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Prophylactic Administration of Diphenhydramine to Reduce Neuroleptic Side Effects in the Acute Care Setting: A Systematic Review and Meta-Analysis
The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–10, 2020 Ó 2020 Elsevier Inc. All rights reserved. 0736-4679/$ - see front matter
https://doi.org/10.1016/j.jemermed.2020.09.031
Clinical Review PROPHYLACTIC ADMINISTRATION OF DIPHENHYDRAMINE TO REDUCE NEUROLEPTIC SIDE EFFECTS IN THE ACUTE CARE SETTING: A SYSTEMATIC REVIEW AND META-ANALYSIS Akram Mokhtari, Olivia Yip, Judith Alain, MD, MSC, and Simon Berthelot, MD, MSC Centre Hospitalier Universitaire de Que´bec-Universite´ Laval, Me´decine d’urgencem, Que´bec, Que´bec, Canada Reprint Address: Akram Mokhtari, Centre Hospitalier Universitaire de Que´bec-Universite´ Laval, Me´decine d’urgencem 2705 Boulevard Laurier, Que´bec, Que´bec, Canada G1V 4G2
, Abstract—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 coadministration 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. Ó 2020 Elsevier Inc. All rights reserved. , Keywords—neuroleptic; adverse effect; side effect; diphenhydramine; ED; emergency department; acute care; akathisia
INTRODUCTION In emergency medicine, neuroleptics are frequently prescribed to treat a vast array of symptoms and diseases, such as psychosis, nausea, and headache (1). Among them, typical (prochlorperazine and haloperidol) and atypical (olanzapine and risperidone) neuroleptics are commonly prescribed and are considered effective for a growing number of indications in the acute care setting (i.e., agitation, nausea, migraine, and gastroparesia). However, their adverse effects can be disabling, or worse, fatal (2). These include akathisia, dystonia, and other extrapyramidal reactions, as well as neuroleptic malignant syndrome (2). Estimations of the incidence of neuroleptic adverse effects range from 1% to 60%, depending on the adverse effect and the neuroleptic considered (3– 6). These adverse effects are a burden on patient care
RECEIVED: 22 May 2020; FINAL SUBMISSION RECEIVED: 12 August 2020; ACCEPTED: 12 September 2020 1
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(7,8). One of the most frequently prescribed drugs to prevent neuroleptic adverse effects in the acute care setting is diphenhydramine. In a survey of emergency physicians in the United States, 71% of respondents reported using diphenhydramine ‘‘frequently,’’ ‘‘very frequently,’’ or ‘‘always’’ to prevent neuroleptic-induced akathisia (9). Although it seems plausible diphenhydramine provides a prophylactic effect through its anticholinergic properties, this indication remains off-label (10). Furthermore, data on prevention of neuroleptic adverse effects in the acute care setting are scarce. Similarly, in the chronic care setting, the utility of administrating prophylactic drugs against neuroleptics remains unclear, although propranolol and high-potency anticholinergic drugs are used frequently (3,6,11). However, their numerous side effects and contraindications can make their use impractical in fast-paced, high-pressure, acute care settings (12,13). Scarce data also suggest that off-label benzodiazepines can be effective (14,15). In comparison, diphenhydramine is a potential affordable and usually well-tolerated option, although it can cause certain adverse effects (e.g., delirium), especially in the elderly (16). We performed a systematic review to determine whether, in the acute care setting, prophylactic administration of diphenhydramine with a neuroleptic, compared with placebo or any inactive comparator, reduces the incidence of neuroleptic adverse effects in patients with acute conditions. METHODS The present study is fully compliant with the Preferred Reporting Items for Systematic Reviews and MetaAnalyses statement (Appendix 1) (17). Search Strategy Main strategy. We conducted a systematic review of randomized controlled trials (RCTs). Searched years ranged from inception to July 2019 for all databases. We developed, with the help of a professional librarian, a specific search strategy for MEDLINE (PubMed; Appendix 2), EMBASE (Elsevier), the Cochrane Central Register of Controlled Trials (Cochrane), and PsycINFO (Ovid). To identify RCTs in MEDLINE and EMBASE, we included validated filters (18,19). We used similar search strategies to search the gray literature through the International Clinical Trials Registry Platform, ClinicalTrials.gov, Biosis, and Web of Science. We reviewed references of pertinent reviews and of eligible studies for inclusion. We described the intervention using descriptors (e.g., medical subject headings) and free terms describing both the neuroleptics and the intervention (diphenhydramine). To maximize sensitivity of the search strategy, we included every neuro-
leptic indexed under the NO5A label (neuroleptic) of the Anatomical Therapeutic Chemical classification of the World Health Organization, a drug registry containing the vast majority of drugs used worldwide (20). All studies were reviewed for eligibility by two independent reviewers (A.M., J.A.). Studies were screened by title, abstract and, then, by full text publications. Differences in assessment were resolved by discussion and, if disagreement persisted, a third review author was consulted. Unreported data. In the case of eligible studies in which data pertaining to neuroleptic adverse effects were not reported, or in which we suspected data were not fully reported, we contacted study authors. Study Selection Inclusion criteria. Population The study population included any individual necessitating the administration of a neuroleptic for an acute medical condition in any care setting. No restrictions based on age, sex, or comorbidities were imposed during the search.Studies We considered for inclusion randomized control trials evaluating any neuroleptic with diphenhydramine vs. the same neuroleptic alone or with any inactive agent. Active agents with potential confounding effect (co-medications) were defined as agents with the same side effects as neuroleptics or with an approved indication against neuroleptic side effects (Appendix 3). We still included studies evaluating these co-medications as long as they were used in the intervention and in the control group (i.e., neuroleptic, diphenhydramine, and co-medication vs. neuroleptic and co-medication). No restrictions were made in terms of number of doses administered. We included abstracts, conference proceedings, and peerreviewed articles. No restriction was made regarding language or year of publication. Exclusion criteria. We excluded studies that evaluated chronic neuroleptic prescription. Outcomes Our primary outcome was the incidence of any extrapyramidal adverse effect. Extrapyramidal symptoms include any symptom related to the extra-pyramidal system including, but not limited to, Parkinsonism, akathisia, chorea, hemiballism, athethosis, and dystonia (21). Our secondary outcomes were the incidence of akathisia, subjective restlessness, neuroleptic malignant syndrome, sedation, and rescue medication. Akathisia, restlessness, and neuroleptic malignant syndrome were counted toward the main outcome and as individual outcomes.
Diphenhydramine to Reduce Neuroleptic Side Effects
Data Extraction Data extraction method. We extracted data using a standardized extraction form, pretested using a landmark study (22). We collected the characteristics of the study population (age, sex, and comorbidities). We also reported trial characteristics, the intervention and its description, inclusion and exclusion criteria, and the results associated to our outcomes. When an outcome was evaluated multiple times, we extracted the data of the first evaluation, as neuroleptic adverse effects fade over time. For dosage of diphenhydramine and of the neuroleptic, we converted, when necessary, relative doses (mg/kg) into fixed doses (mg) to ensure a common unit of analysis (23). When weight was not available, we used a standard weight of 60 kg for women and 70 kg for men, adopting an approach similar to that of Plante et al. in a systematic review published in 2012 (23). Two independent reviewers (A.M., J.A.) extracted the data and a third reviewer was consulted if disagreements arose. Risk of Bias Evaluation of risk of bias was carried out by two independent reviewers (A.M., O.Y.) using Cochrane Collaboration’s risk-of-bias tool (24). We assessed for random sequence generation, allocation concealment, blinding, completeness of outcome data, reporting bias, and reported any additional concern. Data Analysis We analyzed collected data using Cochrane Review Manager, version 5.0 (25). For studies with multiple intervention and control groups, the groups were merged together to correspond to our main comparison. Incidence of neuroleptic adverse effects were summarized using MantelHaenszel random effect models (26). Within these models, data are pooled based on the weight of each individual study. The weight of a specific study’s data within the analysis is based on the individual study’s risk ratio (RR) and number of participants. In addition, the weight of each study is adjusted based on the heterogeneity between the intervention effects of each study (i.e., extreme results or results with very large confidence intervals [CIs] are given less weight). We presented the results in the form of RRs. We presented all data with a 95% CI. We used funnel plot analyses to assess potential publication bias (27). Sub-group and Sensitivity Analyses To better assess and isolate the potential efficacy of diphenhydramine against neuroleptic adverse effects, we conducted the following sub-group analyses.
