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PubMed1987

Transport of diphenhydramine in the central nervous system.

The transport and metabolism of diphenhydramine was studied in vitro in the isolated rabbit choroid plexus and in vivo in New Zealand white rabbits and Sprague-Dawley rats. In vitro, [14C] diphenhydramine was accumulated by a saturable, energy-requiring system in choroid plexus. In vivo, 20 min after intraventricular injection into rabbits, [14C]diphenhydramine was cleared from cerebrospinal fluid much more rapidly than [3H]sucrose, a molecule transported in the central nervous system by simple diffusion. In vivo, employing the in situ rat brain perfusion technique, [14C]diphenhydramine was cleared from the cerebral perfusion fluid as rapidly as [14C]diazepam. However, the clearance of [14C]diphenhydramine, but not [14C]diazepam, was inhibited by the addition of 10 mM unlabeled diphenhydramine to the perfusate. These in vivo and in vitro results show that diphenhydramine, unlike diazepam, is transported between blood, brain and cerebrospinal fluid, in part, by saturable, carrier-mediated transport processes at both the blood-brain and blood-cerebrospinal fluid barriers.

Animals↗

PubMed2001

Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients.

BACKGROUND: Diphenhydramine hydrochloride is a commonly prescribed medicine in hospitalized patients, but its adverse effects on older patients remain unclear. METHODS: We enrolled 426 hospitalized medical patients aged 70 years or older in a prospective cohort study in a university hospital. Measurements included baseline and daily assessments including Mini-Mental State Examination scores, Confusion Assessment Method ratings, direct observations for medical devices (urinary catheter or physical restraints), and blinded medical record extractions for diphenhydramine use. RESULTS: Of the 426 patients, 114 (27%) received diphenhydramine during hospitalization and shared similar baseline characteristics including age, sex, delirium risk, and Mini-Mental State Examination scores compared with nonexposed patients. The diphenhydramine-exposed group was at an increased risk for any delirium symptoms (relative risk [RR], 1.7; 95% confidence interval [CI], 1.3-2.3) and for individual delirium symptoms, including inattention (RR, 3.0; 95% CI, 1.5-5.9), disorganized speech (RR, 5.5; 95% CI, 1.0-29.8), and altered consciousness (RR, 3.1; 95% CI, 1.6-6.1). Exposed patients also had increased risk for urinary catheter placement (RR, 2.5; 95% CI, 1.0-6.0) and longer median length of stay (7 vs 6 days; P =.009). A dose-response relationship was demonstrated for most adverse outcomes. Overall, 24% of diphenhydramine doses were administered inappropriately. CONCLUSIONS: Diphenhydramine administration in older hospitalized patients is associated with an increased risk of cognitive decline and other adverse effects with a dose-response relationship. Careful review of its use is necessary in this vulnerable population.

Aged↗

PubMed2006

The trial of infant response to diphenhydramine: the TIRED study--a randomized, controlled, patient-oriented trial.

OBJECTIVE: To determine if infants aged 6 to 15 months with frequent parent-reported nighttime awakenings require reduced parental aid during a week of diphenhydramine hydrochloride treatment and 2 and 4 weeks after its discontinuation. DESIGN: Double-blind, randomized, controlled clinical trial. SETTING: The study was conducted from May 1, 2004, through May 1, 2005; patients were recruited nationally. PARTICIPANTS: Forty-four participants aged 6 to 15 months. INTERVENTIONS: Placebo or diphenhydramine was administered in infants 30 minutes before anticipated bedtime. MAIN OUTCOME MEASURES: The primary outcome was dichotomous: a parental report of improvement in the number of night awakenings requiring parental assistance during the intervention week, which ended on day 14. Secondary outcomes were improved sleep during the 2 weeks before days 29 and 43, parental overall happiness with sleep, and improved sleep latency. RESULTS: On June 6, 2005, the data safety monitoring board voted unanimously to stop the trial early because of lack of effectiveness of diphenhydramine over placebo. Only 1 of 22 children receiving diphenhydramine showed improvement compared with 3 of 22 receiving placebo. To reach the a priori determined sample size and have a positive outcome (ie, rejecting the null hypothesis), the trial would have needed to enroll 16 more participants in each arm, with 15 of the 16 in the diphenhydramine group and 0 of 16 in the placebo group improving. CONCLUSION: During 1 week of therapy and at follow-up 2 and 4 weeks later, diphenhydramine was no more effective than placebo in reducing nighttime awakening or improving overall parental happiness with sleep for infants.

