Aspirin, ASA; Butalbital; Caffeine Adverse Reactions
- abdominal pain
- acneiform rash
- agranulocytosis
- anaphylactoid reactions
- anemia
- angioedema
- anxiety
- aplastic anemia
- azotemia
- bleeding
- bone pain
- bronchospasm
- confusion
- constipation
- dehydration
- delirium
- depression
- diaphoresis
- diarrhea
- disseminated intravascular coagulation (DIC)
- dizziness
- drowsiness
- dyspepsia
- dysphagia
- erythema nodosum
- esophageal stricture
- esophageal ulceration
- esophagitis
- excitability
- fever
- gastritis
- GI bleeding
- hallucinations
- headache
- hearing loss
- hemolysis
- hemolytic anemia
- hepatic encephalopathy
- hepatic necrosis
- hepatitis
- hyperammonemia
- hyperbilirubinemia
- hyperglycemia
- hypernatremia
- hypertension
- hyperuricemia
- hyperventilation
- hypoglycemia
- hypokalemia
- hypoprothrombinemia
- impotence (erectile dysfunction)
- insomnia
- interstitial nephritis
- jaundice
- lethargy
- leukocytosis
- leukopenia
- libido decrease
- maculopapular rash
- metabolic acidosis
- miosis
- mydriasis
- nausea/vomiting
- nystagmus
- odynophagia
- osteopenia
- palpitations
- pancytopenia
- photosensitivity
- polyuria
- proteinuria
- pruritus
- ptosis
- pulmonary edema
- purpura
- pyrosis (heartburn)
- renal failure (unspecified)
- renal papillary necrosis
- renal tubular necrosis
- respiratory depression
- Reye’s syndrome
- rhinitis
- seizures
- sinus tachycardia
- Stevens-Johnson syndrome
- thrombocytopenia
- tinnitus
- tolerance
- toxic epidermal necrolysis
- tremor
- urticaria
- visual impairment
- weight loss
- wheezing
Aspirin, ASA; Butalbital; Caffeine Adverse Reactions
NOTE: This monograph discusses the use of aspirin-butalbital-caffeine combination products. Clinicians may wish to consult the individual monographs for more information about the adverse effects of each agent.
Although generally not severe, GI effects (i.e., nausea/vomiting, diarrhea, and constipation) and CNS effects (i.e., dizziness, drowsiness, headache, and lethargy) have been reported during therapy with aspirin-butalbital-caffeine. Patients undertaking activities requiring mental alertness should be warned of possible adverse effects. Excitability, depression, anxiety, and confusion may be seen, and geriatric patients may experience an increased incidence of these reactions. Adverse behavioral reactions can be seen in individuals with developmental disabilities. Overuse of combination analgesics containing barbiturates 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 aspirin; butalbital; caffeine products has been defined as taking 3 or more doses per day more often than 3 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. Dizziness, drowsiness, headache, lightheadedness, and lethargy may also be signs of salicylism, mild salicylate toxicity. Other symptoms of salicylism include uncontrollable flapping movements of the hands, increased thirst, and visual impairment. In severe overdose, seizures, hallucinations, severe nervousness, excitement, confusion, wheezing or shortness of breath, and unexplained fever may occur. During acute or chronic aspirin toxicity, moderate-to-severe non-cardiogenic pulmonary edema may occur.
Anaphylactoid reactions, including angioedema and acute bronchospasm, may occur with aspirin therapy. Most allergic reactions occur within minutes and almost always within an hour of ingestion, although delayed reactions have been noted. Aspirin hypersensitivity may manifest as a respiratory reaction including rhinitis and/or asthma or with urticaria and angioedema. Aspirin hypersensitivity, however, is uncommon and occurs in only 0.3% of the general population. Patients with chronic urticaria have the highest incidence (20%), followed by patients with asthma (4%) and patients with chronic rhinitis (1.5%). Sensitivity is manifested primarily as bronchospasm in asthmatic patients and is most commonly associated with nasal polyps. The correlation of aspirin hypersensitivity, asthma, and nasal polyps is known as the aspirin triad.
Barbiturates can cause respiratory depression. Respiratory depression is more common in elderly or debilitated patients or when these drugs are given with other agents that cause CNS depression.
