Abstract

Dopamine D₂ antagonists are known to induce akathisia, the emergency management of which remains undetermined. We sought to evaluate the effectiveness of diphenhydramine in the treatment of akathisia induced by 10 mg intravenous prochlorperazine. This prospective, open-label, uncontrolled study evaluated a cohort of akathisic adult Emergency Department patients who were participating in a series of three studies of acute akathisia at an academic medical center. Each subject received intravenous diphenhydramine, with akathisia measurements (graded from 0–17 points) performed just before and 30 min after infusion. Mean scores were calculated using descriptive statistical analyses. The effect of treatment was evaluated using the paired t-test. For the 87 akathisic patients, the mean score before treatment was 9.8 ± 3.6, and after treatment was 1.2 ± 2.6, a mean reduction of 8.5 ± 3.8 (95% confidence interval [CI], 7.8 to 9.4; p < 0.0001). In conclusion, intravenous diphenhydramine rapidly reduces signs and symptoms of acute akathisia induced by prochlorperazine.

Author Keywords: Author Keywords: akathisia; diphenhydramine; prochlorperazine; antiemetics

Article Outline

• Introduction

• Materials and methods

• Results

• Discussion

• Acknowledgements

• References

Introduction

Prochlorperazine was first introduced as an antiemetic nearly 50 years ago and its efficacy in this role has been repeatedly confirmed [1 and 2]. In the last decade, it has assumed a prominent role in the abortive treatment of benign headache in both adults and children [3, 4, 5 and 6]. Its principle side effects are sedation and the restless compulsion to move known as akathisia. Akathisic patients complain of feeling jittery, may literally be unable to sit or stand still, and have a dysphoric feeling of inner tension [7 and 8]. Akathisia occurs in 20% to 40% of patients within 1 h after a single 10-mg dose of intravenous prochlorperazine [9, 10, 11, 12, 13 and 14]. The natural course and duration of akathisia caused by a single dose of a parenteral drug is poorly described. Acute drug-induced akathisia has been shown to be distressing to patients and disruptive to their medical care, leading to patient dissatisfaction and premature Emergency Department (ED) discharge against medical advice [9]. Slowing the rate of drug infusion has failed to prevent akathisia [11 and 12]. However, co-administration of adjunct diphenhydramine reduces the incidence by 60%, but this practice has not been widely adopted [13, 14 and 15]. Given that akathisia is a common side effect of dopamine D₂ antagonists that is disturbing and not altogether preventable, an effective treatment would be welcome. Diphenhydramine has been employed for years in this capacity, but few data exist regarding its efficacy [13].

Three prior studies were undertaken to determine the incidence of akathisia induced by prochlorperazine and to evaluate methods of prevention [9, 11 and 13]. Throughout these studies, ED patients who developed acute akathisia were administered intravenous (i.v.) diphenhydramine. This prospective, open-label descriptive analysis assesses that cohort of akathisic patients drawn from the three serial studies. We describe the effectiveness of i.v. diphenhydramine in the treatment of acute drug-induced akathisia.

Materials and methods

This prospective, open-label, uncontrolled cohort study was performed in the ED of a 400-bed, academic, tertiary-care U.S. military hospital with an annual census of 65,000 emergency patient visits. Evaluating the efficacy of diphenhydramine treatment was a secondary objective of three serial ED studies of the incidence and prevention of prochlorperazine-induced akathisia undertaken from 1997 to 1999 (Table 1; references [9, 11 and 13]. Combined, these primary studies included 360 ED patients between 16 and 65 years of age who received 10 mg of i.v. prochlorperazine in the treatment of either nausea or vomiting, or moderate-to-severe headache. Patients who appeared eligible were specifically queried about exclusion criteria. Patients were excluded from the series if they had no designated driver; were known to be pregnant or lactating; had a pre-existing motor disorder; had a contraindication to anticholinergic medication; within 3 days of study entry had taken an antiemetic, antihistamine, antipsychotic, antispasmotic, alpha-blocker, or Ca⁺⁺-channel blocker; or within 2 weeks of study entry had taken an antidepressant, barbiturate, benzodiazepine, other sedative/hypnotic, opioid, lithium, or illicit sympathomimetic agent. All subjects who met the entry criteria provided written, informed consent before enrollment. The institutional review board approved each study and consent form.

