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PubMed2000

Diphenhydramine transport by pH-dependent tertiary amine transport system in Caco-2 cells.

Substrate specificity and pH dependence of the transport system for diphenhydramine were investigated in Caco-2 cell monolayers. Diphenhydramine uptake was not affected by any typical substrate for the renal organic cation transport system except procainamide. Along with procainamide, tertiary amine compounds with N-dimethyl or N-diethyl moieties in their structures inhibited the diphenhydramine uptake. Moreover, accumulation of diphenhydramine was stimulated by preloading the Caco-2 cells with these tertiary amines (trans-stimulation effect), indicating the existence of the specific transport system for tertiary amines with N-dimethyl or N-diethyl moieties. Efflux of diphenhydramine from monolayers was enhanced by medium acidification. In addition, intracellular acidification resulted in marked stimulation of diphenhydramine accumulation. ATP depletion of the cells caused an enhancement of diphenhydramine accumulation, suggesting the involvement of an active secretory pathway. However, P-glycoprotein did not mediate the diphenhydramine transport. These findings indicate that a novel pH-dependent tertiary amine transport system that recognizes N-dimethyl or N-diethyl moieties is involved in diphenhydramine transport in Caco-2 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Diphenhydramine as an adjunct to sedation for colonoscopy: a double-blind randomized, placebo-controlled study.

BACKGROUND: Intravenous benzodiazepines in combination with opiates are used to achieve moderate sedation for colonoscopy. Although effective, these agents have potential adverse effects, such as respiratory depression and hypotension. Diphenhydramine hydrochloride possesses central nervous system depressant effects that theoretically could provide a synergistic effect for sedating patients. OBJECTIVE: The objective was to assess the efficacy of adding diphenhydramine hydrochloride as an adjunct to improve sedation and to reduce the amount of standard sedatives used during colonoscopy. DESIGN: We conducted a prospective, randomized, double-blind, placebo-controlled study. SETTING: The study was conducted in a university hospital with an active GI fellowship training program. PATIENTS: The study group comprised 270 patients undergoing screening/diagnostic/therapeutic colonoscopy were enrolled. INTERVENTIONS: Patients were randomized to receive either 50 mg of diphenhydramine or placebo, given intravenously 3 minutes before starting conscious sedation with intravenous midazolam and meperidine. MAIN OUTCOME MEASUREMENTS: The main outcome measure was anesthetic effect as assessed by the endoscopy team and by the patient; quantity of adjunctive sedatives to achieve adequate sedation. RESULTS: Of 270 patients, data were analyzed for 258 patients, with 130 patients in the diphenhydramine group and 128 patients in the placebo group. There was a 10.1% reduction in meperidine usage and 13.7% reduction in midazolam usage in favor of the diphenhydramine group. The mean evaluation scores as judged by the faculty, the fellows, and the nurses were statistically significant in favor of the diphenhydramine group. In addition, patient scores for overall sedation and pain level favored the group that received diphenhydramine. CONCLUSIONS: Intravenous diphenhydramine given before initiation of standard sedation offers a significant benefit to conscious sedation for patients undergoing colonoscopy.

Colonoscopy↗

PubMed2003

A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis.

BACKGROUND: Decrements in cognitive performance are associated with the use of sedating antihistamines. Most, but not all, second-generation antihistamines have been found to be nonsedating. OBJECTIVE: To examine the central nervous system (CNS) profile of a new second-generation antihistamine, desloratadine. METHODS: Subjects with ragweed-induced allergic rhinitis (aged 18-60 years) who demonstrated a predetermined severity of symptoms after priming with ragweed pollen in the Environmental Exposure Unit were randomized to receive a single dose of desloratadine, 5 mg; diphenhydramine, 50 mg; or placebo. A comprehensive battery of repeatable, automated neuropsychological tests was administered to subjects before treatment (symptomatic baseline) and 90 minutes after taking study medication. RESULTS: Both desloratadine (P = .04) and diphenhydramine (P < .01) alleviated the symptoms of allergic rhinitis compared with placebo, but treatment with diphenhydramine was associated with clinically meaningful decrements on all vigilance parameters (P < .05 for desloratadine-diphenhydramine contrasts). Also, subjects treated with diphenhydramine performed significantly worse than subjects given desloratadine or placebo across all cognitive domains evaluated. Most effect sizes for the mean desloratadine and diphenhydramine differences were between 0.4 and 0.8 (moderate to high). Stanford Sleepiness Scale scores also indicated significantly more somnolence with diphenhydramine vs desloratadine or placebo (P < .001). There were no significant differences on any of the cognitive parameters between subjects treated with desloratadine and those given placebo. CONCLUSIONS: Desloratadine improved ragweed-induced allergic rhinitis symptoms without adversely affecting performance. Diphenhydramine improved allergic rhinitis symptoms but caused significant decrements in vigilance and cognitive functioning. Thus, efficacy of antihistamine treatment must be balanced against the associated effects on CNS functioning.