Aspirin may cause reversible hepatotoxicity primarily manifested as mild focal hepatic necrosis and portal hypertension with elevated hepatic enzymes (usually transaminases) and hyperbilirubinemia. Jaundice has been reported in some patients. Rarely, salicylates are associated with hypoprothrombinemia resulting in a prolonged prothrombin time and chronic hepatitis. Usually salicylate-induced hepatotoxicity is mild, but in some cases fatalities or hepatic encephalopathy have occurred.
With chronic, high-dose use, analgesic abuse, or aspirin overdose a marked reduction in creatinine clearance, renal papillary necrosis, interstitial nephritis, or renal tubular necrosis with renal failure (unspecified) may be seen; however, in usual doses, aspirin rarely cause clinically significant renal effects in patients with normal renal function. Aspirin may cause transient urinary excretion of renal tubular epithelial cells, azotemia, albuminuria, and proteinuria. Caffeine is a mild diuretic; polyuria can occur.
Dermatologic reactions are uncommon in patients taking aspirin-butalbital-caffeine. Barbiturates may cause photosensitivity, acneiform rash, and purpura; however, discontinuing the drug may not be sufficient to reverse cutaneous reactions because of the slow metabolism and excretion of butalbital. When aspirin is associated with dermatologic reactions it is usually reported in patients who receive aspirin therapy for > 1 week continually or with overdosage. Dermatologic reactions associated with aspirin include acneiform rash, erythema nodosum, maculopapular rash, pruritus, purpura, and urticaria. Rarely, aspirin has been associated with Stevens-Johnson syndrome and toxic epidermal necrolysis.
Leukopenia, pancytopenia, thrombocytopenia, agranulocytosis, aplastic anemia, and disseminated intravascular coagulation (DIC) have been reported rarely with salicylate therapy. Leukocytosis has occurred in patients with salicylate overdose. If hemolytic anemia occurs in patients receiving aspirin, it almost always occurs in G6PD-deficient individuals. It appears that aspirin can induce hemolysis at therapeutic concentrations if other oxidative stressors are present. Otherwise, hemolysis only occurs at much higher concentrations.
Symptomatic GI disturbances occur in 2 - 10% of individuals receiving normal doses of aspirin for analgesia or fever, 10 - 30% of individuals receiving doses > 3.6 grams/day, and 30 - 90% of patients with preexisting GI disease. Nausea/vomiting, dyspepsia, abdominal pain, pyrosis (heartburn), and other symptoms of gastric distress can be reduced if aspirin and aspirin-containing products are taken with food or a full glass of water. Diarrhea or constipation may also occur. Rare cases of esophagitis have been reported in patients receiving aspirin. Aspirin-induced esophagitis is characterized by sudden onset odynophagia, retrosternal pain, and dysphagia. Severe complications including esophageal ulceration, esophageal stricture, bleeding, and perforation have been reported rarely. Risk factors for aspirin-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication. Raising the intragastric pH increases the amount of aspirin in the unionized form, and some data indicate that agents such as cimetidine or antacids can reduce mucosal injury from aspirin. GI bleeding or erosive gastritis can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and an increased bleeding time. In general, the severity of GI bleeding with aspirin is dose-related. Occult GI bleeding occurs in many patients and is not necessarily correlated with GI distress. While the amount of blood lost is usually not significant, blood loss can result in iron deficiency anemia. Patients taking aspirin in large doses (> 15 tablets per week) or regularly (>= 4 days/week) are at increased risk of GI bleeding or gastric ulceration. GI bleeding is more common with aspirin than with other salicylates and is not reduced by administering aspirin with food.
Ocular adverse reactions with barbiturates occur most commonly after chronic use or toxic doses. Miosis is seen most frequently, but mydriasis predominates during toxic states. Disturbances in ocular movement may be seen with weakness of the extraocular muscles and nystagmus. Ptosis has been reported after chronic use.
Tinnitus and hearing loss may occur in patients receiving high-dose and/or long-term salicylate therapy. These effects are early manifestations of salicylate toxicity. Tinnitus and hearing loss are usually dose-related and reversible upon dose reduction or discontinuation.
Reye’s syndrome, which exclusively affects children under 15 years of age, has been associated with aspirin use following active varicella infection or other viral illnesses. Reye’s syndrome is a multisystem disorder evidenced by persistent vomiting, altered sensorium, elevated hepatic enzymes, hypoprothrombinemia, and hyperammonemia.