Table 1. Characteristics of Serial ED Akathisia Studies

i.v. = Intravenous.
 

Throughout this series, participants who met diagnostic criteria for acute akathisia 1 h after prochlorperazine infusion were considered for diphenhydramine treatment. This secondary analysis assesses that cohort of akathisic patients who were treated with i.v. diphenhydramine (25 to 50 mg, dosed at the investigator's discretion). Our diagnostic criteria (Table 2), explicitly derived from the Prince Henry Hospital Rating Scale of Akathisia, required a pre-determined minimal increase in both subjective symptoms and objective signs of restlessness [9 and 16]. The severity of drug-induced akathisia was graded using a standard 17-point scale ( Table 2), the details of which have been previously described [9, 11 and 13]. For all subjects, a data sheet was prospectively completed that included patient demographics, the complaint for which prochlorperazine was indicated, and serial assessments of akathisia just before the infusion of diphenhydramine and 30 min thereafter. Investigators noted any dystonic reactions, ataxia, severe dizziness, syncope, or hallucinations requiring interruption of the protocol or additional intervention. The degree of sedation in the diphenhydramine-treated cohort was not measured. Delayed symptoms of akathisia 48 h after prochlorperazine administration were measured in a subgroup of patients enrolled in Study I ( Table 1; reference [11], some of whom were included in this present study.

Table 2. Acute Drug-Induced Akathisia Diagnostic* and Severity Scale †

Continuous variables are presented as means with standard deviation. Categorical data are presented as percent frequency of occurrence. The effect of treatment was evaluated using the paired t-test. Exact confidence intervals (CIs) were calculated with binomial distributions. Analyses were performed using SAS statistical software (SAS Institute Inc., Cary, NC).

Results

Of the 360 prochlorperazine recipients enrolled in the primary series, 118 met formal diagnostic criteria for akathisia and 102 of those received treatment with i.v. diphenhydramine (Table 1). Sixteen akathisic patients did not receive parenteral therapy for the following reasons: patient refusal of akathisia treatment (6), leaving against medical advice before treatment (4), symptoms thought by the provider to be mild enough not to warrant treatment (4), oral diphenhydramine administration (2). Of the 102 treated patients, 15 were excluded from analysis due to incomplete data collection (8), prior receipt of prophylactic diphenhydramine (4), and post-akathisia receipt of confounding medication (i.e., benzodiazepines) (3). The mean age of the 87 remaining analyzable subjects was 28.3 ± 8.9 years (range: 17–63 years). Fifty-five (63%) were female and 46 (53%) received prochlorperazine principally in the treatment of headache.

The mean akathisia score before diphenhydramine was 9.8 ± 3.6 and after diphenhydramine was 1.2 ± 2.6 (Figure 1). The mean reduction induced by diphenhydramine was 8.5 ± 3.8 (95% CI, 7.8 to 9.4; p < 0.0001), an 87% reduction in the akathisia score. Only two patients failed to experience any improvement with diphenhydramine, one of whom actually worsened. These patients with diphenhydramine-refractory akathisia were treated with a parenteral benzodiazepine (lorazapam) with modest benefit. Throughout the study, no adverse event occurred that required interruption of the study protocol or medical intervention.

(4K)

Figure 1. Box plot of akathisia scores before and after treatment with i.v. diphenhydramine.

The majority of treated subjects (83 of 87; 95%) received 50 mg of diphenhydramine. The four patients who received the 25-mg dose had a notable reduction in their akathisia scores: from 15 to 8, from 4 to 1, and from 8 to 0 (2 patients), respectively. As only four participants received the lower dose, a meaningful statistical comparison between the two groups cannot be made.

