Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

[Comparative study of the clinical efficacy and safety of the fixed dose combination Levroso Long with Melaxen and Diphenhydramine in patients with insomnia]. / Rezul'taty sravnitel'nogo klinicheskogo issledovaniya effektivnosti i bezopasnosti kombinirovannogo lekarstvennogo preparata Levroso Long s preparatami Melaksen i Dimedrol u patsientov s bessonnitsei.

OBJECTIVE: Evaluation of the efficacy and safety of Levroso Long (fixed dose combination (hereinafter referred to as «FDC¼) diphenhydramine and melatonin, 25 mg + 3 mg and FDC diphenhydramine and melatonin 50 mg + 3 mg, respectively, capsules with modified release, NovaMedica Innotech LLC) in comparison with diphenhydramine medicines 50 mg (Diphenhydramine tablets, DALHIMFARM OJSC, Russia) and 3 mg melatonin (Melaxen tablets, Unipharm Inc., USA) in patients with insomnia. MATERIALS AND METHODS: Material and methods. A multicenter open randomized comparative clinical trial was conducted in parallel groups. The study included 312 patients with an insomnia diagnosis verified in accordance with the DSM-IV criteria (ICD code F51.0-10) and an insomnia severity index (ICI) >8 points. The patients were randomized into 4 groups and took the following medications for 10 days: patients of group 1 - Levroso Long (25 mg diphenhydramine and 3 mg melatonin), group 2 - Levroso Long combination drug (50 mg diphenhydramine and 3 mg melatonin), Group 3 -Diphenhydramine 50 mg, 4th - Melaxen 3 mg. A comparative assessment was performed on the 7th and 10th days of therapy according to the primary endpoint - ICI, and secondary endpoints - the results of the assessment based on the Leeds Sleep Assessment Questionnaire, the Pittsburgh Sleep Quality Questionnaire, the Scale of the overall clinical impression of improvement and the analysis of the profile of adverse events (NA). RESULTS: The FDC of diphenhydramine 25 mg + melatonin 3 mg was more effective than diphenhydramine 50 mg, and FDC diphenhydramine 50 mg + melatonin 3 mg was more effective than diphenhydramine 50 mg or melatonin 3 mg on both primary and secondary endpoints. In a safety assessment, the highest incidence of adverse events (48.7%) in the diphenhydramine 50 mg group was significantly lower in groups 1 (29.5%), 2 (12.8%) and 4 (1.3%). All reported adverse events in the FDC groups were mild or moderate in severity. CONCLUSION: The study showed that Levroso Long in two dosages surpassed monotherapy with 50 mg of Diphenhydramine (50 mg) or Melaxen (3 mg) in patients with insomnia in terms of efficacy parameters. The benefit/risk ratio of the studied drug is favorable compared to monotherapy.

Diphenhydramine induced acute dystonia: a case report.

Acute dystonia has notably been a challenge in the emergency unit. Drug-induced dystonia is reported in a limited number of cases in the literature. Rarely, diphenhydramine was found to be the culprit. We report the case of a 25-year-old female patient who developed an acute dystonic reaction following the administration of 25 mg of intravenous diphenhydramine as a treatment for an allergic reaction. The patient was given 5 mg diazepam, admitted for monitoring, and discharged home. Diphenhydramine-induced acute dystonia is a user drug-induced threatening reaction that warrants further investigation on the metabolism of these drugs and the contributing phenotypes to this adverse reaction.

Cetirizine more potently exerts mast cell-stabilizing property than diphenhydramine.

Cetirizine, a second-generation antihistamine, and diphenhydramine, a first-generation antihistamine, are among the most widely used anti-allergic drugs. In addition to longer duration of action and less incidence of sedative side effects, recent clinical studies also indicate a higher potency of cetirizine than diphenhydramine in the treatment or prevention of allergic disorders. In the present study, using the differential-interference contrast (DIC) microscopy, we examined the effects of cetirizine and diphenhydramine (1 µM to 1 mM) on the degranulation from rat peritoneal mast cells. Using fluorescence imaging of a water-soluble dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. At relatively higher concentrations (100 µM, 1 mM), both cetirizine and diphenhydramine significantly reduced the numbers of degranulating mast cells. Of note, at 1 mM, cetirizine more markedly reduced the number than diphenhydramine, almost entirely suppressing the degranulation of mast cells. Additionally, 1 mM cetirizine and levocetirizine, another second-generation antihistamine, almost totally inhibited the process of exocytosis in mast cells and washed out the trapping of the lucifer yellow on the cell surface, while diphenhydramine and chlorpheniramine, another first-generation antihistamine, did not. This study provided in vitro evidence for the first time that cetirizine more potently inhibited the process of exocytosis in mast cells than diphenhydramine, indicating its higher potency as a mast cell-stabilizer. Such mast cell-stabilizing property of cetirizine could be ascribed to its counteracting effect on the plasma membrane deformation in degranulating mast cells.

