A Comprehensive Monograph on Diphenhydramine (DB01075): Pharmacology, Clinical Utility, and Safety Profile

Executive Summary

Diphenhydramine is a first-generation ethanolamine-derivative antihistamine that, since its initial approval in 1946 [1], has become one of the most widely available and recognized over-the-counter (OTC) medications worldwide.[2] While primarily known for its role in treating acute allergic reactions, its diverse pharmacological profile lends it to a broad spectrum of uses, including as an antiemetic for motion sickness, an antitussive in cold preparations, and a hypnotic agent for short-term insomnia.[2]

The drug's primary mechanism of action is potent inverse agonism at the histamine H1 receptor. However, its clinical effects and extensive side-effect profile are profoundly influenced by its ability to readily cross the blood-brain barrier and its significant antagonism of muscarinic acetylcholine receptors.[2] This dual central and peripheral activity, combined with actions on other neurotransmitter systems, is responsible for both its therapeutic versatility and its hallmark sedative and anticholinergic adverse effects.

A central theme of this report is the profound dichotomy between Diphenhydramine's ubiquitous OTC availability and the growing body of evidence and clinical guidelines that caution against its use, particularly in vulnerable populations such as the elderly and young children.[3] Its inclusion in the American Geriatrics Society Beers Criteria as a potentially inappropriate medication for older adults underscores a significant risk profile—including cognitive impairment, delirium, and falls—that is often underappreciated by consumers and even some clinicians.[9]

While Diphenhydramine remains a valuable agent for the management of acute allergic reactions and as an important adjunct in the treatment of anaphylaxis, its utility for other common indications, such as insomnia, is increasingly questioned. The evidence suggests its efficacy for sleep is limited and its risks are substantial, especially when safer, more targeted second-generation antihistamines and other therapies are available. The enduring market presence of Diphenhydramine illustrates a critical public health tension between historical precedent, consumer familiarity, and the principles of modern, evidence-based medicine, suggesting the drug may have reached the end of its therapeutic life cycle for many of its common applications.[3]

Chemical Identity and Physicochemical Properties

Introduction

Establishing the fundamental chemical identity of Diphenhydramine is essential for understanding its pharmacological behavior, formulation characteristics, and interactions with biological systems. As an ethanolamine ether, its structure dictates its lipophilicity, receptor binding profile, and metabolic pathways. This section details the nomenclature, structural identifiers, and key physicochemical properties of Diphenhydramine and its commonly used salt forms.

Chemical Structure and Nomenclature

Diphenhydramine is structurally classified as an ether, specifically the benzhydryl ether of 2-(dimethylamino)ethanol, and is also a tertiary amino compound.[1] This structure is responsible for its characteristic pharmacological activities.

• IUPAC Name: 2-benzhydryloxy-N,N-dimethylethanamine.[4]
• Chemical Formula: The molecular formula for the free base is C17​H21​NO.[2]
• Structural Identifiers:
• SMILES: CN(C)CCOC(C1=CC=CC=C1)C2=CC=CC=C2.[4]
• InChIKey: ZZVUWRFHKOJYTH-UHFFFAOYSA-N.[4]

Physicochemical Properties

The physical and chemical properties of Diphenhydramine influence its absorption, distribution, and formulation into stable dosage forms.

• Molecular Weight: The monoisotopic mass of the free base is 255.1623 g/mol, with an average molecular weight of 255.35 g/mol.[2]
• Physical Description: The free base of Diphenhydramine is an oil.[4] However, it is most commonly encountered as its hydrochloride salt, which is a white or almost-white crystalline powder. This powder is odorless but possesses a bitter taste that produces a numbing sensation upon contact with mucosal surfaces.[12] The hydrochloride salt is known to slowly darken upon exposure to light but is otherwise stable under ordinary storage conditions.[4]
• Solubility: A critical property for formulation is its solubility. The hydrochloride salt is freely soluble in water and alcohol, facilitating its use in aqueous solutions for injection and oral liquids.[12] In contrast, the free base is soluble in organic solvents like dimethyl sulfoxide (DMSO) but not in water.[11]
• Melting Point: The melting point for the hydrochloride salt is reported in the range of 168–172 °C.[4]
• Dissociation Constant (pKa​): With a pKa​ value of approximately 9.0, Diphenhydramine is a weak base.[4] This means that at physiological pH (around 7.4), it exists in a significantly ionized state, which influences its interaction with receptors and transport across membranes.

Salts and Formulations

Diphenhydramine is rarely administered as a free base. Instead, it is formulated as a salt to improve stability, solubility, and handling. The most common forms are the hydrochloride and citrate salts.

• Diphenhydramine Hydrochloride (HCl): CAS Number 147-24-0. This is the most prevalent form, used in oral, topical, and parenteral formulations.[4] Its molecular weight is 291.82 g/mol.[13]
• Diphenhydramine Citrate: CAS Number 88637-37-0. This salt is also used in oral OTC products, particularly sleep aids.[11]
• Diphenhydramine Free Base: CAS Number 58-73-1.[4]

The use of different salt forms has direct and important clinical consequences that are often unappreciated by consumers. For instance, OTC sleep aid monographs from the U.S. Food and Drug Administration (FDA) specify different dosages to achieve an equivalent therapeutic effect: 50 mg for Diphenhydramine HCl versus 76 mg for Diphenhydramine citrate.[15] This distinction arises because the citrate salt has a higher molecular weight than the hydrochloride salt, meaning a greater mass of the citrate salt is required to deliver the same amount of the active Diphenhydramine moiety. A simple "mg-for-mg" comparison between products containing different salts is therefore inaccurate and could lead to under- or over-dosing if a consumer switches between products without understanding this fundamental chemical difference. This subtlety highlights a potential public health issue rooted in the drug's basic chemistry, where precise labeling and pharmacist counseling are crucial for safe use.