The incidence of recurrent symptoms of akathisia post-treatment was measured only in a small sub-group of participants. Only the 100 patients from Study I were given a mail-in questionnaire assessing the development of restless symptoms up to 48 h after ED discharge [9]. Fifty-six of these did not develop akathisia in the ED. Of the 44 akathisic patients, only 39 were treated with diphenhydramine. Fourteen of these diphenhydramine recipients were eligible for analysis of their follow-up assessment as they experienced a complete resolution of akathisia in the ED, did not take any confounding medications post-discharge, and returned their questionnaire. Eleven (79%) of these 14 patients denied further restlessness; three (21%) reported recurrence of self-limited, mild restlessness approximately 3–8 h after receiving i.v. diphenhydramine. The subjective report of restless symptoms does not necessarily equate with the diagnosis of akathisia, as diagnostic criteria require the combination of both symptoms and signs.

Discussion

This cohort study demonstrates that parenteral diphenhydramine is associated with a rapid improvement of the signs and symptoms of akathisia induced by prochlorperazine in a majority of adult Emergency Department patients. The resolution of akathisic symptoms after diphenhydramine seems long lasting in the majority of patients.

The following descriptions illustrate the impact of diphenhydramine in reducing the mean akathisia score from 9.7 to 1.2. Patients with an akathisia score of approximately 10 complain most of the time of a moderate dysphoric urge to move that makes them unable to lie or sit still on the bed. They appear obviously restless, spending about 50% of their time shifting their bodies around and moving their legs in a semi-purposeful or purposeless way. If upright, they are unable to stand still for any length of time, preferring to walk around the ED. But unlike those with akathisia of major severity, patients with moderate akathisia usually do not elope from the ED in a restless flight. On the other hand, patients with an akathisia score of approximately 1 would not appear to an observer to be objectively akathisic. They would feel mildly restless only some of time, often failing to volunteer their symptoms unless asked.

Most other studies of the treatment of drug-induced akathisia have assessed the effectiveness of prolonged orally administered treatments among akathisia patients on chronic antipsychotics. In such a setting, beta-adrenergic receptor antagonists, anticholinergic medications, and benzodiazepines have all shown some benefit, though the data are inconsistent [17 and 18]. In the very few studies that have assessed the efficacy of i.v. treatment, anticholinergics seem superior to the other two drug classes. In a double-blind, single-dose, crossover study comparing i.v. propanolol (1 mg), i.v. benztropine (2 mg), and placebo, the anticholinergic improved subjective and objective measures, whereas the beta-blocker had no effect [19]. Similarly, i.v. diphenhydramine was associated with greater improvement in symptoms of akathisia when compared with i.v. diazepam [20]. It is proposed that anticholinergics are effective in the treatment of neuroleptic-induced akathisia by restoring the balance in central dopaminergic and cholinergic activity [21]. Accordingly, i.v. diphenhydramine also should function in the treatment of akathisia induced by other dopamine antagonists, for example, metoclopramide and droperidol, though this has not been studied [22].

Diphenhydramine has the advantages of being readily available in U.S. EDs, is relatively inexpensive ($0.79 per 50 mg dose of injectable drug during the series), and has a good safety profile. The downside to its use is the potential for anticholinergic symptoms, including cognitive decline, especially among the elderly [23]. Sedation also is a well-documented side effect [24 and 25]. Though we did not measure sedation in the treatment arm of our studies, when evaluating diphenhydramine for the prevention of akathisia (Study III, Table 1), we noted that the addition of adjunct diphenhydramine to prochlorperazine significantly increased sedation [13]. The decision to use diphenhydramine to prevent or treat acute drug-induced akathisia will depend on a number of factors [13]. A high incidence of akathisia and the selective desirability of somnolence support the use of diphenhydramine as a prophylactic agent co-administered with a dopamine antagonist. For example, an ED migraineur who will be treated with a high-dose dopamine antagonist and who intends to go home with a driver upon discharge and sleep would be a good candidate for prophylactic diphenhydramine. Yet, when using a drug or a dose with a lower incidence of akathisia in a patient in whom anticholinergic side effects should be avoided, one may consider foregoing adjunctive diphenhydramine and reserving it as a therapeutic agent as needed [26]. Incidentally, there were four patients with prochlorperazine-induced akathisia excluded from this study because they had received diphenhydramine prophylaxis (50 mg). All were treated with additional diphenhydramine (50 mg) and responded favorably without adverse effects.