Use of tracking drugs for the search of intra-hospital adverse reactions: a pharmacovigilance study.

OBJECTIVE: To estimate the incidence of potential in-hospital adverse reactions  with the use of alert drugs in a general hospital in southern Brazil. Method: Cross-sectional study, carried out in a hospital in southern Brazil. The  electronic medical records (TASY®) of patients hospitalized between January  and August 2020, who were prescribed one of the drugs earmarked for  tracking adverse drug reactions, were evaluated: the drugs included  flumazenil, fexofenadine hydrochloride, naloxone, promethazine, diphenhydramine and loperamide. RESULTS: A total of 13,476 medical records were reviewed and 204 (1.5%)  were included in the study in which tracker use was indicated in the management of adverse drug reactions. In this study a total of 18 different signs or symptoms were found in medical records, with  pruritus/hyperemia/urticaria being the most reported symptoms (n = 76).  Among the drug classes that caused most adverse drug reactions, opioids were  the most mentioned (n = 44). It should be noted that in 49 medical  records the information on which drug caused the adverse events was not  reported. Regarding the cause of hospitalization of patients who used  creening drugs, cancer was the most frequent (n = 37). CONCLUSIONS: This study indicates that the use of trackers can be a tool to  estimate the occurrence of adverse drug reactions and to establish adverse  events related to the use of medications, which should be reported to the  pharmacovigilance service, with a view to patient safety.

OBJETIVO: Estimar la incidencia de potenciales reacciones adversas intrahospitalarias con el uso de prescripciones alertantes en un  hospital general del sur de Brasil.Método: Estudio transversal, realizado en un hospital del sur de Brasil. Se  evaluaron las historias clínicas electrónicas (TASY®) de los pacientes hospitalizados entre enero y agosto de 2020, a los que se les  prescribió uno de los medicamentos destinados al seguimiento de reacciones  adversas a medicamentos: los medicamentos incluían flumazenil, clorhidrato de fexofenadina, naloxona, prometazina, difenhidramina y  loperamida. RESULTADOS: Se revisaron 13.476 historias clínicas y se incluyeron 204 (1,5%) en el estudio en el que se indicó el uso de prescripciones alertantes en  el manejo de reacciones adversas a medicamentos. En este estudio se  encontró un total de 18 signos o síntomas diferentes en las historias clínicas,  siendo el prurito, la hiperemia y la urticaria los síntomas más reportados (n =  76). Entre las clases de fármacos que causaron la mayoría de las reacciones  adversas a medicamentos, los opioides fueron los más mencionados (n = 44).  Cabe señalar que en 49 historias clínicas no se reportó la información sobre  qué fármaco causó los eventos adversos. En cuanto a la causa de  hospitalización de los pacientes que utilizaron prescripciones alertantes, el  cáncer fue la más frecuente (n = 37). Conclusiones: Este estudio indica que el uso de alertadores puede ser una  herramienta para estimar la incidencia de reacciones adversas a medicamentos y establecer eventos adversos relacionados con el uso de medicamentos, los cuales deben ser reportados al servicio de  armacovigilancia, con miras a la seguridad del paciente.

QTc Prolongation in Poison Center Exposures to CredibleMeds List of Substances with "Known Risk of Torsades de Pointes".