Diphenhydramine↗

PubMed1985

Improved control of cisplatin-induced emesis with high-dose metoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Results of consecutive trials in 255 patients.

A series of consecutive trials were undertaken to determine whether higher doses of intravenous metoclopramide and combinations of metoclopramide, dexamethasone, and diphenhydramine would improve antiemetic control or decrease treatment-related side effects in patients receiving cisplatin at 120 mg/m2. Metoclopramide and dexamethasone were studied because of their proven efficacy as single agents and their differing mechanisms of action and side effects. Diphenhydramine was used because of its possible antiemetic properties and its ability to control acute dystonic reactions. Two hundred fifty-five patients who had never received chemotherapy or antiemetics were observed in the hospital for the 24 hours following cisplatin administration. The addition of dexamethasone or dexamethasone plus diphenhydramine to intravenous metoclopramide 2 mg/kg produced both improved antiemetic control and a decrease in treatment-associated diarrhea (P = 0.002). The use of metoclopramide alone at a dose of 3 mg/kg for only two doses appeared as effective as 2 mg/kg for five doses. When dexamethasone and diphenhydramine were given with metoclopramide 3 mg/kg for two intravenous dosages, 81% of patients experienced no emesis and 93% had two or fewer vomiting episodes. The antiemetic results of this 2-hour "short-course" regimen were superior to metoclopramide 2 mg/kg, with (P = 0.002) or without (P = 0.0001) dexamethasone and diphenhydramine. It was concluded that combinations of metoclopramide plus dexamethasone plus diphenhydramine improve antiemetic control, facilitate the usage of higher doses of metoclopramide, and decrease the incidence of treatment-related side effects.

Adult↗

PubMed1975

Hypnotic efficacy of diphenhydramine, methapyrilene, and pentobarbital.

The antihistamines diphenhydramine and methapyrilene were compared with pentobarbital for hypnotic effect in two Veterans Administration Hospital populations using subjective-response methods. In the first part of the study, 60 mg and 180 mg of pentobarbital were compared with 50 mg and 150 mg of diphenhydramine. A positive dose-response relationship was obtained only for pentobarbital; neither dose of diphenhydramine was significantly different from 60 mg of pentobarbital for any response variable. In the second part of the study, 100 mg of pentobarbital, 50 mg of diphenhydramine, and 50 mg of diphenhydramine, and 50 mg of methapyrilene were compared with placebo. One hundred mg of pentobarbital and 50 mg of diphenhydramine were significantly different from placebo, but 50 mg of methapyrilene was not.

Adult↗

PubMed1978

Correlation between plasma diphenhydramine level and sedative and antihistamine effects.

The sedative and antihistamine effects of diphenhydramine were assessed in relation to plasma concentration after placebo, diphenhydramine 50 mg intravenously, and diphenhydramine 50 mg orally to each of 6 healthy volunteers on three separate occasions. Diphenhydramine plasma elimination t1/2 was 3.0 to 4.3 hr, volume of distribution was 188 to 336 L, and clearance was 637 to 1,014 ml/min. Systemic bioavailability of the oral preparation ranged from 0.26 to 0.60. The sedative effect of intravenous diphenhydramine differed from that of placebo only during the first 3 hr. Antihistamine effect, as measured by reduction of histamine provoked skin wheal diameter, was significantly different from that of placebo for at least 8 hr. There was a positive correlation between plasma diphenhydramine level and sedative and antihistamine effects, but wide variation in the extent and rate of change of these effects were observed between the subject. There appears to be a concentration range of 25 to 50 ng/ml, within which there is significant antihistamine effect without significant sedation.

Administration, Oral↗

PubMed1990

Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children.

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 +/- 7.3 mg, 87.9 +/- 12.4 mg, and 39.5 +/- 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 +/- 3.1 mL/min/kg in elderly adults, 23.3 +/- 9.4 mL/min/kg in young adults and 49.2 +/- 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 +/- 22.5% and a maximum flare suppression of 46.5 +/- 32.1% at 5 and 6 hours respectively in the elderly; a maximum wheal suppression of 45.5 +/- 25.0% and a maximum flare suppression of 53.4 +/- 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 +/- 10.2% and a maximum flare suppression of 87.2 +/- 4.2% at 2 hours in children.