Table 1: Chemical and Physical Identifiers for Diphenhydramine

Property	Value	Source(s)
IUPAC Name	2-benzhydryloxy-N,N-dimethylethanamine	4
Common Synonyms	Benadryl, Dimedrol, Diphenhydraminum	1
DrugBank ID	DB01075	2
CAS Number (Free Base)	58-73-1	4
CAS Number (HCl Salt)	147-24-0	4
CAS Number (Citrate Salt)	88637-37-0	11
Molecular Formula (Base)	C17​H21​NO	2
Molecular Weight (Base)	255.35 g/mol	2
Molecular Formula (HCl Salt)	C17​H21​NO⋅HCl	7
Molecular Weight (HCl Salt)	291.82 g/mol	12
Physical Description (HCl Salt)	White or almost-white crystalline powder	12
Melting Point (HCl Salt)	168-172 °C	4
Water Solubility (HCl Salt)	Freely soluble	12
SMILES	CN(C)CCOC(C1=CC=CC=C1)C2=CC=CC=C2	4
InChIKey	ZZVUWRFHKOJYTH-UHFFFAOYSA-N	4

Comprehensive Pharmacology

Introduction

The clinical profile of Diphenhydramine is a direct consequence of its complex pharmacology. While classified as a first-generation antihistamine, its actions extend well beyond histamine receptor blockade. A deep understanding of its interactions with multiple receptor systems and its pharmacokinetic properties is essential to appreciate the full spectrum of its therapeutic effects, its extensive side-effect profile, and its potential for significant drug interactions.

A. Mechanism of Action

Diphenhydramine's effects are mediated through its activity at several distinct molecular targets, both in the peripheral and central nervous systems.

Histamine H1 Receptor

The primary mechanism of action of Diphenhydramine is as a potent inverse agonist at the histamine H1 receptor.[2] Unlike a simple neutral antagonist that merely blocks the binding of histamine, an inverse agonist binds to and stabilizes the receptor in its inactive conformation. This action reverses the receptor's constitutive (baseline) activity, in addition to competitively preventing histamine from binding.[6] By doing so, Diphenhydramine effectively counteracts histamine-mediated physiological responses, such as vasodilation, increased capillary permeability, pain, itching, and bronchial smooth muscle contraction, which are the hallmarks of an allergic reaction.[17]

Muscarinic Acetylcholine Receptors

Diphenhydramine is also a potent muscarinic antagonist, with binding affinities for muscarinic receptors ($K_{i}$s = 100 to 260 nM for M1-M5) that are clinically significant.[2] This anticholinergic activity is not a minor side effect but a core component of its pharmacological identity. It is responsible for several of its therapeutic uses, including the treatment of nausea and vertigo associated with motion sickness (by acting on the vestibular system) and its use in managing drug-induced parkinsonism.[1] However, this same mechanism is the source of the majority of its well-known and troublesome adverse effects, such as dry mouth, blurred vision, urinary retention, constipation, tachycardia, and, at higher doses, confusion and delirium.[5]

Central Nervous System Penetration

A key feature that distinguishes first-generation antihistamines like Diphenhydramine from their second-generation successors is their ability to readily cross the blood-brain barrier. As a small, lipophilic molecule, Diphenhydramine easily penetrates the central nervous system (CNS).[7] Once in the CNS, its antagonism of H1 and muscarinic receptors produces its most prominent effects: sedation, drowsiness, dizziness, and cognitive impairment.[2] This CNS penetration is the very reason it is effective as a sleep aid but also the reason it impairs functions requiring mental alertness, such as driving.

Other Neurotransmitter Systems and Channels

The pharmacology of Diphenhydramine is even more complex, involving interactions with several other systems. Research indicates that it can modulate neurotransmitter systems affecting behavior, including dopamine, norepinephrine, serotonin, and opioid pathways.[2] This polypharmacology may contribute to its potential for abuse and its investigational use for anxiety.[2] Additionally, Diphenhydramine functions as an intracellular sodium channel blocker. This mechanism, similar to that of local anesthetics like lidocaine, underlies its ability to be used topically to relieve pain and itching from insect bites and minor skin irritations.[1]

This "dirty drug" profile, characterized by action at multiple targets, is a double-edged sword. It grants Diphenhydramine a versatile therapeutic profile, allowing it to be used for allergies (H1 antagonism), motion sickness (muscarinic antagonism), and as a local anesthetic (sodium channel blockade). However, these same mechanisms are inextricably linked to its most problematic side effects: sedation (CNS H1 antagonism), confusion and dry mouth (muscarinic antagonism), and potential cardiotoxicity at high doses (sodium channel blockade). This inherent lack of receptor selectivity makes it a suboptimal choice when a specific, targeted therapeutic effect is desired. The development of second-generation antihistamines, which are designed to be more selective for peripheral H1 receptors and lack significant anticholinergic activity, represents a major pharmacological advance aimed directly at overcoming this limitation. The persistence of Diphenhydramine in the market is therefore less a testament to superior efficacy and more a reflection of historical precedent, low cost, and deep-seated consumer familiarity.

B. Pharmacodynamics

The observable effects of Diphenhydramine on the body are a direct result of its mechanisms of action.

• Antihistaminic Effects: It effectively prevents and relieves the symptoms of histamine release, including sneezing, rhinorrhea (runny nose), itchy and watery eyes, and pruritus (itching).[2]
• Sedative/Hypnotic Effects: Antagonism of H1 receptors in the CNS directly leads to drowsiness and sedation, which is the basis for its use as a sleep aid.[4] Studies have shown that a single 50 mg dose produces significant feelings of drowsiness for up to six hours.[19] Tolerance to the sedative effects can develop with repeated daily use, diminishing its utility as a long-term hypnotic.[20]
• Anticholinergic Effects: These are prominent and dose-dependent. They manifest clinically as dryness of the mouth, nose, and throat; blurred vision due to cycloplegia (paralysis of accommodation); urinary retention; and constipation.[5] At supratherapeutic or toxic doses, these effects can escalate to a full anticholinergic toxidrome, characterized by delirium, agitation, and hallucinations.[5]
• Cognitive Impairment: Diphenhydramine consistently demonstrates dose-dependent impairment of cognitive and psychomotor functions. Laboratory and on-the-road driving studies have shown significant impairment in tracking, reaction time, concentration, memory, and vigilance.[19] An important distinction exists between the thresholds for these effects: subjective drowsiness can be observed at plasma concentrations of 30-40 ng/mL, whereas objective mental impairment becomes apparent at higher concentrations, typically above 58-60 ng/mL.[19] This implies that a person may experience significant cognitive deficits even without feeling particularly sleepy.
• Paradoxical Excitation: In a subset of individuals, particularly young children, Diphenhydramine can produce the opposite of its intended sedative effect. This paradoxical reaction manifests as CNS stimulation, leading to restlessness, agitation, nervousness, and irritability.[5]

C. Pharmacokinetics (Absorption, Distribution, Metabolism, and Excretion)

The pharmacokinetic profile of Diphenhydramine describes its movement into, through, and out of the body, which determines the onset, intensity, and duration of its effects.