Many drugs carry some risk of QT interval prolongation, which can lead to life-threatening dysrhythmias including Torsades de Pointes (TdP). CredibleMeds.org identifies medications categorized as "Known Risk of TdP" but does not stratify risk in acute supratherapeutic ingestions. We sought to determine the proportion of cases exhibiting QTc prolongation and life-threatening dysrhythmias including ventricular tachycardia (VT)/ventricular fibrillation (VF), TdP, and asystole in patients exposed to these substances. Retrospective chart review of cases reported to our Regional Poison Center from 2014 to 2019 of exposures to one or more of the "Known Risk" substances was performed. Demographics, therapies, clinical effects, and medical outcome for each case were analyzed. There were 1125 exposures, of which 760 had a documented QTc interval. QTc ≥ 500 ms was reported in 138 (18.2%) of the 760 cases. The most common "Known Risk" substances were citalopram, escitalopram and cocaine. Although not in the "Known Risk" category, mirtazapine, amitriptyline, diphenhydramine, and trazodone had a statistically significant association with QTc > 500 ms. Life-threatening dysrhythmias occurred in 13 cases, with VT/VF in 6 of the 760 (0.8%) cases, and one case of TdP. Flecainide (OR 11.1, 95% CI 2.2-55.8) and methadone (OR 7.1, 95% CI 2.1-23.4) were associated with increased risk of all life-threatening dysrhythmias. Exposures to medications on the Credible Meds list of "Known Risk of TdP" QTc prolongation is common, but life-threatening dysrhythmias are rare. Mirtazapine, amitriptyline, diphenhydramine, and trazodone were associated with prolonged QTc. Flecainide and methadone had the highest associated risk of life-threatening dysrhythmias.

Uso de fármacos alertantes para la detecciónde reacciones adversas intrahospitalarias: estudio de farmacovigilancia / Use of tracking drugs for the search of intra-hospital adverse reactions: a pharmacovigilance study

Objetivo: Estimar la incidencia de potenciales reacciones adversasintrahospitalarias con el uso de prescripciones alertantes en un hospitalgeneral del sur de Brasil.Método: Estudio transversal, realizado en un hospital del sur de Brasil.Se evaluaron las historias clínicas electrónicas (TASY®) de los pacienteshospitalizados entre enero y agosto de 2020, a los que se les prescribióuno de los medicamentos destinados al seguimiento de reacciones adversasa medicamentos: los medicamentos incluían flumazenil, clorhidratode fexofenadina, naloxona, prometazina, difenhidramina y loperamida.Resultados: Se revisaron 13.476 historias clínicas y se incluyeron 204 (1,5%)en el estudio en el que se indicó el uso de prescripciones alertantes en elmanejo de reacciones adversas a medicamentos. En este estudio se encontró untotal de 18 signos o síntomas diferentes en las historias clínicas, siendo el prurito,la hiperemia y la urticaria los síntomas más reportados (n = 76). Entre las clasesde fármacos que causaron la mayoría de las reacciones adversas a medicamentos,los opioides fueron los más mencionados (n = 44). Cabe señalar queen 49 historias clínicas no se reportó la información sobre qué fármaco causólos eventos adversos. En cuanto a la causa de hospitalización de los pacientesque utilizaron prescripciones alertantes, el cáncer fue la más frecuente (n = 37). Conclusiones: Este estudio indica que el uso de alertadores puede seruna herramienta para estimar la incidencia de reacciones adversas a medicamentosy establecer eventos adversos relacionados con el uso demedicamentos, los cuales deben ser reportados al servicio de farmacovigilancia,con miras a la seguridad del paciente.

Objective: To estimate the incidence of potential in-hospital adversereactions with the use of alert drugs in a general hospital in southernBrazil.Method: Cross-sectional study, carried out in a hospital in southernBrazil. The electronic medical records (TASY®) of patients hospitalizedbetween January and August 2020, who were prescribed one of thedrugs earmarked for tracking adverse drug reactions, were evaluated:the drugs included flumazenil, fexofenadine hydrochloride, naloxone, promethazine,diphenhydramine and loperamide.Results: A total of 13,476 medical records were reviewed and 204(1.5%) were included in the study in which tracker use was indicated in themanagement of adverse drug reactions. In this study a total of 18 differentsigns or symptoms were found in medical records, with pruritus/hyperemia/urticaria being the most reported symptoms (n = 76). Among the drugclasses that caused most adverse drug reactions, opioids were the mostmentioned (n = 44). It should be noted that in 49 medical records theinformation on which drug caused the adverse events was not reported.Regarding the cause of hospitalization of patients who used screeningdrugs, cancer was the most frequent (n = 37). Conclusions: This study indicates that the use of trackers can be a toolto estimate the occurrence of adverse drug reactions and to establishadverse events related to the use of medications, which should be reportedto the pharmacovigilance service, with a view to patient safety.