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1. Efficacy of diphenhydramine against placebo vs. efficacy of diphenhydramine against any other inactive agent. 2. Low dose (<25 mg) vs. regular dose (25 mg to 100 mg) vs high dose (>100 mg) of diphenhydramine. 3. High dose vs. regular dose of neuroleptic (e.g., regular dose of metoclopramide < 25 mg). 4. Other planned analyses included age and type of neuroleptic. We conducted a sensitivity analysis excluding studies at a high risk of bias. Subgroups were determined by literature search and clinical expertise and subgroup categories were based on usual treatment regimen dosage (i.e., regular dose). Heterogeneity and Quality of Evidence We assessed heterogeneity using the I2 statistic, a method that estimates the percentage of variation between studies that is due to heterogeneity (28). A result of 20% implies that 20% of the observed variation within the analysis cannot be explained solely by chance and that there is some level of heterogeneity; 0% to 40% was considered as probably low heterogeneity, 30% to 60% as probably moderate heterogeneity, 50% to 90% as probably considerable heterogeneity, 75% to 100% as probably substantial heterogeneity (26). To evaluate the quality of the evidence available, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was employed. Quality of evidence is evaluated based on 5 qualitative criteria: risk-of-bias level, consistency among included studies, directness of outcomes and comparison groups (i.e., direct patient outcomes vs. surrogates), and precision of risk estimates (29).
RESULTS Study Characteristics Of the 1566 identified citations, nine studies (n = 1648 patients) met all eligibility criteria (Figure 1, Table 1). Year of publication ranged from 1987 to 2015. All included studies were published in English-language journals. No trial included patients younger than 18 years. No trial reported comorbidities. Four trials were conducted in the United States (22,30–32), two in Turkey (33,34), one in Greece (35), one in Italy (36), and one in Taiwan (37). Five trials were conducted in the emergency department (22,30,32–34), one in gynecologic surgery (37), and three in oncology (31,35,36). Indications for the neuroleptic were nausea, emesis, or headache. Metoclopramide was the neuroleptic evaluated in all trials except one in which
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Risk of Bias All studies except one had an adequate randomization method (35). Five studies had adequate allocation concealment (22,30–32,37). Four studies had adequate blinding of participants (22,30–32). Five studies had adequate blinding of outcome assessment (22,30–33). All studies had adequate completeness of outcome data. Four studies were specifically designed to evaluate neuroleptic adverse effects (22,30,32–34). Four studies were at high risk of bias (31,34–36); three did not report how they assessed for the presence of extrapyramidal symptoms and one lacked information regarding blinding and allocation concealment (Figure 2). Primary Outcome In our study, the overall incidence of extrapyramidal adverse effects was 12%. Prophylactic administration of diphenhydramine was not associated with a decrease in incidence of extrapyramidal symptoms (Table 2, Figure 3). Subgroup and Sensitivity Analyses Subgroup. When including only studies comparing diphenhydramine with placebo, prophylactic administration of diphenhydramine appeared effective, with an RR of extrapyramidal adverse effects of 0.61 (4 studies, n = 688; 95% CI 0.41–0.90; I2 = 9%) (Table 3). In patients randomized to diphenhydramine vs. any comparator other than placebo, the RR was 1.16 (3 studies, n = 705; 95% CI 0.26–5.16; I2 = 81%). Analyses regarding dosage yielded no further information. For dosage, analysis thresholds for metoclopramide and promethazine were the same, as both drugs are prescribed at similar doses. Subgroup analyses based on age and types of neuroleptic were not achievable.
Figure 1. Flow chart of studies.
Sensitivity. A sensitivity analysis excluding studies at a high risk of bias yielded no further information (4 studies, n = 812; RR 0.71; 95% CI 0.46–1.08; I2 = 31%) (Appendix 4). Secondary Outcomes
it was prochlorperazine (32). Mean age ranged from 29 to 58.6 years. Dose of diphenhydramine, when converted into fixed doses, ranged from 20 mg to 200 mg: three studies with < 25 mg (22,33,34), four between 25 and 100 mg (30–32,36), and one > 100 mg (35). The most common dose administered was 50 mg. Dosage of metoclopramide ranged from 10 mg to approximatively 200 mg. Exact dosage was not provided in one study (37).
Prophylactic administration of diphenhydramine was not associated with a decrease in the incidence of akathisia in the main, subgroup, or sensitivity analyses (Table 2, Appendix 5). One study was ineligible for the metaanalysis because the outcome reported was intensity and not incidence of akathisia (34). In this study, diphenhydramine was associated with a reduction of intensity of
Study First Author, Year
Participants
Kang, 2009 (37)
ASA 1 and 2 adult women undergoing hysterectomy
Erdur, 2012 (33)
Aged 18–65 years and presenting to the ED with nausea or headache Aged 18–65 years and presenting to the ED with nausea
Friedman, 2009 (22) Friedman, 2016 (30)
Aged 18–65 years and presenting to the ED with headache
Kris, 1987 (31)
Adult patients with histologically confirmed cancer
Parlak, 2007 (34)
Aged 17–65 years and presenting to the ED with headache or nausea Consecutive adult patients admitted to or observed at five oncologic centers for chemotherapy
Roila, 1989 (36)
Tsavaris, 1991 (35)
91 patients aged between 18 and 70 years with histologically confirmed cancer
Vinson, 2001 (32)
Patients aged between 18 and 65 years coming to the ED for headache or nausea
Interventions (All Medication Was Administered Intravenously) Base: Morphine 1 mg/mL + metoclopramide 0.5 mg/mL Intervention: Diphenhydramine 0.6 mg/mL Control: Placebo Base: Metoclopramide 10 mg Intervention: Diphenhydramine 20 mg Control: Midazolam 1.5 mg Base: Metoclopramide 10 mg or 20 mg Intervention: Diphenydramine 25 mg Control: Placebo Base: Metoclopramide 10 mg Intervention: Diphenhydramine 50 mg Control: Placebo Base: 2 doses of metoclopramide 3 mg/kg, +1 dose of dexamethasone 20 mg + chemotherapy Intervention: Diphenhydramine 50 mg Control: Lorazepam 1.5 mg/m2 Base: Metoclopramide 10 mg Intervention: diphenhydramine 20 mg Control: 2 mg midazolam Base: 4 doses of metoclopramide 4 mg/ kg + chemotherapy Intervention: Diphenhydramine 50 mg + dexamethasone 20 mg Control: Methylpredisolone 250 mg Base: 5 doses of metoclopramide, 2 mg/kg every 2 h + chemotherapy Intervention: Diphenhydramine 200 mg 4 every 6h Control: Placebo Base 10 mg prochlorperazine Intervention: 50 mg diphenhydramine Control: Placebo
Outcomes
Specifically Designed to Assess for Neuroleptic Side Effects
Nausea, vomiting, morphine consumption, and sedation
No
Akathisia, sedation, blood pressure, and respiratory rate
Yes
Akathisia, subjective restlessness, and rescue medication
Yes
Drowsiness/sedation, subjective restlessness, and rescue medication Anti-emetic efficacy and side effects
No No
Akathisia intensity, blood pressure, and respiratory rate
Yes
Side effects of anti-emetic treatment
No
Vomiting, nausea, chemotherapy, and neuroleptic side effects
No
Akathisia, sedation
Yes
Diphenhydramine to Reduce Neuroleptic Side Effects
Table 1. Characteristics of Included Studies
ASA = american society of anesthesiology physical status classification system; ED = emergency department.
