While diphenhydramine can help sleep, I am very troubled by the daytime confusion it often causes and by the possibility that it increases Alzheimer's disease.  It has anti-cholinergic side-effects.  Medications given to help slow the progression of Alzheimer's disease work in the opposite way.  Several studies have now found that individuals taking more anti-cholinergic medications are more likely to develop mental confusion and Alzheimer's disease.  I would use diphenhydramine before an addictive medication, but I much prefer trying non-pharmaceutical treatments, melatonin, valerian, and the prescription medication trazodone first.

Diphenhydramine Some Benefit for Sleep: In a DB study of 144 Japanese patients with psychiatric difficulties, at least 60% of patients reported some benefit from diphenhydramine 12.5 mg, 25, mg., or 50 mg. at bedtime. Benefit was greatest in those not using diphenhydramine in the past. Clinical evaluation of diphenhydramine hydrochloride for the treatment of insomnia in psychiatric patients: a double-blind study. Kudo Y, Kurihara M. J Clin Pharmacol. 1990 Nov;30(11):1041-8

Diphenhydramine Preferred to Placebo: In a DB PC 2-week crossover study of 111 insomniacs, patients slept longer on diphenhydramine 50 mg. per night and preferred it to placebo despite a higher rate of side-effects. Univ. Pennsylvania. Diphenhydramine in insomniac family practice patients: a double-blind study. Rickels K, Morris RJ, Newman H, Rosenfeld H, Schiller H, Weinstock R. J Clin Pharmacol. 1983 May-Jun;23(5-6):234-42

Diphenhydramine Helped Childhood Insomnia: In a DB PC study of 50 children, diphenhydramine 1 mg/kg at bedtime did better than placebo on sleep duration and sleep onset without any increase in nightmares, restlessness, or difficulty awaking. The effectiveness of diphenhydramine HCI in pediatric sleep disorders. Russo RM, Gururaj VJ, Allen JE. J Clin Pharmacol. 1976 May-Jun;16(5-6):284-8. Ed: This dosage is less than in over-the-counter remedies. 

Diphenhydramine Better than Temazepam in Short Nursing Home Study: In a DB PC 5-day crossover study of 18 patients, diphenhydramine 50 mg. resulted in significantly more sleep than temazepam 15 mg.  Cognitive side-effects were detected on seven of eights tests with temazepam vs. five with diphenhydramine. Evaluation of temazepam and diphenhydramine as hypnotics in a nursing-home population. Meuleman JR, Nelson RC, Clark RL Jr. Drug Intell Clin Pharm. 1987 Sep;21(9):716-20

Diphenhydramine: Tolerance to Impairment Develops Quickly: In a DB PC study of normal adults, those given diphenhydramine 50 mg. three time a day for three days found considerable impairment of alertness and performance on the first day, but by the third day there was no daytime somnolence or impairment. No impairment occurred with cetirizine 10 mg. once a day. Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. Schweitzer PK, Muehlbach MJ, Walsh JK. J Allergy Clin Immunol. 1994 Oct;94(4):716-24. Ed: Since patients almost always take diphenhydramine more than once, single dose studies are of little value in view of the tolerance effect.

Diphenhydramine Can Kill Infants: In five reported fatalities of infants under 13 weeks of age dying from diphenhydramine intoxication, authors note that the infants had lower blood levels than found in adult cases.  In at least two cases, infants were given the diphenhydramine as a sleep remedy.  Diphenhydramine often causes a paradoxical hyperstimulation syndrome in infants and should never be given to them. Fatal diphenhydramine intoxication in infants. Baker AM, Johnson DG, Levisky JA, Hearn WL, Moore KA, Levine B, Nelson SJ. J Forensic Sci. 2003 Mar;48(2):425-8

Diphenhydramine Most Common Sleep Remedy in Elderly: In a 9 year follow-up study of 1,627 U.S. elderly age 73 at the beginning of the study, benzodiazepine used increased from 1.8% to 3.1% by the end of the study while diphenhydramine usage increased from 0.4% to 8.1%. Cognitive impairment was associated with diphenhydramine usage. Univ. Pittsburgh. Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based cohort: effects on cognition. Basu R, Dodge H, Stoehr GP, Ganguli M. Am J Geriatr Psychiatry. 2003 Mar-Apr;11(2):205-13. 

Diphenhydramine and Other Common Sleep Remedies: Of 176 Canadian elderly with a mean age of 74, 48% had used one or more therapies for sleep within the past year. These included non-prescription products (50% of therapies), prescription products (17%) and non-drug activities such as walking or drinking milk (34%). Non-prescription products were dimenhydrinate (21%), acetaminophen (19%), diphenhydramine (15%), alcohol (13%) and herbal products (11%). Most took them at least 1 day per week (79%) and 32% took them daily. These products subjectively improved sleep latency (mean 32 vs. 61 minutes, p<0.001), number of nocturnal awakenings (mean 2 vs. 3 awakenings, p<0.001) and total hours of sleep (mean 6.6 vs. 5.4 hours, p<0.001). Mild side-effects were reported by 35 respondents (75%), the most common being dry mouth (N=22) and daytime drowsiness (N=13). Respondents were taking an average of four other medications currently. The use of non-prescription sleep products in the elderly. Sproule BA, Busto UE, Buckle C, Herrmann N, Bowles S. Int J Geriatr Psychiatry. 1999 Oct;14(10):851-7

