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Aspirin / diphenhydramine Side Effects

Applies to aspirin/diphenhydramine: oral tablet.

Nervous system

Some investigators have suggested that tinnitus may be a less reliable indicator of salicylate toxicity than previously believed. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In a study of rheumatoid arthritis patients, those with tinnitus had no greater salicylate levels than those without tinnitus. Elderly patients may be less likely to perceive tinnitus than younger patients.

The CNS depressant effect of diphenhydramine parallels its plasma concentrations. The plasma concentration threshold for sedation is 30 to 42 ng/mL, and to cause mental impairment is 58 to 74 ng/mL. Patients should be warned against driving while taking diphenhydramine.

Dystonic reactions have been accompanied by dizziness, mental confusion, rigidity, lip and tongue protrusion, trismus, torticollis, and swallowing difficulties and generally resolve spontaneously. Toxic encephalopathy has been reported in a child with chicken pox treated generously with topical diphenhydramine.

Delirium has been reported in elderly patients with mild dementia following a small oral dose of diphenhydramine.[Ref]

Central nervous system side effects of aspirin have included agitation, cerebral edema, coma, confusion, dizziness, headache, cranial hemorrhage, lethargy, and seizures. Tinnitus and subjective hearing loss (or both) may occur. Some investigators have reported that modest doses may result in decreased frequency selectivity and may therefore impair hearing performance, particularly in the setting of background noise.

Nervous system side effects of diphenhydramine have been reported frequently. These have included depression with drowsiness and sedation in nearly all patients treated. Motor skills may be impaired. Dystonic reactions have been reported after single doses of diphenhydramine.[Ref]

Gastrointestinal

Endoscopically identifiable gastric mucosal lesions occur in most patients who receive a single dose of aspirin. Clinically evident gastrointestinal bleeding has been reported in as many as 3% of treated elderly patients. Anorectal ulceration and rectal stenosis have been reported in patients who abuse aspirin-containing rectal suppositories. One case-controlled study has suggested that an association between aspirin (and other NSAID) consumption and appendicitis may exist.[Ref]

Gastrointestinal side effects of aspirin have included epigastric distress (in as many as 83% of patients treated with regular aspirin), abdominal discomfort or pain, endoscopically identifiable gastric mucosal lesions, nausea, and vomiting. More serious gastrointestinal effects include hemorrhage, peptic ulcers, perforation, and esophageal ulcerations.

Gastrointestinal side effects of diphenhydramine have been usually mild and included nausea and dry mouth.[Ref]

Renal

The mechanism of an aspirin-induced decrease in renal function may be related to inhibition of renal prostaglandin synthesis with consequent decreases in renal blood flow. Vasodilating renal prostaglandins may be particularly important in patients who exhibit arterial underfilling (i.e. heart failure, cirrhosis). The administration of high doses of NSAIDs to such patients has produced acute renal failure in rare instances.[Ref]

Renal side effects of aspirin have included reduction in glomerular filtration rate (particularly in patients who are sodium restricted or who exhibit diminished effective arterial blood volume, such as patients with advanced heart failure or cirrhosis), interstitial nephritis, papillary necrosis, elevations in serum creatinine, elevations in blood urea nitrogen, proteinuria, hematuria, and renal failure.[Ref]

Hematologic

Hematologic side effects of aspirin have included increased blood fibrinolytic activity. In addition, hypoprothrombinemia, thrombocytopenia, thrombocyturia, megaloblastic anemia, and pancytopenia have been reported rarely. Aplastic anemia and eosinophilia have also been reported.

Hematologic side effects such as hemolytic anemia, thrombocytopenia, and agranulocytosis have been rarely caused by antihistamines.[Ref]

Hypersensitivity

The mechanism of aspirin-induced hypersensitivity may be related to an up-regulation of the 5-lipoxygenase pathway of arachidonic acid metabolism with a resulting increase in the products of 5-lipoxygenase (such as leukotrienes).

Most commonly, hypersensitivity has manifested itself in patients receiving systemic drug after being sensitized to it by topical application. Sensitization with systemic administration has also been reported.[Ref]

Hypersensitivity side effects to aspirin have included bronchospasm, rhinitis, conjunctivitis, urticaria, angioedema, and anaphylaxis. Approximately 10% to 30% of asthmatics are aspirin-sensitive (with the clinical triad of aspirin sensitivity, bronchial asthma, and nasal polyps).

