Common long-term side effects of prolonged diphenhydramine use include: Dependence. In the case of interacting with alcohol, Benadryl and Zyrtec are quite similar, even though the second one is a second-generation non-sedative antihistamine. It is available in generic and brand versions. The occurrence of side effects will become more pronounced, and the chances for the user to experience some of the more severe side effects are also significantly increased. The undesirable effects of Benadryl can be minimized and managed so that patients can continue with their day-to-day activities in an efficient manner. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Long-Term Side Effects of Diphenhydramine Abuse. The following tips can be followed to manage these side effects: Nevertheless, morning side effects such as residual sleepiness or hangover can occur, though this typically improved after about four nights of use. In a study of older adults, diphenhydramine reduced awakenings but didn't improve sleep latency, total sleep time, or sleep quality. Certain side effects of Benadryl may affect the normal routines of patients. Benadryl (diphenhydramine) is an antihistamine used to treat symptoms of seasonal allergies including sneezing, runny nose, and itching or watering eyes.It works by blocking the action of histamine which causes allergic symptoms.It is available over-the-counter, and also sold as generic diphenhydramine. Minimizing Side Effects of Diphenhydramine. Continued diphenhydramine use can cause long-term adverse side effects that result in permanent damage. Benadryl Injection (diphenhydramine hydrochloride) is an antihistamine used to treat life-threatening allergic reactions (anaphylaxis) along with epinephrine and other treatments.Benadryl Injection is also used to relieve symptoms of household allergies, hay fever and the common cold when medication cannot be given by mouth. Side Effects of Benadryl. Diphenhydramine (Benadryl, Diphenhist, Unisom, Zzzquil) is an antihistamine used to treat symptoms of seasonal allergies including sneezing, runny nose, and itching or watering eyes.It is also used as an over-the-counter sleep aid. Benadryl (diphenhydramine hydrochloride) is a brand name antihistamine drug with anticholinergic (drying) and sedative side effects manufactured by McNeil Healthcare, a division of Johnson & Johnson. Not only will prolonged use cause harm, but it can lead to other aspects such as dependence on the medication. Benadryl (diphenhydramine) is a well-known antihistamine used to treat allergy symptoms including sneezing, runny nose, and itchy and watery eyes, as well as colds, dry coughs, insomnia, and motion sickness.While typically mild, the side effects of Benadryl may be more intense for some people—making using the drug undesirable, especially during the day, or even unsafe. 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