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Publication Bias and Quality of Evidence Inspection of the funnel plot did not reveal any evidence of publication bias (Appendix 7). Based on the GRADE approach, the quality of evidence was low (Appendix 8). DISCUSSION
Figure 2. Risk-of-bias summary for the main outcome. List of studies: Kang, 2009 (37), Erdur, 2012 (33), Friedman, 2009 (22), Friedman, 2016 (30), Kris, 1987 (31), Parlak, 2007 (34), Roila, 1989 (36), Tsavaris, 1991 (35), Vinson, 2001 (32).
akathisia (Data was reported solely in a plot. Estimating numerical data was not possible without significant imprecision.) Diphenhydramine was not associated with subjective restlessness, rescue medication, or sedation (Table 2, Appendix 6). No study reported neuroleptic malignant syndrome.
In crude analysis, prophylactic administration of diphenhydramine was not associated with a decrease in extrapyramidal symptoms, including akathisia. However, when analyzing studies comparing diphenhydramine to placebo solely, diphenhydramine was associated with a significant reduction of extrapyramidal symptoms. An outlier study post-hoc analysis yielded similar results. Quality of evidence was low. Incidence of extrapyramidal symptoms in the acute care setting varied significantly across the literature. Reported values range from 1% up to 60% (3– 6). In our study, the proportion of extrapyramidal adverse effects was 12%. Such variation can be explained by a lack of standardized methods to diagnose those adverse effects, and by the complex diagnostic challenge that are extrapyramidal adverse effects. A systematic review conducted in 2004 and updated in 2006 to evaluate the efficacy of adjunct anticholinergics for akathisia concluded that there were no RCTs addressing this question (38). This contradicts our findings. A first explanation is that their search strategy included ‘‘akathisia,’’ which prevented inclusion of studies in which akathisia was not specifically mentioned in the abstract. Further, when they updated the study, they only searched the Cochrane Schizophrenia Group’s Register database. In our study, we avoided such pitfalls by excluding the outcomes from the search strategy and by using World Health Organization (WHO) drug classification to maximize sensitivity. Finally, having ‘‘any extrapyramidal symptom’’ as outcome allowed us to include events that were not necessarily identifiable as a specific symptom. Evidence regarding prophylactic intervention for extrapyramidal symptoms in the acute care setting is scarce. A systematic review evaluated promethazine, a drug similar to diphenhydramine, combined with haloperidol for psychosis-induced agitation/aggression (39).
Table 2. Summary of Evidence for Study Outcomes Outcome Extrapyramidal symptoms Akathisia Sedation Subjective restlessness Rescue medication
Studies/No. Of Participants
Quality of Evidence (GRADE)
Summary Result, RR (95% CI)
7/1393 5/1094 5/1079 2/497 2/497
Low Low Low Low Low
0.75 (0.44–1.31) 0.78 (0.33–1.82) 1.46 (0.91–2.35) 0.77 (0.42–1.39) 0.78 (0.39–1.53)
CI = confidence interval; GRADE = Grading of Recommendations Assessment, Development and Evaluation; RR = risk ratio.
Diphenhydramine to Reduce Neuroleptic Side Effects
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Figure 3. Incidence of extrapyramidal symptoms before and after removal of an outlier study. CI = confidence interval; MH = Mantel–Haenszel. Lists of studies: Erdur, 2012 (33); Friedman, 2009 (22); Friedman, 2016 (30); Kris, 1987 (31); Roila, 1989 (36); Tsavaris, 1991 (35); Vinson, 2001 (32); Erdur, 2012 (33); Friedman, 2009 (22); Friedman, 2016 (30); Roila, 1989 (36); Tsavaris, 1991 (35); Vinson, 2001 (32).
According to the review, promethazine may reduce adverse effects associated with haloperidol. However, neuroleptics used in each arm of the included studies were not the same. Limited conclusions can be drawn from these findings. Regarding chronic care, both the guidelines of the American Psychiatric Association and the Schizophrenia Patient Outcomes Research Team recommend prophylactic administration of anticholinergic medication to prevent extrapyramidal symptoms (3,6). Cited studies involved medications with stronger anticholinergic properties than diphenhydramine (i.e., benztropine). These types of medications are not practical for emergency care because of their side effect profile (40). For acute care, diphenhydramine may be sufficient, as our study found that it is effective compared with placebo.
Limitations Three studies did not report how they evaluated extrapyramidal adverse effects and definition of these adverse effects varied across studies. The most common extrapyramidal adverse effect, akathisia, is difficult to diagnose (41). Methods to measure it are abundant and heterogeneous (42). Depending on the severity of the adverse effects encountered, studies may have underreported events. In contrast, the possible lack of blinding of participants, of personnel, or of outcome assessment may have caused an overreporting of events in the comparison group or underreporting in the treatment group, which would have overestimated the efficacy of diphenhydramine.
Table 3. Summary of Evidence of Subgroup Analyses of the Main Outcome Analysis Comparator Placebo Not placebo Dose of diphenhydramine Low dose (<25 mg) Regular dose (25 mg to 100 mg) High dose (>100 mg) Dose of metoclopramide Normal (<25 mg) High (>25 mg) CI = confidence interval.
Risk Ratio (95% CI)
I2 (%)
705 688
0.61 (0.41–0.90) 1.16 (0.26–5.16)
9 81
2 4 1
514 788 91
0.74 (0.50–1.11) 0.84 (0.22–3.25) 0.47 (0.15–1.45)
0 80 NA
4 3
913 480
0.71 (0.46–1.08) 0.91 (0.15–5.53)
31 92
No. of Studies
No. of Participants
4 3
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Comparison groups were heterogeneous across studies and agents not labeled as effective for extrapyramidal adverse effects may still be effective. This factor may explain why diphenhydramine was effective compared with placebo and not in primary analysis. Off-label use of benzodiazepines has previously been studied and scarce data suggest that they may be effective (14,15). As such, inclusion of studies involving a benzodiazepine as the comparator may have underestimated the effectiveness of diphenhydramine, as apparently supported by the subgroup analysis dividing comparators into placebo vs. anything else (Table 3). Finally, one study implied that diphenhydramine may significantly increase neuroleptic side effects (RR 6.47; 95% CI 1.55–28.37) (31). The very low rate of side effects reported in the comparison group may be explained by the fact that the comparator in the study (lorazepam) was administered at unusually high doses (3 mg). It is unclear how neuroleptic adverse effects, especially with those with a subjective component (e.g., akathisia), were assessed in the comparison group as patients were heavily sedated. The inclusion of this study may have underestimated diphenhydramine’s true efficacy, which is consistent with the significant reduction of side effects observed in our placebo subgroup analysis. External Validity Despite maximizing sensitivity of our search strategy, we were only able to find studies involving metoclopramide and prochlorperazine. Metoclopramide and prochlorperazine are very frequently used neuroleptics to treat very common acute clinical conditions, such as nausea and migraine. This may potentially explain why they were the only neuroleptics for which we found studies on the prophylactic use of diphenhydramine against neuroleptic adverse effects in the acute care setting. Nevertheless, we believe that our conclusions are extendable to other neuroleptics. Firstly, prochlorperazine shares the same pharmacologic properties as most first-generation antipsychotics (12). Further, metoclopramide, although it has a potentially lower affinity to D2 receptors, still affects the same central dopaminergic pathways and produces the same spectrum of extrapyramidal side effects as other antipsychotic agents (10,43). Finally, both agents are known to produce frequent neuroleptic side effects (4,44,45). Clinical and Research Implications There are currently no widely approved guidelines regarding prevention of neuroleptic side effects in the acute care setting. Diphenhydramine is the most frequently prescribed treatment to counter them. Other
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treatment options exist, although they are less supported by scientific evidence (e.g., benzodiazepines) or have a riskier side effect profile (e.g., propranolol) that may make them unpractical for usage in the emergency department. From a clinical standpoint, as shown in our study, diphenhydramine represents a low-risk first-line treatment because of its safe side effect profile and because its use does not significantly increase the burden of side effects it has in common with neuroleptics (e.g., sedation). Further, diphenhydramine seems to reduce neuroleptic side effects by 39% compared with placebo. Routine prescription of diphenhydramine as first-line treatment for this indication is then probably beneficial and safe. Further high-quality studies are needed to confirm the trend observed in our review. CONCLUSIONS In this systematic review, prophylactic administration of diphenhydramine, when used in combination with prochlorperazine or metoclopramide, was not associated with a decrease in incidence of extrapyramidal symptom in primary analysis. However, we observed a significant relative risk reduction of 39% in neuroleptic adverse effects when comparing diphenhydramine with placebo. The use of diphenhydramine was not associated with any other reduction of the incidence of side effects. Overall, quality of evidence is low. Diphenhydramine may represent an effective, low-risk, and inexpensive firstline treatment option, although further high-quality studies are warranted. REFERENCES 1. Tintinalli JE, Stapczynski JS, Ma OJ, Yealy DM, Meckler GD, Cline D. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 8th edn. New York: McGraw-Hill Education; 2016. 2. Caroff SN, Hurford I, Lybrand J, Campbell EC. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin 2011;29:127–48. viii. 3. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010;36:71–93. 4. Drotts DL, Vinson DR. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med 1999;34(4 Pt 1):469–75. 5. Lucca JM, Madhan R, Parthasarathi G, Ram D. Identification and management of adverse effects of antipsychotics in a tertiary care teaching hospital. J Res Pharm Pract 2014;3(2):46–50. 6. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004;161(2 suppl):1–56. 7. Yildiz A, Sachs GS, Turgay A. Pharmacological management of agitation in emergency settings. Emerg Med J 2003;20:339–46. 8. Iversen TSJ, Steen NE, Dieset I, et al. Side effect burden of antipsychotic drugs in real life—impact of gender and polypharmacy. Prog Neuropsychopharmacol Biol Psychiatry 2018;82:263–71. 9. Hurtado TR, Vinson DR, Vandenberg JT. ED treatment of migraine headache: factors influencing pharmacotherapeutic choices. Headache 2007;47:1134–43.