• Absorption: Following oral administration, Diphenhydramine is well absorbed from the gastrointestinal tract. Peak plasma concentrations are typically reached within 2 to 3 hours.[20] The onset of action is much more rapid with parenteral administration, occurring within 5 to 10 minutes for intravenous (IV) injection and 30 to 60 minutes for intramuscular (IM) injection.[25] The oral bioavailability is approximately 61%, indicating significant first-pass metabolism.[20]
• Distribution: The drug is widely distributed throughout the body, including effective penetration into the CNS.[13] It exhibits high binding to plasma proteins, around 78%, primarily to albumin.[17] This extensive protein binding has a significant clinical implication: it limits the drug's removal by hemodialysis, making this intervention ineffective for treating overdose in patients with renal failure.[17]
• Metabolism: Diphenhydramine is extensively metabolized in the liver. The primary enzyme responsible for its breakdown is cytochrome P450 2D6 (CYP2D6).[20] Metabolism proceeds via sequential demethylation to form its major metabolites, including the active N-desmethyldiphenhydramine, as well as N,N-didesmethyldiphenhydramine and diphenylmethoxyacetic acid.[2]
• Elimination: The elimination half-life (t1/2​) of Diphenhydramine is variable, with an average of approximately 8.5 hours in healthy adults.[20] This half-life can be significantly longer in elderly individuals and shorter in children, necessitating dose adjustments in these populations.[20] The majority of the drug is eliminated as metabolites in the urine, with less than 2% of a dose being excreted as unchanged drug.[20]

The heavy reliance on CYP2D6 for metabolism represents a critical and often underappreciated source of clinical risk. Diphenhydramine itself is a potent inhibitor of this enzyme.[17] Since CYP2D6 is responsible for the metabolism of a vast number of commonly prescribed medications—including certain antidepressants (SSRIs, TCAs), beta-blockers (metoprolol), and opioids (codeine, hydrocodone)—co-administration can lead to dangerous drug-drug interactions.[17] By inhibiting their metabolism, Diphenhydramine can cause the plasma concentrations of these other drugs to rise to toxic levels, which has been implicated in fatal hydrocodone overdoses.[17]

Furthermore, the activity of the CYP2D6 enzyme varies dramatically across the population due to well-described genetic polymorphisms, which categorize individuals as poor, intermediate, extensive, or ultrarapid metabolizers. This means that a "standard dose" of Diphenhydramine can produce vastly different plasma concentrations and clinical effects in different people. A patient who is a CYP2D6 poor metabolizer will clear the drug more slowly, leading to higher and more prolonged plasma levels, which increases their susceptibility to adverse effects and magnifies the risk of drug interactions. This genetic variability is a major hidden confounder in the drug's safety profile and argues for extreme caution when it is used concurrently with other medications.

Clinical Efficacy and Therapeutic Applications

Introduction

This section critically evaluates the clinical utility of Diphenhydramine, contrasting its formally approved indications with its common off-label uses. Despite the emergence of newer, safer alternatives, Diphenhydramine maintains an immense commercial presence, largely due to its long history, brand recognition, and wide availability in numerous formulations.

A. Approved and Standard Indications

Diphenhydramine is approved for a variety of conditions, leveraging its antihistaminic, anticholinergic, and sedative properties.

• Allergic Conditions: This is the cornerstone of Diphenhydramine's therapeutic use. It is highly effective for providing temporary relief from the symptoms of acute allergic reactions, including allergic rhinitis (hay fever), urticaria (hives), angioedema, and pruritus (itching) from various causes like insect bites and stings.[2] Due to its rapid onset of action when given parenterally, it is a staple in emergency departments for managing acute allergic reactions and is recommended as an adjunct to epinephrine for the treatment of anaphylaxis once acute, life-threatening symptoms are controlled.[5]
• Insomnia: Diphenhydramine is widely marketed and used as a non-prescription, over-the-counter sleep aid for the short-term relief of occasional sleeplessness.[5] Its use for this indication is based entirely on its primary side effect of sedation. However, its efficacy is questionable and its risk profile is significant. Tolerance to the hypnotic effects develops rapidly, often within a few days to two weeks of continuous use.[9] Major clinical bodies, including the American Academy of Sleep Medicine, now formally recommend against the use of Diphenhydramine for treating insomnia, citing poor effectiveness, low-quality evidence, and an unfavorable risk-benefit balance, especially in older adults.[5]
• Motion Sickness and Nausea: The drug's potent anticholinergic properties make it effective for the prevention and treatment of nausea, vomiting, and vertigo associated with motion sickness.[5] It acts on H1 and muscarinic receptors within the vestibular system and brainstem. It is the active antihistamine component in the combination drug Dimenhydrinate (commonly sold as Dramamine), where it is paired with 8-chlorotheophylline, a mild stimulant intended to counteract some of the drowsiness.[2]
• Movement Disorders: Diphenhydramine is used to treat drug-induced extrapyramidal symptoms (EPS), which are common side effects of first-generation (typical) antipsychotic medications. It is effective in managing acute dystonic reactions (e.g., torticollis, oculogyric crisis) and akathisia.[5] It also has a minor role as a second-line agent for reducing tremors and muscle rigidity in parkinsonism.[1]
• Common Cold and Cough: Due to its antihistaminic and anticholinergic (drying) effects, Diphenhydramine is a common ingredient in multi-symptom "night time" cold and cough formulations. It is used to relieve symptoms like runny nose and sneezing and also acts as an antitussive (cough suppressant) for coughs originating from minor throat and bronchial irritation.[2]

B. Off-Label and Investigational Uses

Beyond its approved indications, Diphenhydramine is used for several other purposes, though these are generally not supported by strong evidence or regulatory approval.