Hypersensitivity side effects of diphenhydramine have included rash, pruritus, and eczema. Photosensitivity reactions have also been reported.[Ref]

Dermatologic

Dermatologic side effects to aspirin have included Stevens-Johnson syndrome and a lichenoid eruption.[Ref]

Hepatic

Hepatic side effects of aspirin have included hepatotoxicity and cholestatic hepatitis.[Ref]

Oncologic

Oncologic side effects of aspirin have included reports of pancreatic cancer. Several epidemiologic studies have suggested that chronic aspirin use may decrease the risk of large bowel neoplasms. However, other studies have not found such a beneficial effect.[Ref]

Metabolic

Metabolic side effects of aspirin have included dehydration and hyperkalemia. Respiratory alkalosis and metabolic acidosis, particularly during salicylate toxicity, have been reported. A case of hypoglycemia has been reported in a patient on hemodialysis. Salicylates have also been reported to displace triiodothyronine (T3) and thyroxine (T4) from protein binding sites. The initial effect is an increase in serum free T4 concentrations.[Ref]

Other

Other side effects have included Reye's syndrome with aspirin use in children with an acute viral illness. Reye's syndrome has also been reported even more rarely in adults.[Ref]

Reye's syndrome typically involves vomiting, neurologic dysfunction, and hepatic dysfunction during or shortly after an acute viral infection.[Ref]

Musculoskeletal

Musculoskeletal side effects of aspirin have included rhabdomyolysis.[Ref]

Respiratory

Respiratory side effects of aspirin have included hyperpnea, pulmonary edema, and tachypnea.[Ref]

Aspirin desensitization has been used to decrease disease activity and reduce the need for systemic corticosteroids in patients with aspirin-exacerbated respiratory disease.[Ref]

Endocrine

Endocrine side effects of aspirin have included hypoglycemia (which has been reported in children) and hyperglycemia.[Ref]

Ocular

Ocular side effects of aspirin have included cases of localized periorbital edema.

Ocular side effects of diphenhydramine have included blurred vision, diplopia, and dry eyes due to anticholinergic effects.[Ref]

Cardiovascular

Cardiovascular side effects of diphenhydramine have included hypotension, tachycardia, and palpitations.[Ref]

Genitourinary

Genitourinary side effects have included urinary retention and dysuria as a result of the anticholinergic effects of diphenhydramine.[Ref]

References

1. Davenport PM, Wilhelm RE. An unusual vasculitis due to diphenhydramine. Cutaneous and central nervous system involvement. Arch Dermatol. 1965;92:577-80.

2. Product Information. Benadryl (diphenhydramine). Parke-Davis. 2002;PROD.

3. Sexton JD, Pronchik DJ. Diphenhydramine induced psychosis with therapeutic doses. Am J Emerg Med. 1997;15:548-9.

4. Product Information. Bayer Aspirin (acetylsalicylsyra). Bayer. PROD.

5. Richardson GS, Roehrs TA, Rosenthal L, Koshorek G, Roth T. Tolerance to daytime sedative effects of h1 antihistamines. J Clin Psychopharmacol. 2002;22:511-5.

6. Product Information. Bayer Aspirin PM Extra Strength (aspirin-diphenhydramine). Bayer Pharmaceutical Inc. 2005.

7. Neafsey PJ. Low-dose aspirin interactions. Home Healthc Nurse. 2004;22:54-5.

8. Joseph M. Adverse drug reactions as cause of admission to hospital: only part of the picture was reported for aspirin. BMJ. 2004;329:459; author reply 460.

9. Segal R, Lubart E, Leibovitz A, et al. Early and late effects of low-dose aspirin on renal function in elderly patients. Am J Med. 2003;115:462-6.

10. Cheng TI, Cheng TJ, Chiang SC. Association of aspirin with eosinophilia in peripheral blood (December). Ann Pharmacother. 2004;38:2172-3.

11. Lawrence CM, Byrne JP. Eczematous eruption from oral diphenhydramine. Contact Dermatitis. 1981;7:276-7.

12. Barranco P, LopezSerrano MC, MorenoAncillo A. Anaphylactic reaction due to diphenhydramine. Allergy. 1998;53:814.

13. Higashi N, Taniguchi M, Mita H, Higashi A, Akiyama K. Aspirin-induced urticaria and angioedema, but not bronchoconstriction, associated with cysteinyl leukotriene overproduction in 2 patients with asthma. J Allergy Clin Immunol. 2002;110:666-7.

14. Asero R. Intolerance to nonsteroidal anti-inflammatory drugs might precede by years the onset of chronic urticaria. J Allergy Clin Immunol. 2003;111:1095-8.

15. Juurlink DN. Drug-induced hepatotoxicity. N Engl J Med. 2003;349:1974-6; author reply 1974-6.

16. Spurgeon D. Pancreatic cancer is associated with long term use of aspirin. BMJ. 2004;328:70.

17. McGovern MC, Glasgow JFT, Stewart MC. Lesson of the week - Reye's syndrome and aspirin: lest we forget. Br Med J. 2001;322:1591-2.

18. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis, and management. J Allergy Clin Immunol. 2003;111:913-21.

19. Hopfenbeck JR, Cowley DS, Radant A, Greenblatt DJ, Roybyrne PP. Effects of diphenhydramine on human eye movements. Psychopharmacology (Berl). 1995;118:280-6.

Further information

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Some side effects may not be reported. You may report them to the FDA.

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