
- angioedema
- anorexia
- bleeding
- bradycardia
- cardiac arrest
- confusion
- constipation
- contact dermatitis
- dizziness
- drowsiness
- edema
- elevated hepatic enzymes
- encephalopathy
- erythema
- exfoliative dermatitis
- fever
- hallucinations
- headache
- hemolysis
- hemolytic anemia
- hepatic necrosis
- hypoprothrombinemia
- hypotension
- interstitial nephritis
- jaundice
- maculopapular rash
- methemoglobinemia
- miosis
- nausea/vomiting
- neonatal abstinence syndrome
- neutropenia
- orthostatic hypotension
- palpitations
- pancytopenia
- physiological dependence
- pruritus
- purpura
- rash (unspecified)
- renal failure (unspecified)
- renal papillary necrosis
- renal tubular necrosis
- respiratory depression
- restlessness
- syncope
- thrombocytopenia
- thrombocytosis
- tolerance
- toxic epidermal necrolysis
- urticaria
- withdrawal
Acetaminophen; Codeine Adverse Reactions
NOTE: This monograph discusses adverse reactions with acetaminophen; codeine combination products. Clinicians may wish to consult the individual monographs for more information about each agent.
Opiate agonists present the potential for abuse or psychological dependence although, the true risk of this phenomenon is extremely low. Physiological dependence, however, will occur during chronic acetaminophen; codeine therapy as evidenced by a withdrawal syndrome occurring after abrupt discontinuation of the drug in these patients. Symptoms of withdrawal include nausea and diarrhea, coughing, lacrimation, yawning, sneezing, rhinorrhea, profuse sweating, twitching muscles, abdominal and muscles pain/cramps, hot and cold flashes, and piloerection. Elevations in body temperature, respiratory rate, heart rate, and blood pressure may also occur. Routine use of opiate agonists by an expectant mother can lead to depressed respiration in the newborn and a neonatal abstinence syndrome. Withdrawal symptoms in a newborn occur 1 - 4 days after birth and include generalized tremors, hypertonicity with any form of tactile stimuli, hyperalertness, sleeplessness, excessive crying, vomiting, diarrhea, yawning and fever. It is important to differentiate physiological dependence, the onset of a withdrawal syndrome upon abrupt discontinuation of the drug from psychologic dependence. Psychological dependence is a behavioral syndrome characterized by drug craving, overwhelming concern with acquisition of the drug and other drug-related behaviors such as drug selling and seeking the drug from multiple sources.
Pharmacologic tolerance to the analgesic effects of opiate agonists including acetaminophen; codeine combinations may occur in some patients. Tolerance is the need for increasing doses to maintain initial pain relief. Typically, tolerance presents as a decrease in the duration of analgesia and can be managed by increasing the dose or frequency; however, dosage increases in patients receiving acetaminophen and opiate agonist combination therapy will be limited by the total daily dose of acetaminophen. Some patients may require changing to a pure opiate agonist, such as morphine or oxycodone, which is not limited by a maximum daily dose as is the acetaminophen; codeine combination. When increasing doses of analgesia are required causes may be multi-factorial including tolerance, progression of disease or psychologic distress.
The most significant adverse effect associated with opiate agonist use is respiratory depression. Respiratory depression is more common in elderly or debilitated patients, following large initial doses in non-opioid tolerant patients or when opioids are given with other agents which cause CNS depression. Routine use of opiate agonists by an expectant mother can lead to respiratory depression. When acetaminophen; codeine is appropriately titrated, the risk of respiratory depression is generally small as tolerance rapidly develops to this effect. Caution needs to be employed in patients with chronic obstructive pulmonary disease or decreased pulmonary reserve, cardiovascular disease, or who are taking other CNS depressants. Severe symptomatic respiratory depression should be treated cautiously with an opioid antagonist such as naloxone.
Patients may complain of adverse GI effects while taking acetaminophen; codeine. Opiate analgesics can cause a variety of GI effects, most commonly nausea/vomiting and constipation. Nausea and vomiting is more commonly seen at the initiation of opioid therapy or when switching agents. Opiate agonists affect the vestibular system and may cause more nausea/vomiting in ambulatory patients than bedridden patients. Scheduled treatment with an antiemetic during the first 1 - 2 days, then as needed during opiate therapy will usually control these symptoms until tolerance develops. If patients have nausea associated with movement, an antivertigo agent such as meclizine may be appropriate. Metoclopramide may be helpful in treating the symptoms of early satiety or fullness. Constipation due to decreased GI motility and secretions is common during opiate agonist therapy. Tolerance rarely develops to this effect, therefore, patients require a bowel regimen consisting of a stool softener and mild stimulant throughout chronic acetaminophen; codeine therapy. If the patient does not have a bowel movement for 2 days, an enema or suppository should be administered to prevent impaction.
Acetaminophen can be hepatotoxic. In most cases, acetaminophen-induced hepatotoxicity occurs as a result of an acute overdose; however, moderately excessive doses, if taken chronically, may also produce hepatotoxicity. Acetaminophen-induced hepatotoxicity is manifested as hepatic necrosis, jaundice, bleeding and encephalopathy. After acute overdose, 2 or 3 days pass before maximum liver damage becomes apparent. Nausea, vomiting, anorexia, and abdominal pain usually occur within 2 - 3 hours of ingestion of toxic doses. Elevated hepatic enzymes and hypoprothrombinemia are also seen with acetaminophen overdose. Both cimetidine and ethanol can affect the severity of acetaminophen-induced hepatotoxicity (see Drug Interactions). The exact incidence of acetaminophen-induced hepatotoxicity seen with acetaminophen; codeine is not known and may be limited by the respiratory depression effects of codeine.
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.
Overuse of combination analgesics such as acetaminophen; codeine 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; codeine products has been defined as taking 3 or more doses per day more often than 2 days per week. 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.
Codeine’s effect on opiate receptors in the reticular activating system and striatum produces sedation. Patients should be warned that activity requiring mental alertness can be affected during acetaminophen; codeine treatment because CNS depression, including drowsiness, confusion, and dizziness, can occur. Nervousness, restlessness, sleep disturbances and anxiety have been reported. Depending upon the individual patient tolerance, hallucinations may be reported in patients undergoing rapid dose escalation of acetaminophen; codeine.
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. 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.
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. 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.
Codeine is known to cause pruritus. In the absence of a rash or other symptoms, the pruritus is probably not related to an allergic reaction. Use of H1-blockers or changing to a different opioid may lessen the pruritus. 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. 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. 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 degrees 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.
Codeine can cause cardiovascular adverse reactions due to its anticholinergic effects and ability to release histamine. These reactions include sinus bradycardia, palpitations, hypertension, hypotension, orthostatic hypotension, and syncope. In cases of severe respiratory and/or circulatory depression, shock and cardiac arrest may occur.
Codeine, like other opiate agonists, can cause miosis. Therapeutic doses can increase accommodation and sensitivity to light reflex and decrease intraocular tension in both normal and glaucomatous eyes. The incidence of these effects during acetaminophen; codeine therapy is not known.
[ Last revised: 8/26/2005 9:55:00 PM ]
References
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