• Anxiolytic: The drug has been used off-label as an anxiolytic (anti-anxiety agent), likely due to its sedative effects.[4] However, this is not a recommended practice. Long-term use carries a risk of significant adverse effects, including cognitive impairment and memory loss, and safer, more effective treatments for anxiety disorders are available.[5]
• Pediatric Sedation: A widely condemned off-label use is the administration of Diphenhydramine by parents or caregivers in an attempt to sedate children, for instance, during long-distance flights.[5] Medical and airline industry professionals strongly oppose this practice for several reasons: it poses safety risks, including the potential for a paradoxical hyperactivity reaction, and a sedated child may not be able to react appropriately in an emergency situation.[5]
• Cancer Therapy: There is some preclinical investigation into the use of Diphenhydramine to modulate the effects of platinum-based chemotherapy drugs. The proposed mechanism involves sensitizing tumor cells to treatment while potentially protecting normal cells from toxicity, possibly by affecting drug transport mechanisms.[17] This use remains experimental.

C. Available Formulations and Commercial Brand Names

Diphenhydramine's market longevity and versatility are reflected in the vast array of formulations and products in which it is found.

• Formulations: It is available in nearly every common dosage form to suit different clinical needs:
• Oral: Tablets, capsules, chewable tablets, liquid-filled capsules (e.g., LiquiGels), elixirs, syrups, and orally dissolving strips.[32]
• Parenteral: A sterile solution for intramuscular (IM) or intravenous (IV) injection, typically at a concentration of 50 mg/mL.[5]
• Topical: Creams, gels, lotions, and sprays formulated for the local relief of itching and pain.[5]
• Brand Names and Combination Products: Diphenhydramine is marketed under a multitude of brand names globally, with Benadryl being the most iconic and widely recognized.[4] It is the sole active ingredient in sleep aids like Nytol, Sominex, and ZzzQuil.[21] Furthermore, it is a ubiquitous component in hundreds of OTC combination products. It is frequently paired with analgesics like acetaminophen (e.g., Tylenol PM) or ibuprofen (e.g., Advil PM), and with decongestants (pseudoephedrine, phenylephrine), expectorants (guaifenesin), and other cough suppressants in complex cold, flu, and allergy remedies.[5]

The market presence of Diphenhydramine is a classic example of "indication creep," where a drug initially developed for one purpose (antihistamine) sees its use expand to capitalize on its side effects (sedation for insomnia). This commercial success creates a powerful inertia that resists the influence of modern clinical evidence. Despite authoritative guidelines from bodies like the American Academy of Sleep Medicine recommending against its use for insomnia, it remains a top-selling OTC sleep aid. This situation reveals a significant disconnect between evidence-based medicine and consumer behavior, a gap sustained by decades of marketing and powerful brand recognition. The drug's OTC status empowers consumers to self-treat chronic conditions like insomnia with a medication that experts now consider suboptimal and potentially harmful, especially for the elderly. This raises important public health questions about the life cycle of OTC drugs and whether regulatory mechanisms are needed to re-evaluate and restrict indications as new evidence and safer alternatives emerge.[3]

Dosage and Administration Guidelines

Introduction

Accurate dosing of Diphenhydramine is paramount to maximizing therapeutic efficacy while minimizing the risk of adverse events and toxicity. Dosage must be carefully tailored to the specific indication, route of administration, and patient population (e.g., adult, pediatric, geriatric). This section provides a structured and detailed guide to its administration.

The following table consolidates dosage recommendations from various clinical sources. It is intended as a reference for healthcare professionals. Patients should always follow the directions on the product label or from their healthcare provider.

Table 2: Diphenhydramine Dosage and Administration by Indication and Population

Indication	Patient Population	Route	Dosage and Frequency	Maximum Daily Dose	Key Notes	Source(s)
Allergic Reactions, Urticaria, Pruritus	Adults & Adolescents (≥12 yrs)	PO	25-50 mg every 4-6 hours	300 mg		27
	Adults & Adolescents (≥12 yrs)	IV/IM	10-50 mg every 4-6 hours	400 mg	IV rate not to exceed 25 mg/min.	13
	Children (6 to <12 yrs)	PO	12.5-25 mg every 4-6 hours	150 mg		27
	Children (1 to <12 yrs)	IV/IM	1-2 mg/kg/dose every 6 hours	5 mg/kg or 300 mg		27
Insomnia (Short-Term)	Adults & Adolescents (≥12 yrs)	PO	50 mg at bedtime	50 mg	Not recommended for long-term use.	27
	Geriatric Patients	PO	25-50 mg at bedtime	25 mg (in LTCF)	Not recommended. Use should be avoided. Lower initial dose advisable if used.	27
	Children (<12 yrs)	PO	Not Recommended	N/A	FDA advises against use of OTC sleep aids in children.	27
Motion Sickness	Adults & Adolescents (≥12 yrs)	PO	25-50 mg every 4-6 hours	300 mg	Take 30-60 minutes before travel.	30
	Children (6 to <12 yrs)	PO	12.5-25 mg every 4-6 hours	150 mg	Take 30-60 minutes before travel.	27
Drug-Induced Extrapyramidal Symptoms (EPS)	Adults	PO	25-50 mg, 3-4 times daily	300 mg		33
	Adults	IV/IM	10-50 mg, repeated every 6 hours as needed	400 mg	For acute dystonic reactions.	27
	Children & Adolescents	IV/IM	1-2 mg/kg/dose (Max: 50 mg/dose) every 6 hours	5 mg/kg or 300 mg		27
Cough (Antitussive)	Adults & Adolescents (≥12 yrs)	PO	25 mg every 4 hours	150 mg	For cough from minor throat irritation.	27
	Children (6 to <12 yrs)	PO	12.5 mg every 4 hours	75 mg		27