Diphenhydramine to Reduce Neuroleptic Side Effects 10. Diphenhydramine. Micromedex. 2017. Available at: https://www. micromedexsolutions.com/home/dispatch. Accessed August 5, 2019. 11. Adler LA, Peselow E, Rosenthal M, Angrist B. A controlled comparison of the effects of propranolol, benztropine, and placebo on akathisia: an interim analysis. Psychopharmacol Bull 1993;29: 283–6. 12. Wishart DS, Knox C, Guo AC, et al. DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 2006;34(Database issue):D668–72. 13. Stroup TS, Gray N. Management of common adverse effects of antipsychotic medications. World Psychiatry 2018;17:341–56. 14. Bartels M, Heide K, Mann K, Schied HW. Treatment of akathisia with lorazepam. An open clinical trial. Pharmacopsychiatry 1987; 20(2):51–3. 15. Lima AR, Soares-Weiser K, Bacaltchuk J, Barnes TR. Benzodiazepines for neuroleptic-induced acute akathisia. Cochrane Database Syst Rev 2002;(1):CD001950. 16. Agostini JV, Leo-Summers LS, Inouye SK. Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Arch Intern Med 2001;161(17):2091–7. 17. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009;6(7):e1000100. 18. Wong SS, Wilczynski NL, Haynes RB. Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. J Med Libr Assoc 2006;94(1):41–7. 19. Glanville JM, Lefebvre C, Miles JN, Camosso-Stefinovic J. How to identify randomized controlled trials in MEDLINE: ten years on. J Med Libr Assoc 2006;94:130–6. 20. Norwegian Institute of Public Health. ATC/DDD Index Oslo: World Health Organization. 2017. Available at: https://www.whocc.no/ atc_ddd_index/. Accessed March 16, 2019. 21. Swenson R, Fadul C, Jenkyn L, Ward T. Disorders of basal ganglia function. In: Reeves AG, Swenson R, eds. Disorders of the Nervous System: A Primer. Dartmouth Medical School; 2008. Available at: https://www.dartmouth.edu/dons/part_3/chapter_26.html. Accessed October 2, 2020. 22. Friedman BW, Bender B, Davitt M, et al. A randomized trial of diphenhydramine as prophylaxis against metoclopramide-induced akathisia in nauseated emergency department patients. Ann Emerg Med 2009;53:379–85. 23. Plante J, Turgeon AF, Zarychanski R, et al. Effect of systemic steroids on post-tonsillectomy bleeding and reinterventions: systematic review and meta-analysis of randomised controlled trials. BMJ 2012;345:e5389. 24. Davis J, Riesenberg LA, Mardis M, et al. Evaluating outcomes of electronic tools supporting physician shift-to-shift handoffs: a systematic review. J Grad Med Educ 2015;7:174–80. 25. Review Manager (RevMan) Windows 10. Version 5.3. Copenhagen: The Nordic Cochrane Centre TCC; 2014. 26. Deeks JJHJ, Altman DG. Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration; 2011. Available at. www. handbook.cochrane.org. Accessed November 10, 2018. 27. Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997; 315(7109):629–34. 28. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557–60. 29. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490.
9 30. Friedman BW, Cabral L, Adewunmi V, et al. Diphenhydramine as adjuvant therapy for acute migraine: an emergency department based randomized clinical trial. Ann Emerg Med 2016;67:32–9. 31. Kris MG, Gralla RJ, Clark RA, Tyson LB, Groshen S. Antiemetic control and prevention of side-effects of anticancer therapy with lorazepam or diphenhydramine when used in combination with metoclopramide plus dexamethasone—a double-blind, randomized trial. Cancer 1987;60:2816–22. 32. Vinson DR, Drotts DL. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med 2001;37:125–31. 33. Erdur B, Tura P, Aydin B, et al. A trial of midazolam vs diphenhydramine in prophylaxis of metoclopramide-induced akathisia. Am J Emerg Med 2012;30:84–91. 34. Parlak I, Erdur B, Parlak M, et al. Midazolam vs. diphenhydramine for the treatment of metoclopramide-induced akathisia: a randomized controlled trial. Acad Emerg Med 2007;14:715–21. 35. Tsavaris N, Zamanis N, Zinelis A, et al. Diphenhydramine for nausea and vomiting related to cancer chemotherapy with cisplatin. J Pain Symptom Manage 1991;6:461–5. 36. Roila F, Tonato M, Basurto C, et al. Protection from nausea and vomiting in cisplatin-treated patients: high-dose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: a study of the Italian Oncology Group for Clinical Research. J Clin Oncol 1989; 7:1693–700. 37. Kang TJ, Lu CW, Lin TY. Antiemetic efficacy of metoclopramide and diphenhydramine added to morphine patient-controlled analgesia. Eur J Pain 2009;13:S280–1. 38. Rathbone J, Soares-Weiser K. Anticholinergics for neurolepticinduced acute akathisia. Cochrane Database Syst Rev 2006;(4): CD003727. 39. Wilson MP, Pepper D, Currier GW, Holloman GH Jr, Feifel D. The psychopharmacology of agitation: consensus statement of the american association for emergency psychiatry project Beta psychopharmacology workgroup. West J Emerg Med 2012;13:26–34. 40. Gerretsen P, Pollock BG. Drugs with anticholinergic properties: a current perspective on use and safety. Expert Opin Drug Saf 2011;10:751–65. 41. Weiden PJ, Mann JJ, Haas G, Mattson M, Frances A. Clinical nonrecognition of neuroleptic-induced movement disorders: a cautionary study. Am J Psychiatry 1987;144:1148–53. 42. Sachdev P, Kruk J. Clinical characteristics and predisposing factors in acute drug-induced akathisia. Arch Gen Psychiatry 1994;51:963– 74. 43. Stanley M, Lautin A, Rotrosen J, Gershon S, Kleinberg D. Metoclopramide: antipsychotic efficacy of a drug lacking potency in receptor models. Psychopharmacology (Berl) 1980;71(3):219–25. 44. Schroeder JA, Wolfe WM, Thomas MH, et al. The effect of intravenous ranitidine and metoclopramide on behavior, cognitive function, and affect. Anesth Analg 1994;78:359–64. 45. Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J. Drug Insight: from disturbed motility to disordered movement—a review of the clinical benefits and medicolegal risks of metoclopramide. Nat Clin Pract Gastroenterol Hepatol 2006;3:138–48.
