Table 2.

Summary of Safety and Efficacy of Diphenhydramine

Study	Participant Characteristics	Outcome Measures	Principal Findings/Outcomes	Secondary Observations and Adverse Events	Interpretation and Limitations	Overall Assessment of the Dataa
Healthy volunteers with or without occasional disturbed sleep
Morin et al (2005)23 Design: randomized, double-blind, placebo-controlled, multicenter, objective, self-report Arms: diphenhydramine 50 mg/d (Sominex) vs placebo (vs valerian/hops) Schedule: diphenhydramine for 2 wk followed by placebo for 2 wk	Occasional insomnia (sSL > 30 min and/or awake after sleep onset > 30 min 2–4 nights/wk) 25–65 y N = 184 (mean age: 44.3 y, 59.8% female)	Primary: sleep diary (active agent vs placebo, sleep latency, sleep efficiency, and total sleep time at wk 2) Secondary: overnight PSG (baseline to wk 2, subset n = 75), ISI, CGI, SF-36, withdrawal/rebound effects, adverse events	Diphenhydramine vs placebo: no treatment difference in sSL after 2 wk of treatment (21.6 vs 23.8 min); sSE improved with diphenhydramine vs placebo: 4.6% vs 2.5%*; no significant difference in sTST	Diphenhydramine vs placebo: ISI lower after 2 wk (9.39 vs 11.63**); PSG: no significant improvements on sleep latency, sleep efficiency, or TST vs placebo; no rebound insomnia vs placebo; no. of participants discontinuing due to adverse events and reporting adverse events: diphenhydramine > placebo	“Mild hypnotic effect” but no significant improvements on PSG parameters	U
Katayose et al (2012)24 Design: randomized, double-blind, placebo-controlled, cross-over, objective Arms: diphenhydramine 50 mg vs placebo (vs zolpidem 10 mg vs ketotifen 1 mg) Schedule: single dose	Healthy Japanese volunteers N = 22 (mean age: 22.2 y, 0% female)	Primary: next-day measures of sleepiness (MSLT, AAT, visual analog scale) and psychomotor performance (DSST, reaction time tests, n-back test) Secondary: overnight PSG (active agent vs placebo)	Diphenhydramine vs placebo showed impaired psychomotor performance on 1-back test; % error rate: 6.3% vs 4.7%; reduced wakefulness on AAT: 2.2 vs 2.5*	Diphenhydramine vs placebo: longer REM latency (138.5 vs 99.9 min*) and reduced % REM (16.2 vs 20.5*) No significant differences in other PSG parameters Adverse events not captured	Minimal effects on PSG parameters; significant next-day psychomotor impairment	U
Diagnosed insomnia
Glass et al (2008)25 Design: randomized, double-blind, placebo-controlled, cross-over, self-report Arms: diphenhydramine 50 mg/d vs placebo (vs temazepam) Schedule: 2 wk	DSM-IV insomnia ≥ 70 y N = 20 (mean age: 73.9 y, 50% female)	Primary: sleep diary (active agent vs placebo) Secondary: rebound effects, next-day impairment (DSST, manual tracking task, memory assessment), adverse events	Diphenhydramine vs placebo: no treatment difference for sleep quality: 3.0 vs 2.9, SOL: 34.2 vs 36.8 min, or TST: 6.6 vs 6.3 min; significant decreased awakenings: 1.7 vs 2.0* Temazepam vs placebo: significant on all sleep diary measures	7 of 15 experienced rebound effects with diphenhydramine (5 of 14 for placebo); no changes in DSST, manual tracking task, or memory task with diphenhydramine; adverse events: diphenhydramine similar to placebo	No improvement in sleep quality Limitations: significant improvement in awakenings may not be clinically relevant (0.3/night)	–

^aThe last column provides overall assessment of the data: U = unclear (study interpretation is unclear with regard to use as a sleep aid); – = negative study (did not meet primary endpoint and does not support use as a sleep aid).

^*P < .05.

^**P < .01.

^***P < .001.

Abbreviations: AAT = α attenuation test, CGI = Clinical Global Impressions scale, DSST = Digit Symbol Substitution Test, ISI = Insomnia Severity Index, MSLT = Multiple Sleep Latency Test, PSG = polysomnography, REM = rapid eye movement, SF-36 = 36-Item Short-Form Health Survey, SOL = sleep onset latency/latency to persistent sleep via PSG, sSE = sleep efficiency by participant report, sSL = sleep latency by participant report, sTST = total sleep time by participant report, TST = total sleep time by PSG.