Pain Profiles: Effects of anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetics

Written by: David Cisewski, MD (@PainProfiles – EM Resident Physician, Icahn School of Medicine at Mount Sinai) // Edited by: Manpreet Singh, MD (@MPrizzleER), Alex Koyfman, MD (@EMHighAK), and Brit Long, MD (@long_brit)

Today we bring a practice changer in the Pain Profiles series by Dr. David Cisewski. This post looks at using prophylactic anticholinergics in patients receiving antiemetics to reduce extrapyramidal side effects. We follow the normal post with highlights from Twitter and expert commentary from Sergey Motov.

Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis.

D’Souza, 2018


Diphenhydramine reduces extrapyramidal side effects (EPS) when antidopaminergics (metoclopramide and prochlorperazine) are given rapidly (over 2 min bolus) but offers no benefit over placebo when given slowly (over 15 min infusion); the fewest overall EPS are seen when antiemetic given as a 15 min infusion (with or without diphenhydramine).

Study Characteristics

Clinical question: Are prophylactic anticholinergic medications effective in decreasing extrapyramidal side effects (EPS) from antidopaminergics (D2-R antagonists)?

Design: Systematic review of all randomized control trials through March 2017 of patients receiving dopamine D2 antagonist therapy for acute migraine along with an anticholinergic or placebo.

Study selection: Of 37 full-text articles that were assessed for eligibility, only 4 were included in the analysis.

Sample population: 737 patients from 3 different locations, 76% of which were female; patients received either diphenhydramine (n=367) or placebo (n=370).

Outcome of Interest: Incidence of EPS in each group.

Results: Overall EPS occurred in 11% of those receiving diphenhydramine vs 15% in the placebo group (95% OR 0.7, 0.4-1.2) demonstrating no statistically significant difference.  In the first section of the subgroup analysis (2-min antidopaminergic IV bolus), 14% of the diphenhydramine vs 27% of the placebo group resulted in EPS, favoring diphenhydramine administration (95% OR 0.4, 0.2-0.8).  In the second section of the subgroup analysis, approximately 10% of both the diphenhydramine and placebo group of the 15-min infusion resulted in side effects, suggesting diphenhydramine offered no benefit when antidopaminergic was given over an extended infusion.

Conclusion: Although diphenhydramine can offer benefit when giving antidopaminergics over a short 2-min bolus, the optimal side effect profile is seen in the 15-min slow-infusion in which diphenhydramine offered no benefit over placebo.

Quality Assessment

Though the sample data for these studies were all from ED-based RCT’s conducted over the last 18 years, only 4 studies were chosen for this meta-analysis.  Of the total population, over 50% of the patients came from two studies from the same author in Bronx, NY (Friedman, et al).  These patients were predominantly female, though one could argue this is representative of the population presenting to the ED with similar complaints.

The Upshot

Extrapyramidal side effects associated with anti-dopaminergics are varying in degree and severity, ranging anywhere from 4-25% of metoclopramide users (Saadah, 1992), to 25-67% prochlorperazine users (Taylor, 1987).  These symptoms can include dystonia, akathisia, cramps, torticollis, and oculogyric crisis.  The concern for these symptoms is often weighed against the increased drowsiness and sedation associated with anticholinergics (diphenhydramine).  To date, no universal consensus exists on whether IV, oral, or no diphenhydramine is the solution to EPS, though this meta-analysis provides argument that giving antidopaminergics (prochlorperazine or metoclopramide) as a slow 15-min infusion would result in no need for added diphenhydramine.

Several weeks ago on Pain Profiles, we discussed the Zitek, 2018 study demonstrating that combination of prochlorperazine/diphenhydramine had superior pain relief for headaches in comparison to ketamine/ondansetron (link).   In the always illuminating Twitter discussion that followed, many excellent points were made by leaders in the EM field regarding the pros and cons of  IV diphenhydramine administration.

Rick Pescatore, MD (@Rick_Pescatore) was quick to point out that the abuse of IV diphenhydramine in the ED (typically associated with drug seekers) should serve as a caution to its use, even for antidopaminergic EPS.

Michelle Lin, MD (@M_Lin) offered her insight by referencing this discussed study by D’Souza, et al and the potential misinterpretation it may have had in lumping data on metoclopramide and prochlorperazine together in the analysis.  She indicates that although the conclusion that 15 min slow-infusion of metoclopramide may have the same incidence of EPS with or without diphenhydramine may be correct, the same conclusion is not so easily made with prochlorperazine.

Michelle Lin also pointed  out her own personal approach to using IV diphenhydramine with prochlorperazine  based on the results of one of the four studies included in the meta-analysis (Vinson, 2001).

Dr. Lin references a ‘must-read’ article for anyone who wants to wrap their head around this debate (summary: 10 mg IV prochlorperazine is superior to 10 mg IV metoclopramide for headache relief. Prochlorperazine does benefit from IV diphenhydramine to offset EPS, which can occur up to 48 hours post-administration).

And finally, Rick Pescatore seconds the all-important point made by Dr. Lin…. We need more data!

A large RCT could lay this argument to rest. In the meantime, we can look to our expert discussion from the likes of Lin, Pescatore, D’Souza, Vinson, Motov, et al for their fantastic contributions and pearls shared throughout this FOAM discussion! [I can’t believe we get this knowledge for free!!]

Sergey Motov, MD (@painfreeED) – Pain Specialist Commentary 

To push anti-dopaminergic medication with prophylactic anticholinergics or not?

This systematic review and meta-analysis by D’Souza et al was carried out to evaluate the effects of prophylactic administration of anticholinergics to decrease extrapyramidal side effects (EPS) of anti-dopaminergic medications. The results show reduced rates of EPS with such prophylaxis when anti-dopaminergic agents (metoclopramide or prochlorperazine) were given as an intravenous push dose (over 2 min) in comparison to a slower 15 min infusion. In addition, the strategy of utilizing the 15 min infusion by itself resulted in significantly lower rates of EPS when compared to a two-minute intravenous push (9.8% vs 27.2%). It is a well-conducted meta-analysis despite a relatively small sample size (only four studies included) and high heterogeneity among the included studies.

I was (pleasantly) surprised to find the rates of EPS in the 15 min infusion subgroups for both diphenhydramine and placebo to harbor around 10% as another RCT by Friedman et al (not included in this systematic review) which directly compared prochlorperazine (10 mg IV over 15 min) to metoclopramide (20 mg over 15 min) combined with 25 mg of IV diphenhydramine for both groups, demonstrated EPS rates of 46% for prochlorperazine and 32% for metoclopramide.

In summary, this research paper reinforces the benefits of utilizing the short infusion (over 15 min) of anti-dopaminergic medications to offset very unpleasant EPS with an additional potential to decrease and even avoid co-administration of anticholinergic medications such as diphenhydramine which possess the risk of worsening sedation. Interestingly enough, after reviewing this paper I started to wonder if extending the infusion to 30 or 60 minutes of antidopaminergics would decrease the rates of EPS even further, and if utilizing the infusion of diphenhydramine (15 or 30 minutes) instead of intravenous push would result in lesser degree of sedation?

But for now: Do not push antidopaminergics, do the drip.

Ref: Friedman, 2008 – A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine.

A special thanks to @Rick_Pescatore, @M_Lin, @painfreeED, @EM_StevenMcGuire, for making this is a particularly insightful discussion!

Further Reading:


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