Administration, Oral↗

PubMed1998

Pharmacokinetics and pharmacodynamics of diphenhydramine 25 mg in young and elderly volunteers.

Thirty-seven young and elderly male and female volunteers 21 to 76 years of age received a single 25-mg oral dose of diphenhydramine or matching placebo in a double-blind, randomized, two-way crossover study. Plasma diphenhydramine concentrations, self-ratings of sedation, mood, and autonomic effects, performance on the digit-symbol substitution test (DSST), and heart rate were determined for 24 hours after administration. Information acquisition and recall were tested at 2.5 and 24 hours after administration. Age and gender did not significantly influence diphenhydramine peak plasma concentration, time of peak concentration, elimination half-life, area under the plasma concentration curve, or apparent oral clearance. Effects on psychomotor performance, sedation, mood, and memory did not differ between diphenhydramine and placebo in either group. Thus, the pharmacokinetics of single 25-mg oral doses of diphenhydramine are not influenced by age or gender. This dose of diphenhydramine produces essentially undetectable pharmacodynamic effects in both the young and elderly.

Adult↗

PubMed1989

Determination of diphenhydramine in rat milk and plasma and its effects on milk composition and mammary gland nucleic acids.

To study the excretion of diphenhydramine into rat milk, milk and plasma concentrations of diphenhydramine were determined in lactating rats after single or multiple oral doses. Four hours after a single dose of 40 or 100 mg/kg of diphenhydramine, milk concentrations of the drug averaged 0.30 and 2.2 micrograms/mL, respectively, in two experiments, and the milk:plasma ratios ranged from 4.4 to 7.5. Multiple doses did not significantly affect the plasma or milk concentrations or the milk:plasma ratios, which were similar to the theoretical milk:plasma ratio based on pH partitioning for this compound (i.e., 4.0). Although the concentration of diphenhydramine was higher in milk than in plasma, the estimated dose received by the pups (0.057 mg/kg/d) based on the milk concentrations was much lower than that given to the mother. Oral diphenhydramine treatment at doses which significantly reduced maternal food consumption had no effect on milk solid, lipid, protein, or lactose concentrations, nor on mammary gland RNA or DNA content, indicating that diphenhydramine did not adversely affect lactation.

Animals↗

PubMed1982

[Poisoning by diphenhydramine--forensic-toxicologic interpretation of analytic results ].

Several poisonings by diphenhydramine were reported shortly after it had been introduced as an antihistamine in 1945. In the Federal Republic of Germany its combination with 8-chlorotheophylline (dimenhydrinate) is available as a hypnotic without prescription. Replacing the dangerous diethylpentenamide diphenhydramine is a drug which is also often abused. Fatal poisonings, suicide attempts, and traffic accidents were increasingly observed. In seven cases drug-influenced road users caused traffic accidents. We observed blood concentrations of diphenhydramine as high as in four cases of clinically treated patients after ingestion of large doses. This indicates a serious drug abuse. The measurement of the concentration of diphenhydramine and its major metabolite (diphenmethoxy acetic acid) in blood and urine is a means of recognizing chronic use and misuse of diphenhydramine. As the metabolite accumulates in blood one may find an elevated level after multiple dosing. Shortly after taking a single dose no or only low metabolite concentration is found. The concentration of diphenhydramine and its metabolite was measured in several fatal cases. In one of these cases the concentration in body fluids and tissues was in a range not observed until now.

Accidents, Traffic↗

PubMed1977

The effect of diphenhydramine alone and in combination with ethanol on histamine skin response and mental performance.

The effects of diphenhydramine and diphenhydramine plus ethanol on response to intradermal histamine and on mental performance were assessed in twelve male volunteers. A significant impairment of histamine skin response was found with diphenhydramine. This response was unaffected by ethanol. Ethanol improved performance with a tracking test compared with diphenhydramine alone, the effect was not potentiated by the combination. None of the treatments had a significant effect on a digit symbol substitution test. Co-administration of ethanol and diphenhydramine caused greater impairment of performance in a serial seven subtraction test than diphenhydramine alone. There was no correlation between central and peripheral effects of the antihistamine.

Adult↗

PubMed2000

Metabolism of the ethanolamine-type antihistamine diphenhydramine (Benadryl) by the fungus Cunninghamella elegans.

Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were grown in Sabouraud dextrose broth and screened for the ability to metabolize the ethanolamine-type antihistamine diphenhydramine. Based on the amount of parent drug recovered after 7 days incubation, both C. elegans strains metabolized approximately 74% of the diphenhydramine, 58% of this being identified as organic extractable metabolites. The organic extractable metabolites were isolated by reversed-phase high-performance liquid chromatography and identified by analyzing their mass and nuclear magnetic resonance spectra. Desorption chemical ionization mass spectrometry (DCIMS) with deuterated ammonia was used to differentiate possible isobaric diphenhydramine metabolites and to probe the mechanisms of ion formation under ammonia DCIMS conditions. C. elegans transformed diphenhydramine by demethylation, oxidation, and N-acetylation. The major metabolites observed were diphenhydramine-N-oxide (3%), N-desmethyldiphenhydramine (30%), N-acetyldidesmethyldiphenhydramine (13%), and N-acetyl-N-desmethyldiphenhydramine (12%). These compounds are known mammalian metabolites of diphenhydramine and may be useful for further toxicological studies.

Chromatography, High Pressure Liquid↗

PubMed1991

Diphenhydramine for nausea and vomiting related to cancer chemotherapy with cisplatin.

High dose metoclopramide and adjuvant drugs, such as corticosteroids, benzodiazepines, and drugs with antidopaminergic, anticholinergic, or antihistaminic effects, are the most widely used antiemetics in cancer patients receiving chemotherapy, particularly cis-dichloro-diammine platinum II (cisplatin). The purpose of our prospective randomized study was to investigate the possible antiemetic efficacy of diphenhydramine as an adjuvant antiemetic drug when combined with metoclopramide (MCP). A total of 91 patients were assigned to either group A (N = 44) who received only MCP and group B (N = 47) who received the combination of MCP and diphenhydramine. All patients received cisplatin-based combination chemotherapy for the first time and were evaluated only once in order to exclude the effects of anticipatory nausea and vomiting. There were no statistically significant differences between the two groups except that patients treated with diphenhydramine presented more sedative effects and had more limited activity. Also diphenhydramine did not give absolute protection from the extrapyramidal side effects of MCP. Side effects of diphenhydramine were minimal and well tolerated. We conclude that diphenhydramine is not a useful adjuvant drug in the antiemetic therapy.

Adult↗

PubMed2005

Prolonged QT interval with markedly abnormal ventricular repolarization in diphenhydramine overdose.

Diphenhydramine is a histamine-1 receptor antagonist of ethanolamine origin with anticholinergic, sedative, antivertigo, antiemetic, antidyskinetic, and local anesthetic properties. It inhibits the fast sodium channels and, at higher concentrations, also the potassium channels, inhibition of which may result in QT interval prolongation on electrocardiogram. The markedly abnormal ventricular repolarization is rare with diphenhydramine overdose. We report a case where a young woman who took moderate overdose of diphenhydramine (625 mg) along with acetaminophen developed prolonged QT interval with strikingly abnormal T waves. These changes reverted to normal with treatment. Patient did not experience torsade de pointes, possibly secondary to the protective effect of the diphenhydramine overdose-related tachycardia. As the tachycardia caused by diphenhydramine overdose seems to protect against torsade de pointes, it may be practical to avoid bradycardia in acute phase of diphenhydramine toxicity. Acetaminophen has not been shown to prolong QT interval or effect cardiac repolarization.

Adult↗

PubMed2000

Block of sodium currents in rat dorsal root ganglion neurons by diphenhydramine.

To elucidate the local anesthetic mechanism of diphenhydramine, its effects on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium currents in rat dorsal root ganglion (DRG) neurons were examined by the whole-cell voltage clamp method. Diphenhydramine blocked TTX-S and TTX-R sodium currents with K(d) values of 48 and 86 microM, respectively, at a holding potential of -80 mV. It shifted the conductance-voltage curve for TTX-S sodium currents in the depolarizing direction but had little effect on that for TTX-R sodium currents. Diphenhydramine caused a shift of the steady-state inactivation curve for both types of sodium currents in the hyperpolarizing direction. The time-dependent inactivation became faster and the recovery from the inactivation was slowed by diphenhydramine in both types of sodium currents. Diphenhydramine produced a profound use-dependent block when the cells were repeatedly stimulated with high-frequency depolarizing pulses. The use-dependent block was more pronounced in TTX-R sodium currents. The results show that diphenhydramine blocks sodium channels of sensory neurons similarly to local anesthetics.