SUPPLEMENTARY DATA Supplementary data related to this article can be found at https://doi.org/10.1016/j.jemermed.2020.09.031.
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ARTICLE SUMMARY 1. Why is this topic important? Neuroleptics are one of the most commonly prescribed drugs in the emergency department with common and burdensome side effects. Diphenhydramine is the most commonly prescribed drug in prevention of these side effects, with controversial efficacy and safety profile. 2. What does this review attempt to show? This review seeks to assess whether diphenhydramine, the most commonly prescribed drug for prevention of neuroleptic side effects, is safe and effective in that indication. 3. What are the key findings? Diphenhydramine reduces extrapyramidal symptoms by 39% compared with placebo. Diphenhydramine is safe when prescribed for this indication. Overall quality of evidence is low. 4. How is patient care impacted? Further high-quality studies are needed to confirm the trend observed in this study. Diphenhydramine should be considered as first-line treatment for prevention of neuroleptic side effects. Clinicians may consider systemically prescribing diphenhydramine for this indication considering its safety profile.
https://doi.org/10.1016/j.jemermed.2020.09.031
Clinical Review PROPHYLACTIC ADMINISTRATION OF DIPHENHYDRAMINE TO REDUCE NEUROLEPTIC SIDE EFFECTS IN THE ACUTE CARE SETTING: A SYSTEMATIC REVIEW AND META-ANALYSIS Akram Mokhtari, Olivia Yip, Judith Alain, MD, MSC, and Simon Berthelot, MD, MSC Centre Hospitalier Universitaire de Que´bec-Universite´ Laval, Me´decine d’urgencem, Que´bec, Que´bec, Canada Reprint Address: Akram Mokhtari, Centre Hospitalier Universitaire de Que´bec-Universite´ Laval, Me´decine d’urgencem 2705 Boulevard Laurier, Que´bec, Que´bec, Canada G1V 4G2
, Abstract—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 coadministration 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. Ó 2020 Elsevier Inc. All rights reserved. , Keywords—neuroleptic; adverse effect; side effect; diphenhydramine; ED; emergency department; acute care; akathisia
INTRODUCTION In emergency medicine, neuroleptics are frequently prescribed to treat a vast array of symptoms and diseases, such as psychosis, nausea, and headache (1). Among them, typical (prochlorperazine and haloperidol) and atypical (olanzapine and risperidone) neuroleptics are commonly prescribed and are considered effective for a growing number of indications in the acute care setting (i.e., agitation, nausea, migraine, and gastroparesia). However, their adverse effects can be disabling, or worse, fatal (2). These include akathisia, dystonia, and other extrapyramidal reactions, as well as neuroleptic malignant syndrome (2). Estimations of the incidence of neuroleptic adverse effects range from 1% to 60%, depending on the adverse effect and the neuroleptic considered (3– 6). These adverse effects are a burden on patient care
RECEIVED: 22 May 2020; FINAL SUBMISSION RECEIVED: 12 August 2020; ACCEPTED: 12 September 2020 1
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(7,8). One of the most frequently prescribed drugs to prevent neuroleptic adverse effects in the acute care setting is diphenhydramine. In a survey of emergency physicians in the United States, 71% of respondents reported using diphenhydramine ‘‘frequently,’’ ‘‘very frequently,’’ or ‘‘always’’ to prevent neuroleptic-induced akathisia (9). Although it seems plausible diphenhydramine provides a prophylactic effect through its anticholinergic properties, this indication remains off-label (10). Furthermore, data on prevention of neuroleptic adverse effects in the acute care setting are scarce. Similarly, in the chronic care setting, the utility of administrating prophylactic drugs against neuroleptics remains unclear, although propranolol and high-potency anticholinergic drugs are used frequently (3,6,11). However, their numerous side effects and contraindications can make their use impractical in fast-paced, high-pressure, acute care settings (12,13). Scarce data also suggest that off-label benzodiazepines can be effective (14,15). In comparison, diphenhydramine is a potential affordable and usually well-tolerated option, although it can cause certain adverse effects (e.g., delirium), especially in the elderly (16). We performed a systematic review to determine whether, in the acute care setting, prophylactic administration of diphenhydramine with a neuroleptic, compared with placebo or any inactive comparator, reduces the incidence of neuroleptic adverse effects in patients with acute conditions. METHODS The present study is fully compliant with the Preferred Reporting Items for Systematic Reviews and MetaAnalyses statement (Appendix 1) (17). Search Strategy Main strategy. We conducted a systematic review of randomized controlled trials (RCTs). Searched years ranged from inception to July 2019 for all databases. We developed, with the help of a professional librarian, a specific search strategy for MEDLINE (PubMed; Appendix 2), EMBASE (Elsevier), the Cochrane Central Register of Controlled Trials (Cochrane), and PsycINFO (Ovid). To identify RCTs in MEDLINE and EMBASE, we included validated filters (18,19). We used similar search strategies to search the gray literature through the International Clinical Trials Registry Platform, ClinicalTrials.gov, Biosis, and Web of Science. We reviewed references of pertinent reviews and of eligible studies for inclusion. We described the intervention using descriptors (e.g., medical subject headings) and free terms describing both the neuroleptics and the intervention (diphenhydramine). To maximize sensitivity of the search strategy, we included every neuro-
leptic indexed under the NO5A label (neuroleptic) of the Anatomical Therapeutic Chemical classification of the World Health Organization, a drug registry containing the vast majority of drugs used worldwide (20). All studies were reviewed for eligibility by two independent reviewers (A.M., J.A.). Studies were screened by title, abstract and, then, by full text publications. Differences in assessment were resolved by discussion and, if disagreement persisted, a third review author was consulted. Unreported data. In the case of eligible studies in which data pertaining to neuroleptic adverse effects were not reported, or in which we suspected data were not fully reported, we contacted study authors. Study Selection Inclusion criteria. Population The study population included any individual necessitating the administration of a neuroleptic for an acute medical condition in any care setting. No restrictions based on age, sex, or comorbidities were imposed during the search.Studies We considered for inclusion randomized control trials evaluating any neuroleptic with diphenhydramine vs. the same neuroleptic alone or with any inactive agent. Active agents with potential confounding effect (co-medications) were defined as agents with the same side effects as neuroleptics or with an approved indication against neuroleptic side effects (Appendix 3). We still included studies evaluating these co-medications as long as they were used in the intervention and in the control group (i.e., neuroleptic, diphenhydramine, and co-medication vs. neuroleptic and co-medication). No restrictions were made in terms of number of doses administered. We included abstracts, conference proceedings, and peerreviewed articles. No restriction was made regarding language or year of publication. Exclusion criteria. We excluded studies that evaluated chronic neuroleptic prescription. Outcomes Our primary outcome was the incidence of any extrapyramidal adverse effect. Extrapyramidal symptoms include any symptom related to the extra-pyramidal system including, but not limited to, Parkinsonism, akathisia, chorea, hemiballism, athethosis, and dystonia (21). Our secondary outcomes were the incidence of akathisia, subjective restlessness, neuroleptic malignant syndrome, sedation, and rescue medication. Akathisia, restlessness, and neuroleptic malignant syndrome were counted toward the main outcome and as individual outcomes.