Allergens↗

PubMed1993

Lidocaine versus diphenhydramine for anesthesia in the repair of minor lacerations.

This prospective study compared the effectiveness of 1% diphenhydramine with 1% lidocaine for local anesthesia in repair of minor skin lacerations in adults with simple linear lacerations treated at our Emergency Department. Wounds were anesthetized with either lidocaine or diphenhydramine according to a random numbers table. Ninety-nine patients were included in the final analysis (51 received lidocaine; 48 diphenhydramine). Patients and physicians rated the pain of injection and suturing using a standard visual analog scale. Univariate and multivariate linear models were used on rank transformed scores of the patient and physician ratings of injection and suturing with p < 0.05 considered statistically significant. According to patient rating lidocaine was less painful for injection than diphenhydramine, with a statistically significant difference between the two anesthetics (p = 0.0017). There was no statistically significant difference in pain rating by physicians between the two anesthetics (p > 0.05). Pain with suturing was rated as minimal for both lidocaine and diphenhydramine with no statistically significant difference in the effectiveness according to either patients or physicians (p > 0.05). Lidocaine injection appears to hurt less than diphenhydramine injection according to the patients. Pain of suturing corresponding to anesthetic effectiveness appears to be equivalent for lidocaine and diphenhydramine according to both physicians and patients. Although diphenhydramine should not be substituted for lidocaine, it appears to be a viable alternative in the management of patients with allergy to amides or extremely large lacerations in which a maximum of amide anesthetic has been used.

Adolescent↗

PubMed1999

Transport characteristics of diphenhydramine in human intestinal epithelial Caco-2 cells: contribution of pH-dependent transport system.

Transport characteristics of diphenhydramine, an antihistamine, were studied in cultured human intestinal Caco-2 cell monolayers to elucidate the mechanisms of its intestinal absorption. Diphenhydramine accumulation in the monolayers increased rapidly and was influenced by extracellular pH (pH 7.4 > 6.5 > 5.5). Diphenhydramine uptake was temperature dependent, saturable, and not potential sensitive. Kinetic analysis revealed that the apparent Km values were constant (0.8-1.0 mM) in all pH conditions tested, whereas Vmax values decreased at the lower pH. The initial uptake of diphenhydramine was competitively inhibited by another antihistamine, chlorpheniramine, with a Ki value of 1.3 mM. On the other hand, cimetidine and tetraethylammonium, typical substrates for the renal organic cation transport system, had no effect. Moreover, biological amines and neurotransmitters, such as histamine, dopamine, serotonin, and choline, also had no effect on the diphenhydramine accumulation. Finally, diphenhydramine uptake was stimulated by preloading monolayers with chlorpheniramine (trans-stimulation effect). These findings indicate that diphenhydramine transport in Caco-2 cells is mediated by a specific transport system. This pH-dependent transport system may contribute to the intestinal absorption of diphenhydramine.

Biological Transport, Active↗

PubMed1991

Antitussive effects of diphenhydramine on the citric acid aerosol-induced cough response in humans.

