Clinical Question:

Does giving Benadryl prophylactically prevent metoclopramide induced akathisia?

Bottom Line:

1. You do not need to give diphenhydramine prophylactically with 10 mg of metoclopramide as it does not prevent akathisias.
2. You can consider giving diphenhydramine prophylactically with 20 mg of metoclopramide as it prevents subjective symptoms of akathisia.  

Background:

Akathisia is motor disorder characterized by restlessness with a desire to move, a side effect of metoclopramide. It is thought that metoclopramide blocks the dopamine receptors which have an inhibitory effect in the CNS, thus causing an imbalance between the excitatory acetylcholine and dopamine causing symptoms of akathisia. It is believed that by blocking acetylcholine receptors with diphenhydramine, this balance can be restored and reducing akathisia.

Study 1: Friedman, B. W., Bender, B., Davitt, M., Solorzano, C., Paternoster, J., Esses, D., ... & Gallagher, E. J. (2009). A randomized trial of diphenhydramine as prophylaxis against metoclopramide-induced akathisia in nauseated emergency department patients. Annals of emergency medicine, 53(3), 379-385.

This study was a randomized, double blind, factorial design study to determine whether prophylactic administration of diphenhydramine can prevent metoclopramide induced akathisia and whether metoclopramide induced akathisia is dose dependent. Patients were eligible for the study if they were between 21-65-years old and came to the ED with a complaint of nausea. Patients were excluded if they had extrapyramidal illnesses, movement disorders, tardive dyskinesia, restless leg syndrome, pregnant, allergic, use of antiemetic, histamine or antipsychotic within the past 3 days. 289 patients were placed into one of the following four groups: metoclopramide 10 mg IV with placebo, metoclopramide 10 mg IV with diphenhydramine 25 mg IV, metoclopramide 20 mg IV with placebo or metoclopramide 20 mg IV with diphenhydramine 25 mg IV. The primary outcome was the development of akathisia which was assessed using the Short Akathisia Instrument. Patients taking diphenhydramine were equally likely to develop akathisia as those not taking it (OR 1.0; 95% CI 0.5-2). Patient who were taking 20 mg of metoclopramide had higher odds of developing akathisia than those taking 10 mg, but it was not statistically significant (OR 1.7; 95% CI 0.8-3.6).

Study 2: Erdur, B., Tura, P., Aydin, B., Ozen, M., Ergin, A., Parlak, I., & Kabay, B. (2012). A trial of midazolam vs diphenhydramine in prophylaxis of metoclopramide-induced akathisia. The American journal of emergency medicine, 30(1), 84-91.

This study is a randomized, double blind, placebo-controlled study conducted in an emergency department in Turkey. The study aimed to evaluate the utility of prophylactic midazolam and diphenhydramine for prevention of metoclopramide-induced akathisia. Patients were eligible for the study if they were between 18-65 and had a complaint of nausea or a headache. Patients were excluded if they had a preexisting motor disorder, restless leg syndrome or allergic to anticholinergic among others. 225 patients were randomized into three groups – metoclopramide 10 mg with midazolam 1.5 mg, metoclopramide 10 mg with 20 mg diphenhydramine and metoclopramide 10 mg with placebo. Akathisia was assessed using the Prince Henry Hospital akathisia rating scale. Patients taking midazolam were less likely to develop akathisia compared to placebo (P=0.004), but patients taking diphenhydramine were not less likely to develop akathisia compared to placebo (P=0.20)

Limitations/Strength:

Study #1: This study had a specific clinical question, which was adequately approached by their study design. One of the limitations was that patients were only followed for 60 minutes after administration. It is not known whether patients had any late development of extrapyramidal effects like dystonic reactions or tardive dyskinesia. The dose of diphenhydramine was 25 mg though doses of 25-50 mg are usually used in the ED. An arm with 50 mg may have been useful. Akathisia is also a dynamic process and the measurement at 30 minutes and 60 minutes may not have been appropriate as shown by the study that some patients received rescue medication before 30 minutes for symptoms. 

Study #2: This study had an adequate sample size and used the extended Prince Henry Hospital akathisia rating scale. However, similar to the previous study, patients were only followed for 60 minutes after administration and there was not any post discharge follow up. Akathisia can develop any time up to 48 hours post administration so it is unknown whether there were late manifestations. The dose of diphenhydramine was 20 mg, which is less than the recommended 25-50 mg dose. According to the authors, this was due to the formulation of medication available in Turkey. 

Conclusion: 

Both studies claim that giving diphenhydramine prophylactically does not decrease the risk of metoclopramide induced akathisia compared to placebo. Based on these studies, we do not need to prophylactically give diphenhydramine when the dose of metoclopramide is 10 mg. However, we need more studies where diphenhydramine is given at doses of 50 mg with 20 mg metoclopramide to see if it is effective in preventing akathisias at those higher doses. This study also raises the possibility that we should consider giving midazolam instead of diphenhydramine if concerned about akathisias. However, more studies are needed to explore this. Furthermore, these studies should explore whether giving midazolam or diphenhydramine increased time to discharge.