Diphenhydramine to Reduce Neuroleptic Side Effects
Data Extraction Data extraction method. We extracted data using a standardized extraction form, pretested using a landmark study (22). We collected the characteristics of the study population (age, sex, and comorbidities). We also reported trial characteristics, the intervention and its description, inclusion and exclusion criteria, and the results associated to our outcomes. When an outcome was evaluated multiple times, we extracted the data of the first evaluation, as neuroleptic adverse effects fade over time. For dosage of diphenhydramine and of the neuroleptic, we converted, when necessary, relative doses (mg/kg) into fixed doses (mg) to ensure a common unit of analysis (23). When weight was not available, we used a standard weight of 60 kg for women and 70 kg for men, adopting an approach similar to that of Plante et al. in a systematic review published in 2012 (23). Two independent reviewers (A.M., J.A.) extracted the data and a third reviewer was consulted if disagreements arose. Risk of Bias Evaluation of risk of bias was carried out by two independent reviewers (A.M., O.Y.) using Cochrane Collaboration’s risk-of-bias tool (24). We assessed for random sequence generation, allocation concealment, blinding, completeness of outcome data, reporting bias, and reported any additional concern. Data Analysis We analyzed collected data using Cochrane Review Manager, version 5.0 (25). For studies with multiple intervention and control groups, the groups were merged together to correspond to our main comparison. Incidence of neuroleptic adverse effects were summarized using MantelHaenszel random effect models (26). Within these models, data are pooled based on the weight of each individual study. The weight of a specific study’s data within the analysis is based on the individual study’s risk ratio (RR) and number of participants. In addition, the weight of each study is adjusted based on the heterogeneity between the intervention effects of each study (i.e., extreme results or results with very large confidence intervals [CIs] are given less weight). We presented the results in the form of RRs. We presented all data with a 95% CI. We used funnel plot analyses to assess potential publication bias (27). Sub-group and Sensitivity Analyses To better assess and isolate the potential efficacy of diphenhydramine against neuroleptic adverse effects, we conducted the following sub-group analyses.
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1. Efficacy of diphenhydramine against placebo vs. efficacy of diphenhydramine against any other inactive agent. 2. Low dose (<25 mg) vs. regular dose (25 mg to 100 mg) vs high dose (>100 mg) of diphenhydramine. 3. High dose vs. regular dose of neuroleptic (e.g., regular dose of metoclopramide < 25 mg). 4. Other planned analyses included age and type of neuroleptic. We conducted a sensitivity analysis excluding studies at a high risk of bias. Subgroups were determined by literature search and clinical expertise and subgroup categories were based on usual treatment regimen dosage (i.e., regular dose). Heterogeneity and Quality of Evidence We assessed heterogeneity using the I2 statistic, a method that estimates the percentage of variation between studies that is due to heterogeneity (28). A result of 20% implies that 20% of the observed variation within the analysis cannot be explained solely by chance and that there is some level of heterogeneity; 0% to 40% was considered as probably low heterogeneity, 30% to 60% as probably moderate heterogeneity, 50% to 90% as probably considerable heterogeneity, 75% to 100% as probably substantial heterogeneity (26). To evaluate the quality of the evidence available, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was employed. Quality of evidence is evaluated based on 5 qualitative criteria: risk-of-bias level, consistency among included studies, directness of outcomes and comparison groups (i.e., direct patient outcomes vs. surrogates), and precision of risk estimates (29).
RESULTS Study Characteristics Of the 1566 identified citations, nine studies (n = 1648 patients) met all eligibility criteria (Figure 1, Table 1). Year of publication ranged from 1987 to 2015. All included studies were published in English-language journals. No trial included patients younger than 18 years. No trial reported comorbidities. Four trials were conducted in the United States (22,30–32), two in Turkey (33,34), one in Greece (35), one in Italy (36), and one in Taiwan (37). Five trials were conducted in the emergency department (22,30,32–34), one in gynecologic surgery (37), and three in oncology (31,35,36). Indications for the neuroleptic were nausea, emesis, or headache. Metoclopramide was the neuroleptic evaluated in all trials except one in which
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Risk of Bias All studies except one had an adequate randomization method (35). Five studies had adequate allocation concealment (22,30–32,37). Four studies had adequate blinding of participants (22,30–32). Five studies had adequate blinding of outcome assessment (22,30–33). All studies had adequate completeness of outcome data. Four studies were specifically designed to evaluate neuroleptic adverse effects (22,30,32–34). Four studies were at high risk of bias (31,34–36); three did not report how they assessed for the presence of extrapyramidal symptoms and one lacked information regarding blinding and allocation concealment (Figure 2). Primary Outcome In our study, the overall incidence of extrapyramidal adverse effects was 12%. Prophylactic administration of diphenhydramine was not associated with a decrease in incidence of extrapyramidal symptoms (Table 2, Figure 3). Subgroup and Sensitivity Analyses Subgroup. When including only studies comparing diphenhydramine with placebo, prophylactic administration of diphenhydramine appeared effective, with an RR of extrapyramidal adverse effects of 0.61 (4 studies, n = 688; 95% CI 0.41–0.90; I2 = 9%) (Table 3). In patients randomized to diphenhydramine vs. any comparator other than placebo, the RR was 1.16 (3 studies, n = 705; 95% CI 0.26–5.16; I2 = 81%). Analyses regarding dosage yielded no further information. For dosage, analysis thresholds for metoclopramide and promethazine were the same, as both drugs are prescribed at similar doses. Subgroup analyses based on age and types of neuroleptic were not achievable.
Figure 1. Flow chart of studies.
Sensitivity. A sensitivity analysis excluding studies at a high risk of bias yielded no further information (4 studies, n = 812; RR 0.71; 95% CI 0.46–1.08; I2 = 31%) (Appendix 4). Secondary Outcomes
it was prochlorperazine (32). Mean age ranged from 29 to 58.6 years. Dose of diphenhydramine, when converted into fixed doses, ranged from 20 mg to 200 mg: three studies with < 25 mg (22,33,34), four between 25 and 100 mg (30–32,36), and one > 100 mg (35). The most common dose administered was 50 mg. Dosage of metoclopramide ranged from 10 mg to approximatively 200 mg. Exact dosage was not provided in one study (37).
Prophylactic administration of diphenhydramine was not associated with a decrease in the incidence of akathisia in the main, subgroup, or sensitivity analyses (Table 2, Appendix 5). One study was ineligible for the metaanalysis because the outcome reported was intensity and not incidence of akathisia (34). In this study, diphenhydramine was associated with a reduction of intensity of
Study First Author, Year
Participants
Kang, 2009 (37)
ASA 1 and 2 adult women undergoing hysterectomy
Erdur, 2012 (33)
Aged 18–65 years and presenting to the ED with nausea or headache Aged 18–65 years and presenting to the ED with nausea
Friedman, 2009 (22) Friedman, 2016 (30)
Aged 18–65 years and presenting to the ED with headache
Kris, 1987 (31)
Adult patients with histologically confirmed cancer
Parlak, 2007 (34)
Aged 17–65 years and presenting to the ED with headache or nausea Consecutive adult patients admitted to or observed at five oncologic centers for chemotherapy
Roila, 1989 (36)
Tsavaris, 1991 (35)
91 patients aged between 18 and 70 years with histologically confirmed cancer
Vinson, 2001 (32)
Patients aged between 18 and 65 years coming to the ED for headache or nausea
Interventions (All Medication Was Administered Intravenously) Base: Morphine 1 mg/mL + metoclopramide 0.5 mg/mL Intervention: Diphenhydramine 0.6 mg/mL Control: Placebo Base: Metoclopramide 10 mg Intervention: Diphenhydramine 20 mg Control: Midazolam 1.5 mg Base: Metoclopramide 10 mg or 20 mg Intervention: Diphenydramine 25 mg Control: Placebo Base: Metoclopramide 10 mg Intervention: Diphenhydramine 50 mg Control: Placebo Base: 2 doses of metoclopramide 3 mg/kg, +1 dose of dexamethasone 20 mg + chemotherapy Intervention: Diphenhydramine 50 mg Control: Lorazepam 1.5 mg/m2 Base: Metoclopramide 10 mg Intervention: diphenhydramine 20 mg Control: 2 mg midazolam Base: 4 doses of metoclopramide 4 mg/ kg + chemotherapy Intervention: Diphenhydramine 50 mg + dexamethasone 20 mg Control: Methylpredisolone 250 mg Base: 5 doses of metoclopramide, 2 mg/kg every 2 h + chemotherapy Intervention: Diphenhydramine 200 mg 4 every 6h Control: Placebo Base 10 mg prochlorperazine Intervention: 50 mg diphenhydramine Control: Placebo
Outcomes
Specifically Designed to Assess for Neuroleptic Side Effects
Nausea, vomiting, morphine consumption, and sedation
No
Akathisia, sedation, blood pressure, and respiratory rate
Yes
Akathisia, subjective restlessness, and rescue medication
Yes
Drowsiness/sedation, subjective restlessness, and rescue medication Anti-emetic efficacy and side effects
No No
Akathisia intensity, blood pressure, and respiratory rate
Yes
Side effects of anti-emetic treatment
No
Vomiting, nausea, chemotherapy, and neuroleptic side effects
No
Akathisia, sedation
Yes
Diphenhydramine to Reduce Neuroleptic Side Effects
Table 1. Characteristics of Included Studies
ASA = american society of anesthesiology physical status classification system; ED = emergency department.
