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• Reply to: Diphenhydramine should be co-administered with intravenous prochlorperazine to prevent akathisia
  Ryan S D'Souza, Anthony Donato
  Published on: 19 April 2018
• Diphenhydramine should be co-administered with intravenous prochlorperazine to prevent akathisia
  David R Vinson, Benjamin W Friedman
  Published on: 19 April 2018

• Published on: 19 April 2018

  Reply to: Diphenhydramine should be co-administered with intravenous prochlorperazine to prevent akathisia

  • Ryan S D'Souza, Anesthesiologist Department of Anesthesiology and Perioperative Medicine, Mayo Clinic College of Medicine, Rochester, MN
  • Other Contributors:
    • Anthony Donato, Internal Medicine Physician and Professor of Medicine

  Dear Editor,
  We thank Drs. Vinson et al. for their thoughtful comments as well as their important research that was the basis for our systematic review.1 While we proposed that difference in administration time was one possible explanation for the heterogeneity that we identified, Dr. Vinson’s proposal that the between-drug differences could also explain the heterogeneity is just as plausible. Although we did not include the two trials investigating different administration times of prochlorperazine since we limited our inclusion criteria to trials that used diphenhydramine prophylaxis, we do acknowledge the importance that infusion time of prochlorperazine does not affect the incidence of akathisia given the current evidence.2 3 We completely concur with Dr. Vinson’s conclusion that the differences between prochlorperazine and metoclopramide deserve to be further explored in a randomized trial, but until then, his suggestions of how to proceed appear consistent with our study’s findings.

  References
  1. D'Souza RS, Mercogliano C, Ojukwu E, et al. Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis. Emerg Med J 2018.
  2. Collins RW, Jones JB, Walthall JD, et al. Intravenous administration of prochlorperazine by 15-minute infusion versus 2-minute bolus does not affect the incidence of akathisia: a prospective, randomized, contro...

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  Dear Editor,
  We thank Drs. Vinson et al. for their thoughtful comments as well as their important research that was the basis for our systematic review.1 While we proposed that difference in administration time was one possible explanation for the heterogeneity that we identified, Dr. Vinson’s proposal that the between-drug differences could also explain the heterogeneity is just as plausible. Although we did not include the two trials investigating different administration times of prochlorperazine since we limited our inclusion criteria to trials that used diphenhydramine prophylaxis, we do acknowledge the importance that infusion time of prochlorperazine does not affect the incidence of akathisia given the current evidence.2 3 We completely concur with Dr. Vinson’s conclusion that the differences between prochlorperazine and metoclopramide deserve to be further explored in a randomized trial, but until then, his suggestions of how to proceed appear consistent with our study’s findings.

  References
  1. D'Souza RS, Mercogliano C, Ojukwu E, et al. Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis. Emerg Med J 2018.
  2. Collins RW, Jones JB, Walthall JD, et al. Intravenous administration of prochlorperazine by 15-minute infusion versus 2-minute bolus does not affect the incidence of akathisia: a prospective, randomized, controlled trial. Ann Emerg Med 2001;38(5):491-6.
  3. Vinson DR, Migala AF, Quesenberry CP. Slow infusion for the prevention of akathisia induced by prochlorperazine: a randomized controlled trial. J Emerg Med 2001;20(2):113-9.

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  Conflict of Interest:
  None declared.

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• Published on: 19 April 2018

  Diphenhydramine should be co-administered with intravenous prochlorperazine to prevent akathisia

  • David R Vinson, Emergency physician and clinical researcher The Permanente Medical Group and the KP CREST Network, Oakland, California, USA
  • Other Contributors:
    • Benjamin W Friedman, Emergency physician and clinical researcher

  Dear Editor,

  We commend Dr D’Souza et al for their systematic review of the effects of prophylactic diphenhydramine in the reduction of akathisia induced by intravenous dopamine D2 antagonist antiemetics.¹ Akathisia is a dysphoric feeling of restlessness that ranges from mild to severe, the more severe expressions of which can be quite distressing to patients.² Attention to its prevention is welcome. We took particular interest in the systematic review because we led three of the four studies included in the meta-analysis.^2-4

  The authors conclude that adjunct diphenhydramine reduces akathisia when dopamine D2 antagonist antiemetics are administered over 2 minutes, but diphenhydramine fails to augment the reduction in akathisia achieved by simply slowing the antiemetic infusion to 15 minutes. They report moderately high heterogeneity among the four included studies (I² =43%).⁵ This reveals an inconsistency in results between studies that precludes a one-size-fits-all recommendation on the use of prophylactic diphenhydramine. Such an elevated I² requires explanation. The authors attribute this heterogeneity to rates of infusion and determine that a 15-minute infusion is less likely to cause akathisia.

  But another explanation for the heterogeneity is at hand that the authors did not explore: prochlorperazine and metoclopramide behave differently when it comes to akathisia preventio...