A randomized double-blind feasibility study comparing cetirizine and diphenhydramine in the prevention of paclitaxel-associated infusion-related reactions: the PREMED-F1 study.

PURPOSE: Cetirizine is a less sedative alternative to diphenhydramine for the prevention of infusion-related reactions (IRR) to paclitaxel. However, its use remains controversial. In this study, we assessed feasibility for a future definitive non-inferiority trial comparing cetirizine to diphenhydramine as premedication to prevent paclitaxel-related IRR. METHODS: This was a single-center randomized prospective feasibility study. Participants were paclitaxel-naive cancer patients scheduled to start paclitaxel chemotherapy. They were randomly assigned to receive either intravenous diphenhydramine 50 mg + oral placebo (control) or intravenous placebo + oral cetirizine 10 mg (intervention) for their first two paclitaxel treatments. The percentage of eligible patients completing a first paclitaxel treatment and the recruitment rate were assessed (feasibility outcomes). Drowsiness was measured at baseline and at selected time points using the Stanford Sleepiness Scale (SSS) (safety outcome). IRR events were also documented (efficacy outcome). RESULTS: Among 37 eligible patients, 27 were recruited and randomized (control 13; intervention 14) and 25 completed the study. The recruitment rate was 4.8 participants/month, meeting the primary feasibility target. Drowsiness was the main adverse effect associated with the premedication. The increase in drowsiness compared to baseline (ΔSSS) was greater in the diphenhydramine group compared to the cetirizine group (median ΔSSS 2 (IQR 3.25) vs median ΔSSS 0 (IQR 1), p < 0.01) when measured one hour after the premedication administration. One participant had an IRR and no unexpected serious adverse event occurred. CONCLUSION: The trial methods were feasible in terms of recruitment, retention, and safety. Cetirizine was significantly less sedating than diphenhydramine. IRR were infrequent and a larger trial is warranted to confirm non-inferiority for IRR prevention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04237090 (22.01.2020).

The Role of Cetirizine in the Changing Landscape of IV Antihistamines: A Narrative Review.

Since 1955, the only available H1 antihistamines for intravenous administration have been first-generation formulations and, of those, only intravenously administered (IV) diphenhydramine is still approved in the USA. Orally administered cetirizine hydrochloride, a second-generation H1 antihistamine, has been safely used over-the-counter for many years. In 2019, IV cetirizine was approved for the treatment of acute urticaria. In light of this approval, this narrative review discusses the changing landscape of IV antihistamines for the treatment of histamine-mediated conditions. Specifically, IV antihistamines will be discussed as a treatment option for acute urticaria and angioedema, as premedication to prevent infusion reactions related to anticancer agents and other biologics, and as an adjunct treatment for anaphylaxis and other allergic reactions. Before the development of IV cetirizine, randomized controlled trials of IV antihistamines for these indications were lacking. Three randomized controlled trials have been conducted with IV cetirizine versus IV diphenhydramine in the ambulatory care setting. A phase 3 trial of IV cetirizine 10 mg versus IV diphenhydramine 50 mg was conducted in 262 adults who presented to the urgent care/emergency department with acute urticaria requiring antihistamines. For the primary efficacy endpoint, defined as change from baseline in a 2-h patient-rated pruritus score, non-inferiority of IV cetirizine to IV diphenhydramine was demonstrated (score - 1.6 vs - 1.5, respectively; 95% CI - 0.1, 0.3). Compared with IV diphenhydramine, IV cetirizine demonstrated fewer adverse effects including less sedation, a significantly shorter length of stay in the treatment center, and fewer returns to the treatment center at 24 and 48 h. Similar findings were demonstrated in another phase 2 acute urticaria trial and in a phase 2 trial assessing IV cetirizine for pretreatment for infusion reactions in the oncology/immunology setting. IV cetirizine is associated with similar patient outcomes, fewer adverse effects, and increased treatment center efficiency than IV diphenhydramine.