This controlled crossover study in twenty healthy volunteer subjects utilized the citric acid aerosol-induced cough response as a means to demonstrate the effectiveness of 25 mg of diphenhydramine as an antitussive. Entry was limited to only those subjects who manifested a consistent, quantitatively definable response to a 5% citric acid challenge. Subjects were initially dosed with either a placebo vehicle or 25 mg diphenhydramine in a 10 ml formulation. Following drug ingestion, subjects were challenged at 15, 30, 45, 60, 120, and 240 minutes. Three days later, subjects were administered the alternate treatment and rechallenged at the same time points. Diphenhydramine was effective at the earliest time point assessed, 15 minutes, and continued to be as effective over the entire 4-hour duration of the test period. For the placebo vehicle, the mean cough counts did not change significantly from baseline. Neither the putative soothing effect of a liquid formulation nor accommodation to the citric acid spray can account for all the early and consistently significant activity of diphenhydramine in suppressing the cough response. The early onset of activity of diphenhydramine may be due to its local anesthetic properties or may indicate that the dose of diphenhydramine required for effective antitussive activity is lower than that required for effective antihistaminic activity. These results require further corroboration in direct comparisons of various doses of diphenhydramine with positive controls in both this model and clinical cough counting models employing pathologic cough indices. A 25 mg dose of diphenhydramine appears to be effective as an antitussive agent.

Administration, Inhalation↗

PubMed2000

Absence of pharmacokinetic interaction between orally co-administered naproxen sodium and diphenhydramine hydrochloride.

The potential for a pharmacokinetic interaction between naproxen and diphenhydramine was examined in a randomized three-way crossover design with a 1-week washout between dosing. Single oral doses of 220 mg of naproxen sodium and 50 mg of diphenhydramine hydrochloride were given separately and together to 30 healthy male and female subjects. Heparinized blood samples obtained for 48 h postdose were assayed for plasma naproxen and diphenhydramine concentrations using validated high-performance liquid chromatography (HPLC) and gas chromatography (GC) assay methods, respectively. The area under the plasma concentration-time curve (AUC), maximum plasma concentrations (C(max)), time of C(max) (T(max)) and terminal exponential half-life (t(1/2,z)), were analysed for significant treatment differences by analysis of variance (ANOVA). Based on absence of significant treatment effects on AUC and C(max), single-dose oral co-administration of 220 mg of naproxen sodium with 50 mg of diphenhydramine hydrochloride does not alter the pharmacokinetics of either naproxen or diphenhydramine. Significant treatment differences seen for naproxen T(max) (0.3 h, males only) and diphenhydramine t(1/2,z) (0.8 h, females only) were minor and are unlikely to have therapeutic consequences. Thus, efficacy and safety of concomitant naproxen and diphenhydramine should not be altered due to a pharmacokinetic interaction.

Adolescent↗

PubMedDate not supplied

Diphenhydramine in insomniac family practice patients: a double-blind study.

One hundred eleven mildly to moderately insomniac patients participated in a double-blind, placebo-controlled study to establish the efficacy of diphenhydramine as an over-the-counter (OTC) sleep aid. A two-week crossover design was employed in which all patients received both diphenhydramine and placebo for one week each. The daily diphenhydramine dose was 50 mg at bedtime. Results obtained indicate that diphenhydramine improved various sleep parameters, including sleep latency, to a significantly higher degree than did placebo. In addition, patients on diphenhydramine reported feeling more restful the following morning and patients preferred the diphenhydramine drug to placebo despite experiencing more side effects. This study thus supports the use of 50 mg diphenhydramine as an OTC sleep aid in the treatment of temporary mild to moderate insomnia.

Adult↗

PubMed1995

Effects of diphenhydramine on human eye movements.

Peak saccadic eye movement velocity (SEV) and average smooth pursuit gain (SP) are reduced in a dose-dependent manner by diazepam and provide reliable, quantitative measures of benzodiazepine agonist effects. To evaluate the specificity of these eye movement effects for agents acting at the central GABA-benzodiazepine receptor complex and the role of sedation in benzodiazepine effects, we studied eye movement effects of diphenhydramine, a sedating drug which does not act at the GABA-benzodiazepine receptor complex. Ten healthy males, aged 19-28 years, with no history of axis I psychiatric disorders or substance abuse, received 50 mg/70 kg intravenous diphenhydramine or a similar volume of saline on separate days 1 week apart. SEV, saccade latency and accuracy, SP, self-rated sedation, and short-term memory were assessed at baseline and at 5, 15, 30, 45, 60, 90 and 120 min after drug administration. Compared with placebo, diphenhydramine produced significant SEV slowing, and increases in saccade latency and self-rated sedation. There was no significant effect of diphenhydramine on smooth pursuit gain, saccade accuracy, or short-term memory. These results suggest that, like diazepam, diphenhydramine causes sedation, SEV slowing, and an increase in saccade latency. Since the degree of diphenhydramine-induced sedation was not correlated with changes in SEV or saccade latency, slowing of saccadic eye movements is unlikely to be attributable to sedation alone. Unlike diazepam, diphenhydramine does not impair smooth pursuit gain, saccadic accuracy, or memory. Different neurotransmitter systems may influence the neural pathways involved in SEV and smooth pursuit again.