Diphenhydramine Not Sedative for Children: In a DB PC 4 day study of 83 children ages 8-10 with seasonal allergic rhinitis, neither loratadine nor diphenhydramine caused somnolence, or impairment of reaction time, verbal comprehension or reading performance. Children's school performance is not impaired by short-term administration of diphenhydramine or loratadine. Bender BG, McCormick DR, Milgrom H. J Pediatr. 2001 May;138(5):656-60.  The order of potency of H1-antagonists for the reduction in sleep latency (from greatest to least) was promethazine>chlorpheniramine>diphenhydramine and pyrilamine, and that for the increase in sleep duration was chlorpheniramine>promethazine>diphenhydramine and pyrilamine. Japan. Slow wave sleep-inducing effects of first generation H1-antagonists. Saitou K, Kaneko Y, Sugimoto Y, Chen Z, Kamei C. Biol Pharm Bull. 1999 Oct;22(10):1079-82

Diphenhydramine Cognitive Side-Effects

Diphenhydramine Associated with an Increase in Mental Difficulty: A group of 1,627 rural southwestern Pennsylvania elderly age 65 and over were followed for 10 years. Use of prescription sedative-hypnotics (primarily benzodiazepines) increased from 1.8% to 3.1%, and over-the-counter sedative-hypnotic use (primarily diphenhydramine) increased from 0.4% to 7.6%. After adjusting for age and sex, diphenhydramine use was associated with higher education and more depressive symptoms, the latter becoming nonsignificant after controlling for initial insomnia. MMSE became significantly associated with diphenhydramine use when 143 subjects with dementia were excluded from the analysis. The association of this drug with cognitive impairment in persons without dementia highlights its potential for causing adverse reactions in older adults. Sedative-hypnotic use of diphenhydramine in a rural, older adult, community-based cohort: effects on cognition. Basu R, Dodge H, et al University of Pittsburgh. Am J Geriatr Psychiatry. 2003 Mar-Apr;11(2):205-13 

Diphenhydramine (Benadryl) Confuses Elderly: 426 patients over 70 at Yale Hosp were studied and researchers found that of 114 treated with diphenhydramine, 68% received it for sleep and some others for prophylaxis of transfusion reactions. Cognitive decline occurred in 42% with vs. 24% without diphenhydramine. Diphenhydramine is associated with increased hospital stay of one day and many more urinary catheters. Arch Internal Med 01;161:2091. Ed: This is purely a correlational study and does not imply cause-effect.

Diphenhydramine (Benadryl) Slight Effect on Driving Tests: In a single dose DB PC study of 18 normal adults comparing desloratadine 5 mg. vs. diphenhydramine 50 mg., diphenhydramine caused a 6% increase in breaking reaction time with no effect on speed or distance behind the next car. Effects of desloratadine, diphenhydramine, and placebo on driving performance and psychomotor performance measurements. Vuurman EF, Rikken GH, Muntjewerff ND, De Halleux F, Ramaekers JG. Eur J Clin Pharmacol. 2004 May 28

Diphenhydramine Less Psychomotor Impairment than Temazepam; Valerian no Benefit for Sleep: In a DB PC single dose crossover study of 12 healthy elderly adults, temazepam 15 mg. and 30 mg. had considerably more impairment of psychomotor ability than diphenhydramine 50 mg. or 75 mg. and valerian 400 mg. or 800 mg. caused no impairment.  Temazepam 30 mg. had the most sedative effect followed by diphenhydramine at either dosage.  Valerian had no sedative effect at either dosage. Acute pharmacological effects of temazepam, diphenhydramine, and valerian in healthy elderly subjects. Glass JR, Sproule BA, Herrmann N, Streiner D, Busto UE. J Clin Psychopharmacol. 2003 Jun;23(3):260-8

Dementia Cholinesterase Inhibitor Patients Often Receive Inappropriate Anti-Cholinergics:

Anti-Cholinergics May Increase Alzheimer's Disease: The hypothesis that blockade of muscarinic receptors is associated with increased Alzheimer-type pathology was investigated in Parkinson's disease. Amyloid plaque densities were more than 2.5-fold higher in cases treated with antimuscarinic medication in the long term compared with untreated or short-term treated cases (p = 0.005 and 0.00005, respectively). Neurofibrillary tangle densities were also highest in chronic compared with untreated or acute-treated groups (p = 0.02 and 0.05, respectively). The findings, if replicated, have potential implications for the use of anticholinergic medication in elderly Parkinson's disease patients.  Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs. Perry EK, Kilford L, et al. Newcastle upon Tyne, United Kingdom. Ann Neurol. 2003 Aug;54(2):235-8.

Dementia Cholinesterase Inhibitor Patients Do Worse If on an Anti-Cholinergic: In a study of 69 Alzheimer patients on cholinesterase inhibitor treatment, those receiving one or more concomitant medications with significant anticholinergic properties (N=16) after 2 years had MMSE scores which were significantly worse than for those not on anticholinergics. Anticholinergics may be associated with significant deleterious effects on acetylcholinesterase therapy, or, more speculatively, that chronic exposure to anticholinergics may have adverse effects on the clinical course of AD. Chronic exposure to anticholinergic medications adversely affects the course of Alzheimer disease. Lu CJ, Tune LE. Emory University Atlanta.Am J Geriatr Psychiatry. 2003 Jul-Aug;11(4):458-61

Thomas E. Radecki, M.D., J.D.

modern-psychiatry.com

Email: [email protected]