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  Dear Editor,

  We commend Dr D’Souza et al for their systematic review of the effects of prophylactic diphenhydramine in the reduction of akathisia induced by intravenous dopamine D2 antagonist antiemetics.¹ Akathisia is a dysphoric feeling of restlessness that ranges from mild to severe, the more severe expressions of which can be quite distressing to patients.² Attention to its prevention is welcome. We took particular interest in the systematic review because we led three of the four studies included in the meta-analysis.^2-4

  The authors conclude that adjunct diphenhydramine reduces akathisia when dopamine D2 antagonist antiemetics are administered over 2 minutes, but diphenhydramine fails to augment the reduction in akathisia achieved by simply slowing the antiemetic infusion to 15 minutes. They report moderately high heterogeneity among the four included studies (I² =43%).⁵ This reveals an inconsistency in results between studies that precludes a one-size-fits-all recommendation on the use of prophylactic diphenhydramine. Such an elevated I² requires explanation. The authors attribute this heterogeneity to rates of infusion and determine that a 15-minute infusion is less likely to cause akathisia.

  But another explanation for the heterogeneity is at hand that the authors did not explore: prochlorperazine and metoclopramide behave differently when it comes to akathisia prevention. Their systematic review assumes a drug-class consistency that is absent in the clinical trials. The meta-analysis includes three studies of metoclopramide and one of prochlorperazine.¹ This combination at first appears reasonable: both medications are dopamine D2 antagonists and both are effective in the treatment of migraine and vomiting. However, these two drugs may not respond the same way to interventions aimed at akathisia prevention.

  Slower infusion rates of metoclopramide are associated with a reduction in akathisia, as multiple studies have shown.^2,6,7 The 15-minute infusion of metoclopramide is sufficiently effective to render adjunct diphenhydramine redundant: “Routine prophylaxis with diphenhydramine to prevent akathisia is unwarranted when intravenous metoclopramide is administered over 15 minutes.”² 

  One might think that slowing the infusion rate of prochlorperazine would have a similar akathisia-reducing effect. The authors mention that “some studies have shown a lower [extra-pyramidal symptom] incidence with [slower] infusion dosing,”¹ then reference two studies.^6,7 Interestingly, both references are studies of metoclopramide, not prochlorperazine. There are randomized trials of prochlorperazine that compare slow infusion (15 minutes) with more rapid administration (2 minutes), but these were not mentioned in the systematic review.^8,9 These studies found that slow infusion of prochlorperazine failed to reduce akathisia. Such results undermine the conclusion of D’Souza et al that slow infusion rates reduce akathisia for all dopamine D2 antagonists across the board. Though a slower infusion rate seems an ineffective method to reduce prochlorperazine-induced akathisia, prophylactic intravenous diphenhydramine is effective.¹⁰

  Until further studies challenge these unexpected differences between prochlorperazine and metoclopramide, we advocate the following: when administering intravenous prochlorperazine, co-administer diphenhydramine to reduce akathisia; slow infusion is not beneficial. When administering intravenous metoclopramide, infuse it over 15 minutes; adjunct diphenhydramine is not necessary. This approach is in sync with the evidence to date and avoids the drug-class assumption that besets the otherwise helpful review by D’Souza et al.¹  

  References

  1. D'Souza RS, Mercogliano C, Ojukwu E, et al. Effects of prophylactic anticholinergic medications to decrease extrapyramidal side effects in patients taking acute antiemetic drugs: a systematic review and meta-analysis. Emerg Med J 2018 Feb 3 [Epub ahead of print].

  2. 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.

  3. 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.

  4. Vinson DR, Drotts DL. Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med 2001;37:125–31.

  5. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.

  6. Cavero-Redondo I, Álvarez-Bueno C, Pozuelo-Carrascosa DP, et al. Risk of extrapyramidal side effects comparing continuous vs. bolus intravenous metoclopramide administration: a systematic review and meta-analysis of randomised controlled trials. J Clin Nurs 2015;24:3638–46.

  7. Regan LA, Hoffman RS, Nelson LS. Slower infusion of metoclopramide decreases the rate of akathisia. Am J Emerg Med 2009;27:475–80.

  8. Collins RW, Jones JB, Walthall JD, et al. Intravenous administration of prochlorperazine by 15-minute infusion versus 2-minute bolus does not affect the incidence of akathisia: a prospective, randomized, controlled trial. Ann Emerg Med 2001;38:491-6.

  9. Vinson DR, Migala AF, Quesenberry CP Jr. Slow infusion for the prevention of akathisia induced by prochlorperazine: a randomized controlled trial. J Emerg Med 2001;20:113-9.

  10. Drotts DL, Vinson DR. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med 1999;34:469-475.  

   

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  Conflict of Interest:
  None declared.

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