Adult↗

PubMed1994

1% lidocaine versus 0.5% diphenhydramine for local anesthesia in minor laceration repair.

STUDY OBJECTIVE: Our previous study demonstrated that 1% diphenhydramine is as effective as 1% lidocaine for anesthesia in minor laceration repair, but that it also is more painful to inject. The purpose of this study was to compare 0.5% diphenhydramine to 1% lidocaine for pain of injection and adequacy of local anesthesia. STUDY DESIGN: Randomized, double-blinded, prospective study from December 1991 through June 1992. SETTING: University-affiliated, urban, inner-city emergency department. PARTICIPANTS: Ninety-eight adults with linear skin lacerations without end-organ involvement were included; 48 received lidocaine and 50 received diphenhydramine. INTERVENTIONS: Wounds were anesthetized with either diphenhydramine or lidocaine according to a random table. Both patients and physicians rated the pain of injection and suturing according to a standard, previously tested, visual analog scale. MEASUREMENTS AND MAIN RESULTS: Patient and physician ratings were ranked without regard to treatment group, and rank sum scores were calculated for each group. General linear models and multivariate analysis of variance were used to analyze the ranked sum scores. The power of the study to detect a ranked sum difference of 15 was 0.8 with P < .05 considered statistically significant. Lidocaine was found to be significantly more effective as a local anesthetic for facial lacerations according to both patients (P < .002) and physicians (P < .004). There was no statistically significant difference between 1% lidocaine and 0.5% diphenhydramine for pain of injection or suturing for all other locations according to both patients and physicians. Overall mean and median scores for injection and suturing with diphenhydramine corresponded to the mild pain category according to patients. CONCLUSION: Although not a replacement for lidocaine, diphenhydramine is a viable alternative for anesthesia in the repair of minor lacerations.

Adult↗

PubMed1998

Randomized trial of diphenhydramine versus benzyl alcohol with epinephrine as an alternative to lidocaine local anesthesia.

STUDY OBJECTIVES: We compared the pain of infiltration and anesthetic effects of.9% benzyl alcohol with epinephrine, 1% diphenhydramine, and.9% buffered lidocaine. METHODS: A prospective, randomized, double-blind study comparing benzyl alcohol, diphenhydramine, and lidocaine was carried out on adult volunteers. Each subject received all 3 injections in a standardized manner. Pain of infiltration was measured on a 100-mm visual analog pain scale and analyzed with a Kruskal-Wallis test. Duration of anesthesia was assessed at 5-minute intervals for a maximum of 45 minutes and compared with the use of survival analysis techniques by a log-rank test. Return of sensation by 45 minutes was evaluated with an exact chi2 test. All tests were 2-tailed, with significance defined as P <.05. RESULTS: Thirty subjects were enrolled. The diphenhydramine median pain score was 55 mm, compared with 12.5 mm for lidocaine and 5 mm for benzyl alcohol (P =.001). Pairwise comparisons showed that all possible combinations were statistically significant. The 3 anesthetics were different with respect to duration of anesthesia (P <.001). Pairwise comparisons revealed a longer duration of anesthesia for lidocaine than for diphenhydramine or benzyl alcohol, but no significant difference was found between diphenhydramine and benzyl alcohol. Pain sensation returned within the 45-minute study period in only 3 of 30 lidocaine injections, compared with 11 of 30 benzyl alcohol injections and 19 of 30 diphenhydramine injections (P =.001). CONCLUSION: Benzyl alcohol is a better alternative than diphenhydramine as a local anesthetic for lidocaine-allergic patients.