Key Dosing Principles

• Geriatric Considerations: For elderly patients, if use is deemed absolutely necessary, it should begin at the lowest end of the dosing range. For insomnia, the U.S. Omnibus Budget Reconciliation Act (OBRA) guidelines for long-term care facilities (LTCF) recommend a maximum of 25 mg/day unless higher doses are clinically justified to maintain function.[27] However, the overarching recommendation is to avoid use in this population for insomnia.[9]
• Pediatric Considerations: Dosing in children is often calculated based on body weight (typically 1-2 mg/kg per dose) to a maximum daily dose of 5 mg/kg or 300 mg, whichever is less.[27] OTC product labeling provides age-stratified doses. OTC use is generally not recommended for children under 6 years of age.[33]
• Route of Administration:
• For the prevention of motion sickness, oral doses should be administered 30 to 60 minutes prior to the start of travel to allow sufficient time for absorption and onset of action.[30]
• Intravenous (IV) administration should be performed slowly, at a rate not exceeding 25 mg/minute. Rapid IV infusion can increase the risk of adverse effects like hypotension and dizziness.[13]
• Topical formulations should be applied sparingly to the affected area and should not be used on large areas of the body, broken skin, or mucous membranes to avoid significant systemic absorption.[33]

Safety and Tolerability Profile

Introduction

This section provides a comprehensive analysis of Diphenhydramine's safety profile, consolidating data on adverse reactions, contraindications, and drug interactions. A central argument of this monograph is that the drug's safety risks are far more complex and significant than its ubiquitous OTC status would suggest to the average consumer. Its potent anticholinergic properties and CNS effects are the primary drivers of its adverse event profile.

A. Adverse Drug Reactions (ADRs)

The adverse effects of Diphenhydramine are extensive and directly related to its pharmacology, primarily its antihistaminic, anticholinergic, and CNS-depressant activities.

Common Adverse Reactions

These effects are frequently experienced and are often dose-limiting:

• Nervous System: The most common adverse effects are drowsiness/sedation, dizziness, fatigue, and disturbed coordination. These effects can significantly impair the ability to perform tasks requiring mental alertness, such as driving or operating machinery.[13]
• Anticholinergic Effects: Dry mouth, nose, and throat are very common. Blurred vision, constipation, and difficulty with urination are also frequently reported.[21]
• Gastrointestinal System: Upset stomach or epigastric distress can occur.[13]
• Respiratory System: A characteristic side effect is the thickening of bronchial secretions, which can be problematic for individuals with asthma or COPD.[13]

Serious Adverse Reactions

Though less common, Diphenhydramine is associated with a number of serious and potentially life-threatening adverse reactions.

• Anticholinergic Toxicity: In susceptible individuals (e.g., the elderly) or at high doses, the anticholinergic effects can become severe, leading to urinary retention (particularly in men with benign prostatic hypertrophy), precipitation of acute angle-closure glaucoma in at-risk individuals, and a central anticholinergic syndrome characterized by confusion, delirium, and hallucinations.[5]
• Cardiovascular System: While often well-tolerated at therapeutic doses, adverse cardiovascular effects can include hypotension, tachycardia, and palpitations. In overdose situations, Diphenhydramine can block cardiac sodium channels, leading to QRS widening and QT interval prolongation on an electrocardiogram (ECG), which creates a risk for fatal ventricular arrhythmias.[5]
• Neurological System: Seizures have been reported, particularly in the context of overdose and in young children.[5] As noted previously, paradoxical excitation (agitation, restlessness, insomnia) can occur, especially in the pediatric population.[23] It can also worsen the symptoms of restless legs syndrome.[5]
• Dermatologic System: Photosensitivity, leading to an exaggerated sunburn reaction, can occur with both systemic and topical use.[13] Allergic reactions to the drug itself can manifest as a drug rash or urticaria, and in rare cases, anaphylactic shock.[13]

Table 3: Adverse Drug Reactions Associated with Diphenhydramine by System Organ Class

System Organ Class	Common (1-10%) Adverse Reactions	Less Common / Serious Adverse Reactions
Nervous System	Drowsiness, sedation, dizziness, disturbed coordination, fatigue, difficulty concentrating, headache	Confusion, delirium, hallucinations, seizures, paradoxical excitation (esp. in children), tremor, paresthesia, memory loss, worsening of restless legs syndrome
Cardiovascular System		Hypotension, tachycardia, palpitations, extrasystoles, QT prolongation (in overdose)
Gastrointestinal System	Dry mouth, nausea, upset stomach, constipation	Anorexia, vomiting, diarrhea, epigastric distress
Genitourinary System		Urinary retention, urinary frequency, difficult urination
Ocular System	Blurred vision	Pupil dilation (mydriasis), dry eyes, precipitation of acute angle-closure glaucoma
Respiratory System	Thickening of bronchial secretions	Chest tightness, wheezing, nasal stuffiness
Dermatologic System		Photosensitivity, skin rash, urticaria, excessive perspiration
General / Immune System		Chills, anaphylactic shock (rare)
Hematologic System		Hemolytic anemia, thrombocytopenia, agranulocytosis (all rare)

Sources: [13]

B. Contraindications, Warnings, and Precautions

The use of Diphenhydramine is inappropriate or requires significant caution in several populations and clinical scenarios.

Absolute Contraindications

Use of Diphenhydramine is strictly contraindicated in the following situations:

• Known hypersensitivity to Diphenhydramine or other ethanolamine-derivative antihistamines.[23]
• Use in neonates and premature infants, due to their immature metabolic pathways and increased risk of adverse effects.[5]
• Use in nursing mothers, as the drug is excreted in breast milk and poses a risk of sedation to the infant. It may also reduce milk supply.[5]

Warnings and Precautions

Extreme caution should be exercised when using Diphenhydramine in patients with the following conditions:

• Lower Respiratory Disease: Including asthma and chronic obstructive pulmonary disease (COPD). The drug's anticholinergic effect can thicken bronchial secretions, making mucus plugs and airway obstruction more likely.[13]
• Narrow-Angle Glaucoma: The mydriatic (pupil-dilating) effect of Diphenhydramine can increase intraocular pressure and precipitate an acute, painful attack of angle-closure glaucoma.[24]
• Genitourinary Obstruction: Including benign prostatic hypertrophy (BPH) or bladder-neck obstruction. The drug's anticholinergic action can decrease bladder detrusor muscle contractility, leading to acute urinary retention.[23]
• Cardiovascular Disease: Including hypertension, ischemic heart disease, and hyperthyroidism, due to the potential for tachycardia and increased blood pressure.[13]
• Hepatic or Renal Impairment: Since the drug is extensively metabolized by the liver and its metabolites are cleared by the kidneys, impairment of either organ can lead to drug accumulation and increased risk of toxicity. Dose adjustments may be necessary.[9]

C. Clinically Significant Drug Interactions

Diphenhydramine is involved in numerous drug interactions, with over 400 documented.[39] These can be broadly categorized as pharmacodynamic (additive effects at the receptor level) or pharmacokinetic (alteration of drug metabolism).