The occasional recurrence of akathisic symptoms among patients whose akathisia had completely resolved in the ED suggests that the akathisia effect of prochlorperazine may at times have a longer duration than the treatment effect of diphenhydramine. This finding, however, is far from conclusive given the small subgroup of patients. Yet such an observation is consistent with the marked inter-individual pharmacokinetics of i.v. prochlorperazine [27]. In light of this, it may be warranted to discharge post-akathisic patients with instructions to take supplemental oral diphenhydramine as needed for recurrence of restlessness, though such a practice has yet to be studied.

The impediment to the treatment of acute drug-induced akathisia in Emergency Medicine will not be the lack of an effective agent. Treatment will be jeopardized by the lack of akathisia detection. Akathisic patients may not associate their symptoms of restlessness with the drug that caused it, nor may they realize an effective treatment is available [7]. Motivated by their compulsion to move, they may simply request expeditious discharge from the ED [9]. The physician ironically may interpret this as a sign of patient satisfaction and completion of care, unaware that neither impression is accurate. Unless physicians routinely look for signs and ask about symptoms of akathisia in patients to whom they have administered akathisia-inducing drugs, the disorder may go undetected, and hence untreated.

This study has a number of limitations. That our investigators were un-blinded may have biased our observations in favor of diphenhydramine's effectiveness. Also, the additional sedation caused by diphenhydramine was not measured in the treatment arm. Our prior work, however, demonstrates that adjuvant diphenhydramine increases sedation over and above that caused by prochlorperazine alone [13]. Lastly, the lack of a placebo-control group deprives us of an understanding of the short-term natural history of drug-induced akathisia. As such, we cannot distinguish between the natural time course of akathisia resolution and the effect of the diphenhydramine treatment. The restlessness caused from a single-dose of i.v. prochlorperazine is known to be self-resolving, "usually" over the course of several hours, though studies have been limited in size [27]. Given the rapid decrement we observed in akathisia after diphenhydramine infusion (within 30 min), diphenhydramine seems to hasten its resolution, a welcome effect given the dysphoria that may be associated with akathisia.

In sum, this prospective open-label cohort study demonstrates that intravenous diphenhydramine rapidly reduces the signs and symptoms of akathisia induced by prochlorperazine. Treatment effect may wane in some patients, suggesting a role for supplemental outpatient diphenhydramine as needed.

Acknowledgements

I am grateful to Charlie P. Quesenberry Jr., PhD, Biostatistician, and Ai-lin Tsai, Consulting Data Analyst, for their generous assistance with the statistical analyses.

References

1. G. Smithy and F. Homburger, Prochlorperazine for the treatment of nausea and vomiting in patients with advanced cancer and other chronic diseases. N Engl J Med 256 (1957), pp. 27–28.

2. A.A. Ernst, S.J. Weiss, S. Park, K.M. Takakuwa and D.B. Diercks, Prochlorperazine versus promethazine for uncomplicated nausea and vomiting in the emergency department: a randomized, double-blind clinical trial. Ann Emerg Med 36 (2000), pp. 89–94. Abstract | Abstract + References | PDF (36 K)

3. D.R. Vinson, Treatment patterns of isolated benign headache in US emergency departments. Ann Emerg Med 39 (2002), pp. 215–222. Abstract | PDF (84 K)

4. M.B. Seim, J.A. March and K.A. Dunn, Intravenous ketorolac vs intravenous prochlorperazine for the treatment of migraine headaches. Acad Emerg Med 5 (1998), pp. 573–576.

5. M. Coppola, D.M. Yealy and R.A. Leibold, Randomized, placebo-controlled evaluation of prochorperazine versus metoclopramide for emergency department treatment of migraine headache. Ann Emerg Med 26 (1995), pp. 541–546.

6. M.A. Kabbouche, A.B. Vockell, S.L. LeCates, S.W. Powers and A.D. Hershey, Tolerability and effectiveness of prochlorperazine for intractable migraine in children. Pediatrics 107 (2001), p. e62.

7. A. Bakheit, The syndrome of motor restlessness—a treatable but unrecognized disorder. Postgrad Med J 73 (1997), pp. 529–530.