Adult↗

PubMed2003

Effects of fexofenadine, diphenhydramine, and placebo on performance of the test of variables of attention (TOVA).

OBJECTIVE: To determine the effects of diphenhydramine 50 mg and fexofenadine 180 mg on cognitive performance using the Test of Variables of Attention (TOVA), and to ascertain whether the TOVA was sufficiently sensitive to differentiate between the effects of these first- and second-generation H1-receptor antagonists on performance. STUDY DESIGN: The study used a double-blind, placebo-controlled, randomized, crossover design. Forty-two subjects completed four separate TOVA tests: at baseline and after administration of placebo, diphenhydramine 50 mg, and fexofenadine 180 mg. On each occasion, subjects rated subjective feelings of drowsiness on a visual analog scale (VAS) before taking the TOVA. RESULTS: Compared with placebo, diphenhydramine caused an increased response time (P = 0.0230) and more omission errors (P = 0.0398). Diphenhydramine was also associated with increased drowsiness VAS ratings (P = 0.0065) compared with placebo. Diphenhydramine caused significantly more commission errors than fexofenadine (P = 0.0354). Neither placebonor fexofenadine 180 mg caused significant changes in any TOVA or VAS measurements compared with baseline. Fexofenadine was not statistically different from placebo for any evaluation. CONCLUSIONS: The TOVA was sufficiently sensitive to differentiate between the central nervous system effects of fexofenadine and diphenhydramine. Fexofenadine 180 mg had no significant effect on the TOVA measures of performance or on self-reported drowsiness compared with placebo. In contrast, diphenhydramine 50 mg caused significant increases in omission errors and response time on the TOVA and increases in self-reported drowsiness compared with placebo [corrected].

Adolescent↗

PubMed2001

Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial.

STUDY OBJECTIVES: The utility of intravenous prochlorperazine as an antiemetic agent and abortive therapy for headache may be limited by the frequent occurrence of akathisia, the distressing effects of which have been shown to disrupt patient care. We tested the hypothesis that adjuvant diphenhydramine reduces the incidence of akathisia induced by prochlorperazine. METHODS: This randomized, double-blind, placebo-controlled trial was conducted in the emergency department of an academic tertiary care medical center with an annual census of 95,000 emergency patient visits. We enrolled a convenience sample of 100 adult patients who received 10 mg of intravenous prochlorperazine for the treatment of nausea/vomiting or headache. Subjects were randomly assigned to receive a 2-minute infusion of prochlorperazine with either 50 mg of diphenhydramine or placebo. The incidence of akathisia at 1 hour was measured by using explicit diagnostic criteria. To measure the influence of treatment on sedation, the subjects noted, on a 100-mm visual analog scale, their degree of sedation before and after treatment. RESULTS: Akathisia developed in 18 (36%) of 50 subjects in the control group and in 7 (14%) of 50 subjects in the diphenhydramine group, a 61% relative reduction. The addition of adjunct diphenhydramine resulted in an absolute reduction of 22% in the incidence of akathisia (95% confidence interval [CI] 6% to 38%; P = .01). The odds ratio for akathisia with the use of adjuvant diphenhydramine was 0.39 (95% CI 0.18 to 0.85). Mean sedation scores increased 12 mm after infusion of prochlorperazine alone (95% CI 3 to 21 mm) compared with a 33-mm increase after infusion of prochlorperazine with adjuvant diphenhydramine (95% CI 24 to 42 mm). The 12-mm difference between the groups was statistically significant (95% CI 9 to 34 mm, P < .001). CONCLUSION: Adjuvant diphenhydramine reduces the incidence of akathisia induced by prochlorperazine and is associated with an increase in sedation.

Adolescent↗

PubMed1994

Diphenhydramine enhances the interaction of hypercapnic and hypoxic ventilatory drive.