Pharmacodynamic Interactions

These interactions involve additive effects with other drugs acting on the same physiological systems.

• CNS Depressants: This is the most significant and common interaction. The sedative effects of Diphenhydramine are profoundly potentiated when it is combined with other CNS depressants. This includes alcohol, opioids, benzodiazepines, barbiturates, skeletal muscle relaxants (e.g., cyclobenzaprine), and other sedative-hypnotic drugs. This combination can lead to severe drowsiness, cognitive and motor impairment, respiratory depression, and an increased risk of accidents.[13]
• Anticholinergic Drugs: The anticholinergic burden is additive. Co-administration with other drugs possessing anticholinergic properties, such as tricyclic antidepressants (TCAs), some antipsychotics, antiparkinsonian agents (e.g., benztropine), and antispasmodics (e.g., glycopyrrolate), significantly increases the risk of side effects like severe dry mouth, blurred vision, constipation, urinary retention, and delirium.[26]
• Monoamine Oxidase Inhibitors (MAOIs): MAOIs can prolong and intensify the anticholinergic effects of antihistamines like Diphenhydramine. This combination should be avoided.[13]

Pharmacokinetic Interactions

These interactions primarily revolve around the CYP2D6 enzyme.

• CYP2D6 Inhibition by Diphenhydramine: As a potent inhibitor of CYP2D6, Diphenhydramine can decrease the metabolism and thereby increase the plasma concentrations of many co-administered drugs. This includes metoprolol and nebivolol (beta-blockers), venlafaxine (an SNRI), many TCAs and SSRIs, and certain antiarrhythmics. This can lead to increased side effects or toxicity from the other drug.[17] For example, inhibiting the metabolism of metoprolol can lead to excessive bradycardia and hypotension.
• Inhibition of Diphenhydramine Metabolism: Conversely, drugs that are strong inhibitors of CYP2D6 can increase plasma levels of Diphenhydramine, enhancing its effects and risks.

The combination of these multiple interaction mechanisms creates a high potential for an "interaction cascade," where one adverse event precipitates another, particularly in vulnerable patients. For example, consider an elderly patient taking the beta-blocker metoprolol (a CYP2D6 substrate) for hypertension. If this patient self-medicates with OTC Diphenhydramine for insomnia, an interaction cascade can be initiated. First, the Diphenhydramine (a CYP2D6 inhibitor) inhibits the metabolism of metoprolol, leading to higher-than-expected plasma levels of the beta-blocker. This can result in excessive bradycardia and hypotension (a pharmacokinetic interaction). Second, this drug-induced hypotension synergizes with the inherent dizziness and sedation caused by Diphenhydramine's own CNS effects (a pharmacodynamic effect). The combination of these effects dramatically increases the patient's risk of syncope, falls, and subsequent injury. This is not merely two separate risks but a synergistic amplification of harm. The fact that this cascade can be initiated by a freely available OTC product, often without the knowledge of the prescribing physician, underscores the profound danger of viewing such medications as inherently "safe" and highlights the critical role of pharmacists and clinicians in patient education and medication reconciliation.

Table 4: Major Clinically Significant Drug Interactions with Diphenhydramine

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
CNS Depressants (Alcohol, Opioids, Benzodiazepines, Barbiturates)	Pharmacodynamic Synergism	Profound sedation, dizziness, cognitive/motor impairment, respiratory depression.	Avoid combination. Counsel patients on the severe risks.	13
Anticholinergic Agents (TCAs, Antipsychotics, Antiparkinsonian drugs)	Pharmacodynamic Synergism (Additive Anticholinergic Effects)	Increased risk of dry mouth, blurred vision, constipation, urinary retention, confusion, delirium.	Use with extreme caution or avoid. Monitor closely for anticholinergic toxicity.	26
MAO Inhibitors	Pharmacodynamic Synergism	Prolongs and intensifies anticholinergic effects of Diphenhydramine.	Avoid combination.	13
CYP2D6 Substrates (e.g., Metoprolol, Nebivolol, Venlafaxine, some SSRIs)	Pharmacokinetic Inhibition (Diphenhydramine inhibits CYP2D6)	Increased plasma concentrations and potential toxicity of the substrate drug.	Use with caution. Monitor for adverse effects of the substrate drug. Consider alternative non-inhibiting antihistamine.	17
Eliglustat	Pharmacokinetic Inhibition (Diphenhydramine is a moderate CYP2D6 inhibitor)	Markedly increased levels of eliglustat.	Contraindicated.	40

Use in Special Populations

Introduction

The risk-benefit balance of Diphenhydramine is not uniform across all individuals; it is significantly altered in specific populations. The drug's widespread, one-size-fits-all availability stands in stark contrast to its highly variable safety profile across different age groups and physiological states. This section focuses on populations where the potential for harm is greatest: geriatric patients, pediatric patients, and pregnant or lactating women.

A. Geriatric Patients (≥65 years)

The use of Diphenhydramine in older adults is a major area of clinical concern, and its avoidance is a key quality metric in geriatric medicine.

• High-Risk Medication: Diphenhydramine is explicitly identified on the American Geriatrics Society (AGS) Beers Criteria as a "potentially inappropriate medication" (PIM) that should be avoided in older adults.[9] The primary reason is its potent anticholinergic properties and the high susceptibility of the aging brain and body to these effects.
• Increased Risk of Adverse Effects: Elderly patients experience a heightened incidence and severity of Diphenhydramine's side effects. These include pronounced confusion, dizziness, sedation, hypotension, blurred vision, and urinary retention.[8] The aging body's reduced ability to metabolize and clear the drug can lead to higher plasma concentrations and a prolonged duration of action, exacerbating these risks.[9]
• Falls and Fractures: The combination of sedation, dizziness, disturbed coordination, and orthostatic hypotension dramatically increases the risk of falls in this population.[8] Falls are a leading cause of morbidity, mortality, and loss of independence in older adults, and resulting fractures can be catastrophic.
• Cognitive Impairment and Dementia: There is a strong and growing body of evidence linking the use of drugs with high anticholinergic activity, like Diphenhydramine, to significant cognitive risks. Short-term use, especially in hospitalized older patients, is associated with a substantially increased risk of developing delirium—an acute state of confusion.[9] Long-term cumulative use has been associated with an increased risk of developing dementia.[5] Studies have linked anticholinergic use to poorer memory, reduced executive function, and even structural brain changes like increased atrophy.[9]
• Clinical Recommendation: The use of Diphenhydramine in older adults should be actively discouraged and avoided whenever possible, particularly for chronic conditions like insomnia.[29] Its use should be reserved for the short-term management of severe, acute allergic reactions where the benefits clearly outweigh the substantial risks, and only under close clinical supervision. If its use is deemed unavoidable, the lowest possible dose should be used for the shortest possible duration.[27]

