Can you take Benadryl and Flexeril (cyclobenzaprine) together?

Why

Cyclobenzaprine (the molecule in Flexeril) is not a simple muscle relaxant — it is structurally a tricyclic. Its own FDA label says animal studies \"showed a similarity between the effects of cyclobenzaprine and the structurally related tricyclic antidepressants, including reserpine antagonism, norepinephrine potentiation, potent peripheral and central anticholinergic effects, and sedation.\" Diphenhydramine, the active ingredient in Benadryl, is a first-generation antihistamine whose sedation and anticholinergic effects come from those same two mechanisms. So this is not two unrelated drugs that happen to interact — it is the same two effects, doubled. The 2023 AGS Beers Criteria table of \"Drugs With Strong Anticholinergic Properties\" lists both cyclobenzaprine and diphenhydramine by name. Both labels say so in their own words. The cyclobenzaprine label states plainly: \"Cyclobenzaprine may enhance the effects of alcohol, barbiturates, and other CNS depressants,\" and, in Information for Patients, \"Cyclobenzaprine, especially when used with alcohol or other CNS depressants, may impair mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle.\" The Benadryl Drug Facts panel warns that \"marked drowsiness may occur,\" that \"alcohol, sedatives, and tranquilizers may increase drowsiness,\" and to \"be careful when driving a motor vehicle or operating machinery\" — and under \"Ask a doctor or pharmacist before use if you are\" it lists \"taking sedatives or tranquilizers,\" which is exactly the situation someone on cyclobenzaprine is in. The anticholinergic half is spelled out even more directly: the cyclobenzaprine label's PRECAUTIONS say \"Because of its atropine-like action, cyclobenzaprine should be used with caution in patients with a history of urinary retention, angle-closure glaucoma, increased intraocular pressure, and in patients taking anticholinergic medication.\" Benadryl IS an anticholinergic medication. The size of each drug's effect is not small. In the immediate-release cyclobenzaprine label's adverse-reaction table, drowsiness was 29% on 5 mg and 38% on 10 mg against 10% on placebo, and dry mouth 21% and 32% against 7% — though the label footnotes that \"Cyclobenzaprine hydrochloride 10 mg data are from one clinical trial. Cyclobenzaprine hydrochloride 5 mg and placebo data are from two studies,\" so the 10 mg column is not a within-study comparison against that placebo group. Cyclobenzaprine also lingers: the immediate-release label reports it \"is eliminated quite slowly, with an effective half-life of 18 hours (range 8 to 37 hours),\" so a dose taken at night is still substantially present the next day — which is when people add a daytime Benadryl and get caught out. Two practical traps. First, \"Benadryl\" is not one dose. Benadryl Allergy Ultratab is diphenhydramine HCl 25 mg per tablet, while Benadryl Allergy Extra Strength tablets and Extra Strength Liqui-Gels are diphenhydramine HCl 50 mg per unit — same brand, similar boxes, and their labeled doses are not the same (each is given separately below). Read the mg on the box in your hand. Second, diphenhydramine hides in products that do not say \"Benadryl\": Extra Strength Tylenol PM contains diphenhydramine HCl 25 mg per caplet as its nighttime sleep aid, and its Drug Facts \"Do not use\" panel says \"with any other product containing diphenhydramine, even one used on skin\" — so anti-itch products applied to skin count as well. A PM product at bedtime plus a Benadryl for allergies plus cyclobenzaprine is three sedating hits, two of them the same molecule. Separately, the cyclobenzaprine contraindications are absolute and frequently missed: the drug is contraindicated with monoamine oxidase (MAO) inhibitors \"or within 14 days after their discontinuation,\" in the \"Acute recovery phase of myocardial infarction, and patients with arrhythmias, heart block or conduction disturbances, or congestive heart failure,\" and in \"Hyperthyroidism.\" In older adults the combination is worse than the sum of its parts. The 2023 AGS Beers Criteria lists first-generation antihistamines including oral diphenhydramine as \"Avoid\" (strong recommendation), rationale: \"Highly anticholinergic; clearance reduced with advanced age, and tolerance develops when used as hypnotic; risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity.\" It separately lists skeletal muscle relaxants including cyclobenzaprine as \"Avoid\" (strong recommendation) because muscle relaxants used for musculoskeletal complaints \"are poorly tolerated by older adults due to anticholinergic adverse effects, sedation, and increased risk of fractures; effectiveness at dosages tolerated by older adults is questionable.\" And it has a drug-drug row for stacking them: \"Use of more than one medication with anticholinergic properties increases the risk of cognitive decline, delirium, and falls or fractures,\" recommendation \"Avoid; minimize the number of anticholinergic drugs\" (strong). The pharmacokinetics back this up — the cyclobenzaprine label reports mean steady-state exposure in people 65 and over was about 1.7-fold higher than in younger adults, and about 2.4-fold higher in elderly men, which is why the label says \"In such patients cyclobenzaprine should be initiated with a 5 mg dose and titrated slowly upward.\"