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Publication Bias and Quality of Evidence Inspection of the funnel plot did not reveal any evidence of publication bias (Appendix 7). Based on the GRADE approach, the quality of evidence was low (Appendix 8). DISCUSSION
Figure 2. Risk-of-bias summary for the main outcome. List of studies: Kang, 2009 (37), Erdur, 2012 (33), Friedman, 2009 (22), Friedman, 2016 (30), Kris, 1987 (31), Parlak, 2007 (34), Roila, 1989 (36), Tsavaris, 1991 (35), Vinson, 2001 (32).
akathisia (Data was reported solely in a plot. Estimating numerical data was not possible without significant imprecision.) Diphenhydramine was not associated with subjective restlessness, rescue medication, or sedation (Table 2, Appendix 6). No study reported neuroleptic malignant syndrome.
In crude analysis, prophylactic administration of diphenhydramine was not associated with a decrease in extrapyramidal symptoms, including akathisia. However, when analyzing studies comparing diphenhydramine to placebo solely, diphenhydramine was associated with a significant reduction of extrapyramidal symptoms. An outlier study post-hoc analysis yielded similar results. Quality of evidence was low. Incidence of extrapyramidal symptoms in the acute care setting varied significantly across the literature. Reported values range from 1% up to 60% (3– 6). In our study, the proportion of extrapyramidal adverse effects was 12%. Such variation can be explained by a lack of standardized methods to diagnose those adverse effects, and by the complex diagnostic challenge that are extrapyramidal adverse effects. A systematic review conducted in 2004 and updated in 2006 to evaluate the efficacy of adjunct anticholinergics for akathisia concluded that there were no RCTs addressing this question (38). This contradicts our findings. A first explanation is that their search strategy included ‘‘akathisia,’’ which prevented inclusion of studies in which akathisia was not specifically mentioned in the abstract. Further, when they updated the study, they only searched the Cochrane Schizophrenia Group’s Register database. In our study, we avoided such pitfalls by excluding the outcomes from the search strategy and by using World Health Organization (WHO) drug classification to maximize sensitivity. Finally, having ‘‘any extrapyramidal symptom’’ as outcome allowed us to include events that were not necessarily identifiable as a specific symptom. Evidence regarding prophylactic intervention for extrapyramidal symptoms in the acute care setting is scarce. A systematic review evaluated promethazine, a drug similar to diphenhydramine, combined with haloperidol for psychosis-induced agitation/aggression (39).
Table 2. Summary of Evidence for Study Outcomes Outcome Extrapyramidal symptoms Akathisia Sedation Subjective restlessness Rescue medication
Studies/No. Of Participants
Quality of Evidence (GRADE)
Summary Result, RR (95% CI)
7/1393 5/1094 5/1079 2/497 2/497
Low Low Low Low Low
0.75 (0.44–1.31) 0.78 (0.33–1.82) 1.46 (0.91–2.35) 0.77 (0.42–1.39) 0.78 (0.39–1.53)
CI = confidence interval; GRADE = Grading of Recommendations Assessment, Development and Evaluation; RR = risk ratio.
Diphenhydramine to Reduce Neuroleptic Side Effects
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Figure 3. Incidence of extrapyramidal symptoms before and after removal of an outlier study. CI = confidence interval; MH = Mantel–Haenszel. Lists of studies: Erdur, 2012 (33); Friedman, 2009 (22); Friedman, 2016 (30); Kris, 1987 (31); Roila, 1989 (36); Tsavaris, 1991 (35); Vinson, 2001 (32); Erdur, 2012 (33); Friedman, 2009 (22); Friedman, 2016 (30); Roila, 1989 (36); Tsavaris, 1991 (35); Vinson, 2001 (32).
According to the review, promethazine may reduce adverse effects associated with haloperidol. However, neuroleptics used in each arm of the included studies were not the same. Limited conclusions can be drawn from these findings. Regarding chronic care, both the guidelines of the American Psychiatric Association and the Schizophrenia Patient Outcomes Research Team recommend prophylactic administration of anticholinergic medication to prevent extrapyramidal symptoms (3,6). Cited studies involved medications with stronger anticholinergic properties than diphenhydramine (i.e., benztropine). These types of medications are not practical for emergency care because of their side effect profile (40). For acute care, diphenhydramine may be sufficient, as our study found that it is effective compared with placebo.
Limitations Three studies did not report how they evaluated extrapyramidal adverse effects and definition of these adverse effects varied across studies. The most common extrapyramidal adverse effect, akathisia, is difficult to diagnose (41). Methods to measure it are abundant and heterogeneous (42). Depending on the severity of the adverse effects encountered, studies may have underreported events. In contrast, the possible lack of blinding of participants, of personnel, or of outcome assessment may have caused an overreporting of events in the comparison group or underreporting in the treatment group, which would have overestimated the efficacy of diphenhydramine.
Table 3. Summary of Evidence of Subgroup Analyses of the Main Outcome Analysis Comparator Placebo Not placebo Dose of diphenhydramine Low dose (<25 mg) Regular dose (25 mg to 100 mg) High dose (>100 mg) Dose of metoclopramide Normal (<25 mg) High (>25 mg) CI = confidence interval.