B. Pediatric Patients

While often used in children for allergies, Diphenhydramine carries unique risks in this population.

• Paradoxical Excitation: A key and unpredictable risk in young children is a paradoxical reaction. Instead of the expected sedation, the child may experience CNS stimulation, manifesting as agitation, nervousness, restlessness, irritability, and insomnia.[5]
• Overdose Risk: Children are particularly vulnerable to overdose, which can be life-threatening. The margin between a therapeutic dose and a toxic dose is narrower than in adults. Overdose can rapidly progress to hallucinations, convulsions, and death.[22] The risk of accidental overdose is especially high when the medication is used off-label for sedation or sleep, as dosing is less standardized and parents may be tempted to increase the dose if it is not effective.[22]
• Clinical Recommendation: The FDA has issued a public health advisory recommending that non-prescription sleep-aid products containing Diphenhydramine not be used for sedation in pediatric patients of any age.[27] Its use for off-label sedation on flights or at home is strongly condemned by medical authorities.[5] When used for approved indications like allergies, dosing should be precise, ideally based on body weight, and OTC product labeling for age and weight must be followed strictly.

C. Pregnancy and Lactation

The use of Diphenhydramine during pregnancy and breastfeeding requires careful consideration of the potential effects on the fetus and infant.

• Pregnancy: Diphenhydramine is classified as a U.S. FDA Pregnancy Category B drug, meaning that animal reproduction studies have not demonstrated a fetal risk, but there are no adequate and well-controlled studies in pregnant women.[5] While occasional, short-term use is generally not thought to pose a clear risk of harm, it is not a recommended first-line agent.[44] The side effects of drowsiness and dizziness can be more pronounced and problematic during pregnancy. Other antihistamines, such as chlorphenamine or second-generation agents, may be preferred after consultation with a healthcare provider.[44]
• Lactation: The use of Diphenhydramine is contraindicated in nursing mothers.[23] The drug is known to be secreted into breast milk and can cause sedation and irritability in the breastfed infant. Furthermore, large or prolonged doses may reduce the mother's breast milk supply, especially when lactation is not yet well established or when combined with a decongestant like pseudoephedrine.[5]

Overdose and Toxicology

Introduction

Diphenhydramine overdose is a significant and common clinical problem, exacerbated by the drug's easy OTC availability, its presence in hundreds of products, and its potential for intentional misuse and abuse. Understanding the clinical presentation and management of toxicity is crucial for emergency medical personnel and public health officials.

A. Clinical Presentation of Overdose

An overdose of Diphenhydramine produces a classic and predictable anticholinergic toxidrome, with symptoms ranging from moderate CNS depression to severe stimulation and life-threatening complications.[13]

• Central Nervous System (CNS) Symptoms: The presentation can be highly variable. Patients may initially be drowsy or lethargic, but this can quickly progress to an agitated delirium with marked confusion, disorientation, and both visual and auditory hallucinations.[22] Ataxia (unsteadiness), tremors, muscle twitching, and myoclonus are common and can precede the onset of generalized seizures. In severe cases, the patient may progress to a coma.[22]
• Peripheral Anticholinergic Symptoms: These are the classic signs described by the mnemonic "hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter."
• Hyperthermia: "Hot as a hare" - Elevated body temperature.
• Mydriasis: "Blind as a bat" - Fixed and widely dilated pupils, leading to blurred vision and photophobia.[45]
• Anhidrosis: "Dry as a bone" - Dry skin and mucous membranes (profoundly dry mouth).[45]
• Flushing: "Red as a beet" - Flushed, red skin due to cutaneous vasodilation.[45]
• Delirium: "Mad as a hatter" - The CNS effects described above.[45]
• Cardiovascular Effects: Sinus tachycardia is nearly universal. Hypotension can also occur.[45] In severe poisonings, Diphenhydramine's sodium channel blocking properties become prominent, leading to ECG changes such as a widened QRS complex and prolongation of the QT interval. These changes are ominous signs that portend a high risk of life-threatening ventricular dysrhythmias, including Torsades de Pointes and ventricular fibrillation.[5]
• Other Symptoms: Urinary retention due to bladder muscle paralysis is common. Bowel sounds are typically diminished or absent.[45] Nausea and vomiting may also be present.[45]

B. Management of Toxicity

Management of Diphenhydramine overdose is primarily supportive and focused on anticipating and treating life-threatening complications.

• Initial Steps: The first priority is to seek immediate medical attention by calling emergency services (e.g., 911) or a regional poison control center (e.g., 1-800-222-1222 in the U.S.) for expert guidance.[22]
• Supportive Care: This is the cornerstone of treatment. It involves:
• Airway, Breathing, Circulation (ABCs): Securing the airway and providing respiratory support (e.g., intubation and mechanical ventilation) if the patient is comatose or has respiratory depression.
• Monitoring: Continuous cardiac monitoring (ECG) to watch for arrhythmias and QRS/QT interval changes, as well as frequent monitoring of vital signs, temperature, and mental status.[45]
• Hydration: Intravenous (IV) fluids to correct dehydration and hypotension.[45]
• Decontamination: For patients who present soon after a significant oral ingestion, a single dose of activated charcoal may be administered to bind the drug in the GI tract and prevent further absorption.[45] Gastric lavage is rarely indicated.
• Specific Treatments:
• Agitation and Seizures: Benzodiazepines (e.g., lorazepam, diazepam) are the first-line treatment for managing agitation, delirium, and seizures. They are safer than antipsychotics, which can worsen anticholinergic effects and lower the seizure threshold.
• Cardiotoxicity: If the QRS interval is widened (>100 ms), intravenous sodium bicarbonate is the treatment of choice. It helps to overcome the sodium channel blockade.
• Antidote (Physostigmine): The specific antidote is physostigmine, an acetylcholinesterase inhibitor that reverses the anticholinergic effects. However, its use is controversial and reserved for severe cases with refractory symptoms (e.g., uncontrolled delirium, seizures, or arrhythmias) and only when there are no contraindications. It should not be used if there is QRS widening on the ECG, as it can precipitate cardiac arrest in this setting. Its use should be guided by a medical toxicologist or poison control center.