A randomized study of IV prochlorperazine plus diphenhydramine versus IV hydromorphone for migraine-associated symptoms: A post hoc analysis.

OBJECTIVE: We conducted a randomized trial among emergency department patients with migraine to determine the relative impact on migraine-associated symptoms of hydromorphone, an opioid, versus prochlorperazine, an antidopaminergic antiemetic. METHODS: This was a post hoc analysis of data from a double-blind study registered at http://clinicaltrials.gov (NCT02389829). Patients who met International Classification of Headache Disorders, 3rd edition criteria for migraine without aura or for probable migraine without aura were eligible for participation. Participants received either hydromorphone 1 mg IV or prochlorperazine 10 mg IV plus diphenhydramine 25 mg IV and could receive a second dose of the same medication 1 h later if needed. The outcomes were sustained relief of nausea, photophobia, and phonophobia. RESULTS: A total of 127 patients were enrolled, of whom 63 received prochlorperazine and 64 received hydromorphone. Of 49 patients in the prochlorperazine arm who reported nausea at baseline, 34 (69.4%) reported complete resolution without relapse versus 15/49 (30.6%) in the hydromorphone arm (absolute risk reduction [ARR] = 38.8%, 95% CI: 20.5%-57.0%, p < 0.001). Of 55 patients in the prochlorperazine arm who reported photophobia at baseline, 23 (41.8%) reported complete resolution without relapse versus 13/62 (20.9%) patients treated with hydromorphone (ARR = 20.8%, 95% CI: 4.3%-37.3%, p = 0.014). Of 56 patients in the prochlorperazine arm who reported phonophobia at baseline, 25 (44.6%) reported complete resolution without relapse versus 16/59 (27.1%) in the hydromorphone arm (ARR = 17.5%, 95% CI: 0.3%-34.8%, p = 0.049). For adverse events, three patients in the prochlorperazine arm reported anxiety or restlessness, and nine patients in the hydromorphone arm reported dizziness or weakness. CONCLUSIONS: Prochlorperazine plus diphenhydramine is more efficacious than hydromorphone for the treatment of migraine-associated symptoms.

A Systematic Review of the Efficacy and Safety of Over-the-Counter Medications Used in Older People for the Treatment of Primary insomnia.

OBJECTIVE: The purpose of this systematic review is to evaluate the available evidence for safety and efficacy of over-the-counter (OTC) sleep aids used for the treatment of insomnia in older people.
DATA SOURCES: PubMed, EBSCO, and International Pharmaceutical Abstracts.
STUDY SELECTION: Five studies were included that involved humans 65 years of age and older being evaluated on OTC sleep aids in the outpatient setting.
DATA EXTRACTION: Data extraction from each study included primary and secondary efficacy endpoints, such as differences in the mean total sleep time, sleep latency, sleep efficiency, and number of awakenings, along with safety endpoints, such as psychomotor ability, cognitive ability, and adverse effect profiles. Both subjective and objective measures of changes in sleep and adverse effects were included.
DATA SYNTHESIS: Diphenhydramine had a statistically significant increase in sedation and decrease in number of awakenings but was not shown to be any less or more safe than compared products. Despite lacking safety issues, valerian was found to have no effect on subjective or objective sleep outcomes. Overall, melatonin had the most evidence and was found to have a statistically significant positive impact on sleep measures without safety issues.
CONCLUSION: Diphenhydramine and melatonin appear to be efficacious in improving some sleep measures while causing minimal adverse effects. However, there are very few studies that examine the use of over-the-counter sleep aids in those 65 years of age and older with primary insomnia. Additional studies are needed in this population.

Diphenhydramine Use in End-Stage Kidney Disease.