Risk Ratio (95% CI)
I2 (%)
705 688
0.61 (0.41–0.90) 1.16 (0.26–5.16)
9 81
2 4 1
514 788 91
0.74 (0.50–1.11) 0.84 (0.22–3.25) 0.47 (0.15–1.45)
0 80 NA
4 3
913 480
0.71 (0.46–1.08) 0.91 (0.15–5.53)
31 92
No. of Studies
No. of Participants
4 3
8
Comparison groups were heterogeneous across studies and agents not labeled as effective for extrapyramidal adverse effects may still be effective. This factor may explain why diphenhydramine was effective compared with placebo and not in primary analysis. Off-label use of benzodiazepines has previously been studied and scarce data suggest that they may be effective (14,15). As such, inclusion of studies involving a benzodiazepine as the comparator may have underestimated the effectiveness of diphenhydramine, as apparently supported by the subgroup analysis dividing comparators into placebo vs. anything else (Table 3). Finally, one study implied that diphenhydramine may significantly increase neuroleptic side effects (RR 6.47; 95% CI 1.55–28.37) (31). The very low rate of side effects reported in the comparison group may be explained by the fact that the comparator in the study (lorazepam) was administered at unusually high doses (3 mg). It is unclear how neuroleptic adverse effects, especially with those with a subjective component (e.g., akathisia), were assessed in the comparison group as patients were heavily sedated. The inclusion of this study may have underestimated diphenhydramine’s true efficacy, which is consistent with the significant reduction of side effects observed in our placebo subgroup analysis. External Validity Despite maximizing sensitivity of our search strategy, we were only able to find studies involving metoclopramide and prochlorperazine. Metoclopramide and prochlorperazine are very frequently used neuroleptics to treat very common acute clinical conditions, such as nausea and migraine. This may potentially explain why they were the only neuroleptics for which we found studies on the prophylactic use of diphenhydramine against neuroleptic adverse effects in the acute care setting. Nevertheless, we believe that our conclusions are extendable to other neuroleptics. Firstly, prochlorperazine shares the same pharmacologic properties as most first-generation antipsychotics (12). Further, metoclopramide, although it has a potentially lower affinity to D2 receptors, still affects the same central dopaminergic pathways and produces the same spectrum of extrapyramidal side effects as other antipsychotic agents (10,43). Finally, both agents are known to produce frequent neuroleptic side effects (4,44,45). Clinical and Research Implications There are currently no widely approved guidelines regarding prevention of neuroleptic side effects in the acute care setting. Diphenhydramine is the most frequently prescribed treatment to counter them. Other
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treatment options exist, although they are less supported by scientific evidence (e.g., benzodiazepines) or have a riskier side effect profile (e.g., propranolol) that may make them unpractical for usage in the emergency department. From a clinical standpoint, as shown in our study, diphenhydramine represents a low-risk first-line treatment because of its safe side effect profile and because its use does not significantly increase the burden of side effects it has in common with neuroleptics (e.g., sedation). Further, diphenhydramine seems to reduce neuroleptic side effects by 39% compared with placebo. Routine prescription of diphenhydramine as first-line treatment for this indication is then probably beneficial and safe. Further high-quality studies are needed to confirm the trend observed in our review. CONCLUSIONS In this systematic review, prophylactic administration of diphenhydramine, when used in combination with prochlorperazine or metoclopramide, was not associated with a decrease in incidence of extrapyramidal symptom in primary analysis. However, we observed a significant relative risk reduction of 39% in neuroleptic adverse effects when comparing diphenhydramine with placebo. The use of diphenhydramine was not associated with any other reduction of the incidence of side effects. Overall, quality of evidence is low. Diphenhydramine may represent an effective, low-risk, and inexpensive firstline treatment option, although further high-quality studies are warranted. REFERENCES 1. Tintinalli JE, Stapczynski JS, Ma OJ, Yealy DM, Meckler GD, Cline D. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 8th edn. New York: McGraw-Hill Education; 2016. 2. Caroff SN, Hurford I, Lybrand J, Campbell EC. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial. Neurol Clin 2011;29:127–48. viii. 3. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010;36:71–93. 4. Drotts DL, Vinson DR. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med 1999;34(4 Pt 1):469–75. 5. Lucca JM, Madhan R, Parthasarathi G, Ram D. Identification and management of adverse effects of antipsychotics in a tertiary care teaching hospital. J Res Pharm Pract 2014;3(2):46–50. 6. Lehman AF, Lieberman JA, Dixon LB, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry 2004;161(2 suppl):1–56. 7. Yildiz A, Sachs GS, Turgay A. Pharmacological management of agitation in emergency settings. Emerg Med J 2003;20:339–46. 8. Iversen TSJ, Steen NE, Dieset I, et al. Side effect burden of antipsychotic drugs in real life—impact of gender and polypharmacy. Prog Neuropsychopharmacol Biol Psychiatry 2018;82:263–71. 9. Hurtado TR, Vinson DR, Vandenberg JT. ED treatment of migraine headache: factors influencing pharmacotherapeutic choices. Headache 2007;47:1134–43.
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9 30. Friedman BW, Cabral L, Adewunmi V, et al. Diphenhydramine as adjuvant therapy for acute migraine: an emergency department based randomized clinical trial. Ann Emerg Med 2016;67:32–9. 31. Kris MG, Gralla RJ, Clark RA, Tyson LB, Groshen S. Antiemetic control and prevention of side-effects of anticancer therapy with lorazepam or diphenhydramine when used in combination with metoclopramide plus dexamethasone—a double-blind, randomized trial. Cancer 1987;60:2816–22. 32. Vinson DR, Drotts DL. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med 2001;37:125–31. 33. Erdur B, Tura P, Aydin B, et al. A trial of midazolam vs diphenhydramine in prophylaxis of metoclopramide-induced akathisia. Am J Emerg Med 2012;30:84–91. 34. Parlak I, Erdur B, Parlak M, et al. Midazolam vs. diphenhydramine for the treatment of metoclopramide-induced akathisia: a randomized controlled trial. Acad Emerg Med 2007;14:715–21. 35. Tsavaris N, Zamanis N, Zinelis A, et al. Diphenhydramine for nausea and vomiting related to cancer chemotherapy with cisplatin. J Pain Symptom Manage 1991;6:461–5. 36. Roila F, Tonato M, Basurto C, et al. Protection from nausea and vomiting in cisplatin-treated patients: high-dose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: a study of the Italian Oncology Group for Clinical Research. J Clin Oncol 1989; 7:1693–700. 37. Kang TJ, Lu CW, Lin TY. Antiemetic efficacy of metoclopramide and diphenhydramine added to morphine patient-controlled analgesia. Eur J Pain 2009;13:S280–1. 38. Rathbone J, Soares-Weiser K. Anticholinergics for neurolepticinduced acute akathisia. Cochrane Database Syst Rev 2006;(4): CD003727. 39. Wilson MP, Pepper D, Currier GW, Holloman GH Jr, Feifel D. The psychopharmacology of agitation: consensus statement of the american association for emergency psychiatry project Beta psychopharmacology workgroup. West J Emerg Med 2012;13:26–34. 40. Gerretsen P, Pollock BG. Drugs with anticholinergic properties: a current perspective on use and safety. Expert Opin Drug Saf 2011;10:751–65. 41. Weiden PJ, Mann JJ, Haas G, Mattson M, Frances A. Clinical nonrecognition of neuroleptic-induced movement disorders: a cautionary study. Am J Psychiatry 1987;144:1148–53. 42. Sachdev P, Kruk J. Clinical characteristics and predisposing factors in acute drug-induced akathisia. Arch Gen Psychiatry 1994;51:963– 74. 43. Stanley M, Lautin A, Rotrosen J, Gershon S, Kleinberg D. Metoclopramide: antipsychotic efficacy of a drug lacking potency in receptor models. Psychopharmacology (Berl) 1980;71(3):219–25. 44. Schroeder JA, Wolfe WM, Thomas MH, et al. The effect of intravenous ranitidine and metoclopramide on behavior, cognitive function, and affect. Anesth Analg 1994;78:359–64. 45. Pasricha PJ, Pehlivanov N, Sugumar A, Jankovic J. Drug Insight: from disturbed motility to disordered movement—a review of the clinical benefits and medicolegal risks of metoclopramide. Nat Clin Pract Gastroenterol Hepatol 2006;3:138–48.
SUPPLEMENTARY DATA Supplementary data related to this article can be found at https://doi.org/10.1016/j.jemermed.2020.09.031.
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ARTICLE SUMMARY 1. Why is this topic important? Neuroleptics are one of the most commonly prescribed drugs in the emergency department with common and burdensome side effects. Diphenhydramine is the most commonly prescribed drug in prevention of these side effects, with controversial efficacy and safety profile. 2. What does this review attempt to show? This review seeks to assess whether diphenhydramine, the most commonly prescribed drug for prevention of neuroleptic side effects, is safe and effective in that indication. 3. What are the key findings? Diphenhydramine reduces extrapyramidal symptoms by 39% compared with placebo. Diphenhydramine is safe when prescribed for this indication. Overall quality of evidence is low. 4. How is patient care impacted? Further high-quality studies are needed to confirm the trend observed in this study. Diphenhydramine should be considered as first-line treatment for prevention of neuroleptic side effects. Clinicians may consider systemically prescribing diphenhydramine for this indication considering its safety profile.