C. Public Health Considerations: Misuse and Abuse

The toxicology of Diphenhydramine has taken on a new dimension with its emergence as a drug of abuse. It is intentionally misused in large doses to induce its psychoactive effects, including euphoria, dissociation, and hallucinations.[5]

This problem has been dangerously amplified by social media. The "Benadryl Challenge," a trend that circulated on platforms like TikTok, encouraged teenagers to take massive overdoses of Diphenhydramine and document the resulting deliriant effects.[22] This has led to a number of emergency department visits, hospitalizations, and documented fatalities.[22] One case report detailed the death of a 14-year-old whose postmortem blood concentration of Diphenhydramine was 500 times higher than a typical therapeutic level.[22]

This phenomenon highlights a modern toxicological crisis where the convergence of three factors—the easy OTC access of a psychoactive drug, adolescent experimentation, and the viral amplification power of social media—creates a significant and acute public health danger. In response, the U.S. FDA has issued specific public warnings about the serious risks of taking high doses of Diphenhydramine and has urged parents and caregivers to secure all medications to prevent misuse.[46]

Regulatory Status and Conclusion

Introduction

This final section synthesizes the extensive data on Diphenhydramine's pharmacology, clinical use, and safety to offer an expert conclusion on its place in modern medicine. An examination of its regulatory history provides a lens through which to view the evolving scientific and clinical understanding of its complex risk-benefit profile.

Regulatory Landscape

Diphenhydramine has a long regulatory history in the United States, reflecting its transition from a prescription-only medication to a ubiquitous OTC product.

• Initial Approval: The drug was first approved for commercial use in 1946, making it one of the oldest antihistamines still in widespread use.[1]
• Over-the-Counter (OTC) Status: Through the FDA's OTC Drug Review process, Diphenhydramine was found to be generally recognized as safe and effective (GRASE) for several indications. It is approved for OTC marketing under multiple final monographs, including those for Antihistamine Drug Products (21 CFR part 341), Antitussive Drug Products, and Nighttime Sleep-Aid Drug Products (21 CFR part 338).[15]
• Labeling and Safety Updates: The FDA has periodically updated the regulations for Diphenhydramine-containing products to enhance safety. A significant rule finalized in 2002 mandated a new warning on all oral OTC products advising consumers not to use them with any other product containing Diphenhydramine, including topical preparations.[49] This was in response to adverse event reports documenting toxicity from the concurrent use of oral and topical forms, leading to excessive systemic absorption.[49] More recently, in 2020, the FDA issued a prominent Drug Safety Communication warning of serious heart problems, seizures, coma, and death associated with high doses, directly addressing the dangers highlighted by the "Benadryl Challenge" on social media.[46]

Expert Conclusion and Recommendations

After more than 75 years on the market, Diphenhydramine stands at a crossroads. Its clinical role and safety profile must be re-evaluated in the context of modern pharmacotherapy and evidence-based practice.

• The End of a Life Cycle? A compelling argument can be made that Diphenhydramine has reached the end of its therapeutic life cycle for many of its common uses.[3] While it was a pioneering medication, it is now largely overshadowed by second-generation antihistamines (e.g., loratadine, cetirizine, fexofenadine). These newer agents offer similar efficacy for allergic conditions but have a vastly superior safety profile, as they do not readily cross the blood-brain barrier and lack significant anticholinergic and sedative effects.[3] The continued widespread use of Diphenhydramine appears to be driven more by historical legacy and brand recognition than by a favorable comparison to current alternatives.
• An Unfavorable Risk-Benefit Imbalance: For indications beyond acute allergic reactions, the risk-benefit profile of Diphenhydramine is often unfavorable. This is particularly true for its use as a sleep aid, where its efficacy is limited and short-lived, while its risks—especially in the elderly—are substantial and well-documented. The potential for harm from next-day cognitive impairment, falls, delirium, urinary retention, and drug interactions is significant.
• The Over-the-Counter Paradox: The drug's status as a freely available OTC product creates a major public health paradox. It empowers consumers to self-diagnose and self-treat conditions like chronic insomnia with a substance that expert clinical guidelines and major medical bodies increasingly recommend against. This disconnect between regulation, marketing, and current clinical evidence is the central problem associated with Diphenhydramine today. Its availability without the guidance of a healthcare professional allows for inappropriate use in vulnerable populations and facilitates dangerous misuse and abuse.
• Final Recommendation: Based on a comprehensive evaluation of the available evidence, a shift in clinical practice and regulatory oversight is warranted.

1. For Clinicians: Healthcare providers should actively counsel patients, particularly the elderly, on the significant risks associated with Diphenhydramine. They should recommend safer alternatives, such as second-generation antihistamines for allergies and evidence-based non-pharmacological interventions (e.g., cognitive-behavioral therapy for insomnia) or safer medications for sleep.
2. For Regulators: There is a strong, evidence-based argument for re-evaluating Diphenhydramine's OTC status. Potential regulatory actions could include moving it to a "behind-the-counter" classification, which would require pharmacist intervention and screening before sale. This would allow for crucial checks for contraindications, drug interactions, and inappropriate use in vulnerable populations. At a minimum, its approved OTC indications should be reviewed and potentially restricted to align with its most favorable risk-benefit profile, which is the short-term management of acute allergic symptoms.

The continued, unguided mass-market availability of Diphenhydramine represents a significant and largely preventable source of patient harm. While it holds a place in medical history, its role in the modern therapeutic arsenal should be substantially diminished in favor of safer, more effective alternatives.

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