Barbiturates have been associated with sexual dysfunction. Impotence (erectile dysfunction) and libido decrease may be seen with aspirin-butalbital-caffeine use.
Barbiturates, especially phenobarbital, can induce osteopenia, particularly with long-term use. Unusual weight loss, bone pain or tenderness, or muscle weakness occurring in patients treated with aspirin-butalbital-caffeine should be investigated.
Pharmacologic tolerance to the sedative/hypnotic or CNS stimulation effects of butalbital or caffeine, respectively, may occur in some patients. Typically, tolerance presents as a decrease in the duration or occurrence of effects. In the case of caffeine or butalbital, tolerance can be a beneficial effect. Tolerance may result in the need for increasing doses to maintain desired therapeutic effects, and can be managed by increasing the dose or frequency. However, the ability to increase the dosage of this combination product will be limited by the maximum recommended total daily dose of aspirin. When increasing doses of analgesia are required, causes may be multi-factorial including tolerance, progression of disease, or psychologic distress.
Physiological dependence can occur during chronic aspirin-butalbital-caffeine therapy as evidenced by a withdrawal syndrome occurring after abrupt discontinuation of the drug in these patients. A distinct caffeine withdrawal syndrome has been described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or headache. Withdrawal syndromes may also be seen following chronic dosing of butalbital. Abrupt withdrawal of aspirin-butalbital-caffeine combinations should be avoided after prolonged therapy to prevent withdrawal effects. 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.
Caffeine is a CNS stimulant. Many adverse reactions to caffeine are an extension of its pharmacologic actions. At therapeutic or nontoxic doses, caffeine can cause tremor, sinus tachycardia, and heightened attentiveness. Other adverse reactions include diarrhea, excitability, palpitations, insomnia, headache, and muscle twitches. After excessive doses, caffeine can cause considerable nausea/vomiting and anxiety. Cardiac arrhythmias, seizures, and delirium are possible after deliberate overdoses. A distinct caffeine withdrawal syndrome has been described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or headache.
Aspirin has dose-dependent effects on plasma uric acid levels. At low doses (1 - 2 g/day) decreased urate excretion and hyperuricemia may be seen. Small doses of aspirin can block the effects of probenecid and other uricosuric agents that decrease the tubular reabsorption of uric acid.
At therapeutic doses, aspirin can cause changes in acid/base balance and electrolytes resulting in respiratory alkalosis. In patients with normal renal and respiratory function, this is usually compensated for appropriately. Severe acid/base disturbances may occur during salicylate toxicity. As salicylate toxicity progresses, changes resembling metabolic acidosis are present (e.g., low blood pH, low plasma bicarbonate levels, and normal or nearly normal plasma PaCO2). In reality, a combination of respiratory acidosis and metabolic acidosis is present. Alterations in water and electrolyte balance also occur in salicylate toxicity. Dehydration due to salicylate-induced diaphoresis and hyperventilation occurs. Since more water than electrolytes are lost, dehydration is associated with hypernatremia. Other laboratory changes noted in salicylate toxicity include hyperglycemia or hypoglycemia (especially in children), ketonuria, hypokalemia, and proteinuria. Prolonged exposure to high doses of aspirin also causes hypokalemia through both renal and nonrenal losses. Hyperventilation occurs due to direct stimulation of the respiratory center in the medulla. At high salicylate plasma concentrations (>= 350 mcg/ml), marked hyperventilation will occur and at serum concentrations of about 500 mcg/ml, hyperpnea will be seen. At high or prolonged doses, aspirin also has a depressant effect on the medulla. Toxic doses of aspirin can cause central respiratory depression as well as cardiovascular collapse secondary to vasomotor depression. Since enhanced CO2 production continues, respiratory acidosis occurs.
[ Last revised: 4/14/2003 3:33:00 PM ]
References
. Sanford-Driscoll M, Knodel LC. Induction of hemolytic anemia by nonsteroidal antiinflammatory drugs. Drug Intell Clin Pharm 1986:20:925 - 34.
. Silberstein SD. Drug-induced headache. Neuro Clinic N America 1998;16:107 - 23.
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