BACKGROUND: Diphenhydramine is commonly used in patients with kidney disease and end-stage kidney disease (ESKD) for sleep, allergic reactions, itching, and dialysis treatment related complications, and misuse associated with diphenhydramine is also reported. Diphenhydramine's pharmacokinetics property is reviewed and discussed. AREAS OF UNCERTAINTY: Diphenhydramine is highly bound to albumin. The safety profile and dosing information of diphenhydramine use in ESKD population is lacking. The purpose of this study is to provide an overview of diphenhydramine pharmacokinetic properties and evaluate diphenhydramine use in ESKD population. DATA SOURCES: A literature search was conducted during Spring 2019 using PubMed, CINAHL, Cochrane, Ovid, and Google Scholar. Search terms used include "diphenhydramine abuse," "diphenhydramine dialysis," and "diphenhydramine kidney disease." RESULTS: There is lack of studies available for diphenhydramine, kidney disease, and dialysis. There were case reports of diphenhydramine abuse and toxicity due to overdose. Diphenhydramine is highly bound to protein that limits its ability to dialyze, and therefore, it may predispose to side effects. Information on diphenhydramine used in the dialysis population is scarce, and dosing toxicity is unknown. CONCLUSIONS: The data available for use of diphenhydramine in ESKD and dialysis are limited. Clinicians should use caution with the use of diphenhydramine in this population.

Trends in adverse events and related health-care facility utilization from cough and cold medication exposures in children.

INTRODUCTION: Initial research following regulatory changes addressing the pediatric safety of cough and cold medications (CCMs) demonstrated decreases in adverse events (AEs). Using a national multi-source surveillance system, we studied subsequent CCM-related AE case rate trends and associated health-care facility (HCF) evaluation in children. METHODS: Data were collected from 2009 to 2016. Case eligibility included: age <12 years; exposure to an over-the-counter product containing ≥1 CCM pharmaceutical ingredient; ≥1 significant AE that occurred in the United States. RESULTS: About 4756 (72.6%) cases were determined at least potentially related to an index ingredient. Accidental unsupervised ingestions (AUIs; 3134; 65.9%) were the most common case type. Nearly half of AE cases involved children 2 to <4 years old (2,159; 45.4%). The AE case rate did not change significantly over time (p = 0.22). The proportion of AE cases resulting in HCF admission increased from 32.4% (207) in 2009 to 43.4% (238) in 2016 (p < 0.01). Exposures to diphenhydramine (1,305; 67.3%) and/or dextromethorphan (591; 30.5%) were involved in the majority of HCF admissions. CONCLUSIONS: The proportion of AE cases resulting in HCF admission increased from 2009 to 2016. Efforts to prevent AUIs such as packaging innovation and engineering controls, particularly for diphenhydramine and dextromethorphan-containing products, should be pursued.

Prophylactic Administration of Diphenhydramine to Reduce Neuroleptic Side Effects in the Acute Care Setting: A Systematic Review and Meta-Analysis.

BACKGROUND: Neuroleptics are commonly prescribed drugs to treat acute conditions (e.g., migraines) in the emergency department, but can cause serious adverse effects. Using diphenhydramine to prevent these adverse effects is very common but remains controversial. OBJECTIVE: We performed a systematic review to determine whether prophylactic administration of diphenhydramine reduces the incidence of neuroleptic adverse effects in patients with acute conditions. METHODS: Medline, Embase, Cochrane, PsycInfo, and Web of Science were searched for randomized controlled trials evaluating any neuroleptic with diphenhydramine vs. the same neuroleptic with any inactive agent. Primary outcome was incidence of any extrapyramidal adverse effect. Secondary outcomes were akathisia, rescue medication, subjective restlessness, neuroleptic malignant syndrome, and sedation. Independent reviewers scanned identified citations, extracted data, and assessed risk of bias. Meta-analysis was performed using random effect models. RESULTS: Of 1566 identified citations, nine studies (n = 1648 patients) met eligibility criteria. Four studies were specifically designed to compare the incidence of neuroleptic adverse effects with and without co-administration of diphenhydramine. Four studies were at high risk of bias. In primary analysis, diphenhydramine had no effect on the incidence of extrapyramidal symptoms (7 studies, n = 1393, risk ratio [RR] 0.75; 95% confidence interval [CI] 0.44-1.31) or akathisia (5 studies, n = 1094; RR 0.78; 95% CI 0.33-1.82) or any of the secondary outcomes. In subgroup analysis, diphenhydramine was associated with a significant decrease in extrapyramidal adverse effects compared with placebo (4 studies, n = 705; RR 0.61; 95% CI 0.41-0.90). Dosage analysis yielded no further information. CONCLUSIONS: When compared with placebo, diphenhydramine was associated with a significant reduction of extrapyramidal adverse effects. Overall quality of evidence is low. Further studies are warranted.