BACKGROUND: Although diphenhydramine is frequently used to treat pruritus and nausea in patients who have received neuraxial opioids, there are no data regarding its effect on ventilatory control. We conducted the current study to evaluate the effects of diphenhydramine on hypercapnic and hypoxic ventilatory control in healthy volunteers. METHODS: First, we measured the steady-state ventilatory response to carbon dioxide during hyperoxia with an end-tidal carbon dioxide tension of 46 or 54 mmHg (alternate subjects) in eight healthy volunteers. We then determined the hypoxic ventilatory response during isocapnic rebreathing at the same carbon dioxide tension. After a 10-min recovery period, we repeated the steady-state and hypoxic ventilatory response measurements at the other carbon dioxide tension (54 or 46 mmHg). Ten minutes after subjects received diphenhydramine 0.7 mg.kg-1 intravenously, we repeated this sequence of ventilatory measurements. RESULTS: Under hyperoxic conditions (inspired oxygen fraction > 0.5) diphenhydramine did not affect the ventilatory response to hypercapnia. Similarly, at an end-tidal carbon dioxide tension of 46 mmHg, neither the slope nor the position of the hypoxic ventilatory response curve changed significantly after diphenhydramine. However, at an end-tidal carbon dioxide tension of 54 mmHg, the slope of the hypoxic ventilatory response increased from 1.28 +/- 0.33 to 2.13 +/- 0.61 l.min-1.%SpO2(-1) (mean +/- standard error), and VE at an arterial hemoglobin oxygen saturation of 90% increased from 31.2 +/- 3.1 to 43.1 +/- 5.4 l.min-1). CONCLUSIONS: We conclude that although it did not affect the ventilatory response to carbon dioxide during hyperoxia or the ventilatory response to hypoxia at an end-tidal carbon dioxide tension of 46 mmHg diphenhydramine augmented the hypoxic response under conditions of hypercapnia in our young healthy volunteers. Although these findings may help to explain the apparent safety of diphenhydramine, they may not be applicable to debilitated patients or those who have received systemic or neuraxial ventilatory depressants.

Adult↗

PubMed2006

Intravenous administration of diphenhydramine reduces histamine-induced vasodilator effects in the retina and choroid.

PURPOSE: Intravenous administration of histamine causes an increase in choroidal blood flow (ChBF) and retinal vessel diameters in healthy subjects. The receptor mediating this response has not yet been identified. The present study was undertaken to clarify whether H1 receptor blockade with diphenhydramine affects the hemodynamic response of histamine in the choroid and the retina. METHODS: A randomized, double-masked, placebo-controlled, two-way crossover study was performed in 18 healthy, male, nonsmoking subjects. Histamine (0.32 microg/kg per minute over 30 minutes) was infused intravenously in the absence (NaCl as placebo) or presence of the H1 blocker diphenhydramine (1.0 mg/min over 50 minutes). Ocular hemodynamic parameters, blood pressure, and intraocular pressure were measured before drug administration, after infusion of diphenhydramine or placebo, and after co-infusion of histamine. Subfoveal ChBF and fundus pulsation amplitude (FPA) were measured with laser Doppler flowmetry and laser interferometry, respectively. Retinal arterial and venous diameters were measured with a retinal vessel analyzer. Retinal blood velocity was assessed with bidirectional laser Doppler velocimetry. RESULTS: Administration of histamine caused a decrease in mean arterial pressure by -4% +/- 9% (ANOVA P = 0.01). This effect was blunted by coadministration of diphenhydramine (ANOVA, P = 0.04). Histamine significantly increased FPA and subfoveal ChBF. Coadministration of diphenhydramine significantly reduced this effect (ANOVA; FPA P = 0.001, ChBF P = 0.049). Histamine significantly increased retinal arterial diameter by +3.5% +/- 4.5% and retinal venous diameter by +3.7% +/- 2.8%. Again, coadministration of diphenhydramine significantly reduced the vasodilative effect to +0.3% +/- 5.5% in retinal arteries (ANOVA, P = 0.00006) and to +0.9% +/- 2.5% in retinal veins (ANOVA, P = 0.004). CONCLUSIONS: The present data confirm that histamine increases ChBF and retinal vessel diameters in healthy subjects. Administration of the H1 receptor blocker diphenhydramine significantly reduced histamine-induced changes in ocular perfusion parameters. These results strongly indicate that in the retina and choroid, H1 receptors are involved in the histamine-mediated hemodynamic effects in vivo.