Animals↗

PubMed1998

Local anesthetic efficacy for oral surgery: Comparison of diphenhydramine and prilocaine.

OBJECTIVE: Diphenhydramine has been suggested as an alternative local anesthetic agent for patients claiming allergy to local anesthetics. The present study attempted to determine the local anesthetic efficacy of diphenhydramine for oral surgery. STUDY DESIGN: Seventeen patients claiming allergy to local anesthetics were given diphenhydramine as anesthetic alternative and compared with seven nonallergic control patients treated with prilocaine. After determining an average value of vitality score of neighboring and contralateral teeth by electrical pulp stimulation, molar and premolar teeth were extracted and postextraction vitality scores determined. Visual analogue scale, anesthesia onset times, and the incidence of pulpal and soft tissue anesthesia were analyzed nonparametrically by means of Mann-Whitney U tests. RESULTS: The mean onset time of pulp anesthesia with diphenhydramine (range, 4 to 7.5 minutes), excluding one failure, was not significantly different from that of prilocaine; (range, 4 to 13 minutes). The duration of anesthesia was significantly longer and the visual analogue scale lower in the group receiving prilocaine in comparison with the group receiving diphenhydramine. CONCLUSION: In the small group studied, diphenhydramine administration provided adequate anesthesia before oral surgery; it may be useful as an anesthetic alternative in patients with histories of allergy to local anesthetics.

Adolescent↗

PubMed2007

Comparison of diphenhydramine and lidocaine for prevention of pain after injection of propofol: a double-blind, placebo-controlled, randomized study.

BACKGROUND AND OBJECTIVE: Pain on injection is still a problem with propofol. The purpose of the study was to compare the effectiveness of diphenhydramine and lidocaine on pain caused by propofol at the site of injection. METHODS: One hundred and eighty ASA I-II adults undergoing elective surgery were randomly assigned into three groups of 60 each. Group I (placebo) received 2 mL normal saline, Group II received 2 mL (40 mg) 2% lidocaine and Group III received 2 mL (20 mg) diphenhydramine intravenously (i.v.) during a 1-min venous occlusion, followed by propofol into a cephalic forearm vein of the antecubital fossa. Pain assessment was made immediately after propofol injection. RESULTS: In the placebo group 25 (41.7%) patients experienced pain during propofol injection as compared to 2 (3.3%) and 3 (5.0%) in the lidocaine and diphenhydramine groups, respectively. The prevalence of pain and pain score were significantly less in both the lidocaine and diphenhydramine groups than in the placebo group (P = 0.00). No difference was found between the diphenhydramine and lidocaine groups (P = 0.60). CONCLUSION: Previous injection of diphenhydramine with venous occlusion can be considered as an alternative to lidocaine for reducing the prevalence of pain caused by injection of propofol into peripheral veins.

Adult↗

PubMed2004

Combination of LC/TOF-MS and LC/Ion trap MS/MS for the identification of diphenhydramine in sediment samples.

Diphenhydramine (Benadryl) is a popular over-the-counter antihistaminic medication used for the treatment of allergies. After consumption, excretion, and subsequent discharge from wastewater treatment plants, it is possible that diphenhydramine will be found in environmental sediments due to its hydrophobicity (log P = 3.27). This work describes a methodology for the first unequivocal determination of diphenhydramine bound to environmental sediments. The drug is removed from the sediments by accelerated solvent extraction and then analyzed by liquid chromatography with a time-of-flight mass spectrometer and an ion trap mass spectrometer. This combination of techniques provided unequivocal identification and confirmation of diphenhydramine in two sediment samples. The accurate mass measurements of the protonated molecules were m/z 256.1703 and 256.1696 compared to the calculated mass of m/z 256.1701, resulting in errors of 0.8 and 2.3 ppm. This mass accuracy was sufficient to verify the elemental composition of diphenhydramine in each sample. Furthermore, accurate mass measurements of the primary fragment ion were obtained. This work is the first application of time-of-flight mass spectrometry for the identification of diphenhydramine and shows the accumulation of an over-the-counter medication in aquatic sediments at five different locations.

Anti-Allergic Agents↗