Patient Fall Risk Caused by Unintended Diphenhydramine Use.

A 62-year-old patient living in a rural community was referred to participate in a pharmacist-led home visit program because of concerns with the patient's increasing falls and medication complexity. The patient reported experiencing an increasing number of falls over the past few months, resulting in a recent hospitalization and mild head trauma. The patient's past medical history included diabetes mellitus type 2, hypertension, hyperlipidemia, gastroesophageal reflux disease, paroxysmal atrial fibrillation, unspecified back pain, and benign prostatic hyperplasia. During the comprehensive medication review, pharmacists determined the patient had inadvertently purchased an acetaminophen/ diphenhydramine combination medication, rather than his usual acetaminophen. According to the 2019 Beers criteria, use of acetaminophen/diphenhydramine for back pain without insomnia is not the best option and may contribute to falls. With an estimated four to eight tablets per day, the patient was taking 200-400 mg of diphenhydramine daily. Pharmacist recommendations included contacting the prescribing physician to obtain a prescription for acetaminophen. By asking the local pharmacy to dispense acetaminophen as a prescription, the risk of the patient inadvertently purchasing an inappropriate product is reduced. After removing the diphenhydramine from the patient's regimen, the falls ceased. This case demonstrates the effects of inappropriate diphenhydramine use in an especially vulnerable population. It also highlights the critical role that rural community pharmacists can play in improving their patients' health care.

Medication Errors From Over-the-Counter Cough and Cold Medications in Children.

OBJECTIVE: Out of hospital medication-related adverse events (AEs) from cough and cold medications (CCMs) can have significant public health impact. The objective of this study was to characterize pediatric medication error AEs involving over-the-counter (OTC) CCMs to identify preventable factors. METHODS: Multisource national data surveillance system study using an expert panel evaluating CCM AEs related to medication errors. INCLUSION CRITERIA: age <12 years, and at least 1 significant AE from at least 1 index ingredient from a CCM OTC product. RESULTS: From 2009 through 2016, 4756 cases were determined to have a significant AE related to an OTC CCM ingredient and 513 (10.8%) cases were due to a medication error. Nearly half of medication errors involved children 2 to <6 years old (n = 235; 45.8%). Many involved administration by a parent (n = 231; 45.0%) or alternative caregiver (n = 148; 28.8%). In nearly all cases (93.2%), the medication error involved the wrong dose of the medication. Health care facility evaluation occurred in 381 (74.3%) cases. Diphenhydramine and dextromethorphan were responsible for most medication errors and medication errors involving health care facility evaluation. There were no deaths from medication errors. CONCLUSION: In this multiyear surveillance study, medication errors most commonly occurred in children <6 years old who received the wrong volume of a liquid product. Diphenhydramine and dextromethorphan dosing errors were the most common cause of medication errors resulting from CCM use. Continued standardization of measuring devices, concentrations, and units of measure along with consumer education are needed to further decrease medication errors from CCMs.

Adverse events associated with diphenhydramine in children, 2008-2015.

Introduction: Diphenhydramine (DPH) exposures in children may be the result of accidental unsupervised ingestions, caregiver error, and intentional misuse of DPH-containing cough and cold medications (CCM). We sought to understand the nature of pediatric ingestions of DPH, particularly the toxicity and outcome of a single product, single ingredient DPH (DPH-only) exposures, in order to derive ingredient-specific information about the clinical effects and course of such cases.Methods: As part of a U.S. multi-year safety surveillance program to assess the safety of over-the-counter (OTC) medications used in cough and cold preparations in children <12 years of age, an expert panel reviewed cases involving symptomatic adverse events potentially related to oral exposures to these medications. After individual review, the cases were categorized by causal relationship of the reported ingredients to the adverse event, exposure intent (therapeutic, non-therapeutic, unknown intent), and dose (therapeutic, supratherapeutic, or unknown). Following panel review, any disagreement on classification was discussed until a consensus was reached. The data were then analyzed with respect to descriptive findings.Results: The panel reviewed 6618 eligible cases and determined 2802 were at least potentially related to oral exposure to DPH. Of these, 2028 were DPH-only cases (39.1% of all cases judged at least potentially related to a cough and cold medication). The majority (79.5%) of DPH-only cases occurred in children 2 to <4 years of age and involved accidental unsupervised ingestions (74.7%). Liquid pediatric formulations were the most common (51.7%) products reported followed by solid pediatric formulations (24.0%). The most common adverse events were tachycardia (53.4%), hallucinations (46.5%), somnolence (34.7%), agitation (33.9%), and mydriasis (26.3%). Seizures occurred in only 5.5% of cases. Five (0.2%) deaths were reported; in the death cases, the DPH dose was judged supratherapeutic in one and unknown in the other four. Child abuse was reported in four of the five death cases and three of the five deaths were homicides.Conclusions: Exposures to DPH-only products were the most common type of exposure detected in our study of adverse events associated with CCM in children. The majority of the DPH-only cases were the result of accidental unsupervised ingestions. Most adverse events were relatively mild self-limited anticholinergic effects and few deaths occurred. Deaths involving DPH were often associated with child abuse or homicide. Interventions targeting the prevention of accidental unsupervised are likely to be impactful in preventing morbidity associated with DPH-only exposure.