8. W.S.D. Chung and H.F.K. Chiu, Drug-induced akathisia revisited. Br J Clin Pract 50 (1996), pp. 270–278.

9. D.L. Drotts and D.R. Vinson, Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med 34 (1999), pp. 469–475.

10. D.R. Vinson and D.L. Drotts, In reply [to akathisia and prochlorperazine] . Ann Emerg Med 36 (2000), pp. 170–171.

11. D.R. Vinson, A.F. Migala and C.P. Quesenberry, Jr, Slow infusion for the reduction of akathisia induced by prochlorperazine: a randomized controlled trial. J Emerg Med 20 (2001), pp. 113–119. Abstract | Full Text + Links | PDF (424 K)

12. R.W. Collins, J.B. Jones, J.D. Walthall 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 38 (2001), pp. 491–496. Abstract | PDF (80 K)

13. D.R. Vinson and D.L. Drotts, Diphenhydramine for the prevention of akathisia induced by prochlorperazine: a randomized, controlled trial. Ann Emerg Med 37 (2001), pp. 125–131. Abstract | PDF (80 K)

14. D.R. Vinson, Akathisia: problematic but preventable. Ann Emerg Med 39 (2002), p. 576.

15. D.R. Vinson, T.R. Hurtado, L. Banwert and J.T. Vandenberg, Variations among emergency departments in the treatment of benign headache. Ann Emerg Med 41 (2003), pp. 90–97. Abstract | PDF (75 K)

16. P. Sachdev, A rating scale for acute drug-induced akathisia: development, reliability, and validity. Biol Psychiatry 35 (1994), pp. 263–271. Abstract | Abstract + References | PDF (1117 K)

17. C.H. Miller and W.W. Fleischhacker, Managing antipsychotic-induced acute and chronic akathisia. Drug Saf 22 (2000), pp. 73–81.

18. L.C. Holloman and S.R. Marder, Management of acute extrapyramidal effects induced by antipsychotic drugs. Am J Health Syst Pharm 54 (1997), pp. 2461–2477.

19. P. Sachdev and C. Loneragan, Intravenous benztropine and propanolol challenges in acute neuroleptic-induced akathisia. Clin Neuropharmacol 16 (1993), pp. 324–331.

20. D. Gagrat, J. Hamilton and R.H. Belmaker, Intravenous diazepam in the treatment of neuoloeptic-induced acute dystonia and akathisia. Am J Psychiatry 135 (1978), pp. 1232–1233.

21. W.W. Fleischhacker, S.D. Roth and J.M. Kane, The pharmacologic treatment of neuroleptic-induced akathisia. J Clin Psychopharmacol 10 (1990), pp. 12–21.

22. D.L. Schreibman, Treatment of a delayed reaction to droperidol with diphenhydramine. Anesth Analg 71 (1990), p. 105.

23. J.V. Agostini, L.S. Leo-Summers and S.K. Inouye, Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Arch Intern Med 161 (2001), pp. 2091–2097.

24. F.E.R. Simons, T.G. Fraser, J.D. Reggin and K.J. Simons, Comparison of the central nervous system effects produced by six H₁-receptor antagonists. Clin Exp Allergy 26 (1996), pp. 1092–1097.

25. T.J. Witek, D.A. Canestrari, R.D. Miller, J.Y. Yang and D.K. Riker, Characterization of daytime sleepiness and psychomotor performance following H₁ receptor antagonists. Ann Allergy Asthma Immunol 74 (1995), pp. 419–426.

26. D.R. Vinson, Reply to Gupta R. Akathisia can be reduced by lowering the dose of D₂ receptor antagonists. Ann Emerg Med 41 (2003), p. 280.

27. W.B. Taylor and D.N. Bateman, Preliminary studies of the pharmacokinetics and pharmacodynamics of prochlorperazine in healthy volunteers. Br J Clin Pharmacol 23 (1987), pp. 137–142.

Corresponding author. Correspondence: David R. Vinson, , Department of Emergency Medicine, The Permanente Medical Group, 1600 Eureka Road, , Roseville, CA 95661, , USA

*1 Original Contributions is coordinated by John Marx, , of Carolinas Medical Center, Charlotte, North Carolina