Adult↗

PubMed2006

Comparison of diphenhydramine and modafinil on arousal and autonomic functions in healthy volunteers.

Arousal is regulated by the interplay between wakefulness- and sleep-promoting nuclei. Major wakefulness-promoting nuclei are the histaminergic tuberomamillary nucleus (TMN) of the hypothalamus and the noradrenergic locus coeruleus (LC) of the pons, which also play a role in autonomic regulation. First generation antihistamines, such as diphenhydramine, are likely to cause sedation by blocking excitatory H1 histamine receptors in the cerebral cortex, and the anti-narcolepsy drug modafinil may promote wakefulness by activating the locus coeruleus. We compared the effects of single doses of diphenhydramine (75 mg) and modafinil (200 mg) on arousal and autonomic functions in 16 healthy male volunteers, using a placebo-controlled, balanced, double-blind design. Arousal was assessed by critical flicker fusion frequency (CFFF), visual analogue scales (VAS) and pupillary fatigue waves (Pupillographic Sleepiness Test (PST)). Autonomic functions measured included resting pupil diameter, light and darkness reflex responses, blood pressure, heart rate and salivation. Data were analysed with ANOVA, with multiple comparisons. Diphenhydramine had sedative effects as shown by reductions in CFFF, VAS alertness ratings and increases of the indices of pupillary fatigue. Modafinil had alerting effects as indicated by reductions in the measures of pupillary fatigue. Comparison of pre-post medication changes in pupil diameter showed a decrease after diphenhydramine and an increase after modafinil. Diphenhydramine reduced salivation, and modafinil increased systolic blood pressure. In conclusion, diphenhydramine and modafinil evoked opposite effects on arousal and sympathetic functions, which are likely to reflect their interaction with the central histaminergic and noradrenergic systems. Hyposalivation by diphenhydramine is likely to be due to its additional anticholinergic property.

Administration, Oral↗

PubMed1991

Diphenhydramine toxicity in three children with varicella-zoster infection.

Diphenhydramine hydrochloride is an antihistamine with anticholinergic properties that is frequently used both orally and topically for the temporary relief of pruritus. Significant systemic absorption may occur following topical administration of diphenhydramine in patients with varicella-zoster lesions. We describe three children with varicella-zoster infection (VZI) who developed bizarre behavior as well as visual and auditory hallucinations following topical applications of large amounts of diphenhydramine to the majority of skin surfaces. In two cases, oral diphenhydramine was also administered. Serum diphenhydramine concentrations approximated or exceeded those previously reported. In each case, a complete resolution of mental status abnormalities occurred within 24 hours after discontinuation of all diphenhydramine-containing products. Pharmacists and other health professionals should be aware of the potential toxicity of topical diphenhydramine in patients with VZI.

Administration, Cutaneous↗

PubMed1997

Evaluation of inhibitory effect of diphenhydramine on benzodiazepine dependence in rats.

Effect of diphenhydramine was investigated on withdrawal signs in lorazepam dependent rats. Physical dependence was produced by giving lorazepam admixed with the food in the following dose schedule: 10 x 4, 20 x 4, 40 x 4, 80 x 4 and 120 x 7 (mg/kg, daily x days). The parameters observed during the periods of administration of lorazepam and after its withdrawal were spontaneous locomotor activity (SLA), body temperature, reaction time to pain, foot shock aggression (FSA) and audiogenic seizures. Diphenhydramine was administered orally in the dose schedules of once daily (10, 20 and 40 mg/kg) and twice daily (5, 10 and 20 mg/kg) in separate groups during the withdrawal period. The withdrawal signs observed in control group (without diphenhydramine) were hyperkinesia, hyperthermia, hyperaggression and audiogenic seizures. Hyperkinesia and hyperthermia were blocked in all the groups of diphenhydramine-treated rats. FSA was inhibited only by diphenhydramine (10 and 20 mg/kg) given twice daily. Audiogenic seizures were completely blocked by once daily (20 and 40 mg/kg) as well as twice daily (20 mg/kg) doses of diphenhydramine. It may be concluded that diphenhydramine exerts a protective effects on benzodiazepine withdrawal syndrome.

Acoustic Stimulation↗