Diphenhydramine (DPH) use is widespread and unrestricted, and chronic abuse can lead to a withdrawal syndrome.
Acts primarily on peripheral and central Histamine H1 receptors but also has antagonist effects at muscarinic acetylcholine receptors. Indirectly interacts with other neurotransmitter systems including serotonin, norepinephrine, dopamine, opioids, adenosine.
Overdose can cause Anticholinergic syndrome: note that symptoms may overlap with serotonin syndrome, neuroleptic malignant syndrome
Intentionally misused (>4x recommended dose) due to behavioral effects like elevated mood, increased energy, mild euphoria: thought to be related to increased dopaminergic transmission in the mesolimbic pathway
Historically, tripelennamine was a first generation antihistamine in the 1970’s that was mixed with pentazocine (an opioid) for its euphoric effects and was known by the name “Ts and blues.”
Consider in patients with history of psychiatric disorder including schizophrenia, depression, substance use disorder, and personality disorder.
Withdrawal syndrome can result from abrupt cessation of use, usually within 24-48 hours of cessation, peak at 3-7 days, with resolution over 1-2 weeks.
Reported with daily DPH use ranging from 180 mg – 3000 mg.
Cholinergic rebound state: presents as tremors, psychosis, seizure-like events.
Physical exam findings may include tachycardia, fever, diaphoresis, hypersalivation, diarrhea, mydriasis, limb rigidity with brisk reflexes, dysarthria, waxing and waning mental status, bowel/bladder incontinence.
Treatment: IV DPH 50 mg q6h to symptom improvement, followed by oral DPH slow taper, e.g.
Oral DPH 50 mg QID, reduced by 25% every 3 days + Clonidine 0.1 mg TID with 0.1 mg transdermal clonidine patch q week.
In case reports, beta blockers and benzodiazepines have also been used for symptomatic relief
References:
Bonham C, Birkmayer F. Severe Diphenhydramine Dependence and Withdrawal: Case Report. Journal of Dual Diagnosis. 2009;5(1):97-103. doi:10.1080/15504260802620269
Halpert AG, Olmstead MC, Beninger RJ. Mechanisms and abuse liability of the anti-histamine dimenhydrinate. Neuroscience & Biobehavioral Reviews. 2002;26(1):61-67. doi:10.1016/S0149-7634(01)00038-0
Nolen A, Dai T. Diphenhydramine Use Disorder and Complicated Withdrawal in a Palliative Care Patient. Journal of Palliative Medicine. 2020;23(9):1279-1282. doi:10.1089/jpm.2019.0308
Saran JS, Barbano RL, Schult R, Wiegand TJ, Selioutski O. Chronic diphenhydramine abuse and withdrawal. Neurol Clin Pract. 2017;7(5):439-441. doi:10.1212/CPJ.0000000000000304