Prophylactic diphenhydramine attenuates postoperative catheter-related bladder discomfort in patients undergoing gynecologic laparoscopic surgery: a randomized double-blind clinical study.

BACKGROUND: To evaluate the effectiveness of diphenhydramine, an antihistamine with anti-muscarinic properties, for prevention of postoperative catheter-related bladder discomfort (CRBD). METHODS: Ninety-six ASA physical status I and II adult female patients (20-60 years) scheduled for elective gynecologic laparoscopic surgery were included. Patients were randomized into two groups of 48 patients each. All patients received a detailed preoperative explanation of the possible consequences of CRBD. The control group received normal saline 2 ml, whereas the diphenhydramine group received diphenhydramine 30 mg intravenously after induction of general anesthesia. Then, all patients were catheterized with a 14F Foley catheter and the balloon was inflated with 10 ml of distilled water. All patients who complained of CRBD in the postoperative room were appeased with nursing. Ketorolac 30 mg was used as the rescue drug on patients' request or when the patient was evaluated as having moderate or severe CRBD. Bladder discomfort and its severity were assessed at 1, 2 and 6 h postoperatively. The severity of CRBD was graded as none, mild, moderate and severe. Adverse effects of diphenhydramine such as sedation, dry mouth or GI upset were recorded. RESULTS: The incidence of CRBD was lower in the diphenhydramine group compared with the control group at 2 h (34.8 vs. 58.7%, p = 0.02) and 6 h (23.9 vs. 56.5%, p < 0.01) postoperatively. Diphenhydramine treatment also reduced the severity of CRBD at 6 h postoperatively (p = 0.01). Moreover, the request for rescue for CRBD was lower in diphenhydramine group at 2 h (8.7 vs. 26.1%, p = 0.03). There were no significant differences in side effects, such as sedation, dry mouth or gastrointestinal upset between the two groups (p > 0.05). CONCLUSION: Prophylactic diphenhydramine 30 mg at induction of general anesthesia reduced the incidence and severity of postoperative bladder discomfort without significant side effects in patients receiving gynecologic laparoscopic surgery.

The becoming-methadone-body: on the onto-politics of health intervention translations.

In this paper, we reflect on health intervention translations as matters of their implementation practices. Our case is methadone treatment, an intervention promoted globally for treating opioid dependence and preventing HIV among people who inject drugs. Tracing methadone's translations in high-security prisons in the Kyrgyz Republic, we notice the multiple methadones made possible, what these afford, and the onto-political effects they make. We work with the idea of the 'becoming-methadone-body' to trace the making-up of methadone treatment and its effects as an intra-action of human and nonhuman substances and bodies. Methadone's embodied effects flow beyond the mere psycho-activity of substances incorporating individual bodies, to material highs and lows incorporating the governing practices of prisoner society. The methadone-in-practice of prisoner society is altogether different to that imagined as being in translation as an intervention of HIV prevention and opioid treatment, and has material agency as a practice of societal governance. Heroin also emerges as an actor in these relations. Our analysis troubles practices of 'evidence-based' intervention and 'implementation science' in the health field, by arguing for a move towards 'evidence-making' intervention approaches. Noticing the onto-politics of health intervention translations invites speculation on how intervening might be done differently.