American Journal of Emergency Medicine (2012) 30, 84-91

Original Contribution

A trial of midazolam vs diphenhydramine in prophylaxis of metoclopramide-induced akathisia^?

Bulent Erdur MD ^a,?, Pinar Tura MD ^a, Berrin Aydin MD ^a, Mert Ozen MD ^a, Ahmet Ergin MD, PhD, MPH ^b, Ismet Parlak MD ^c, Burhan Kabay MD ^d

^aDepartment of Emergency Medicine, Medical Faculty, Pamukkale University, 20070, Denizli, Turkey ^bDepartment of Public Health, Medical Faculty, Pamukkale University, 20070, Denizli, Turkey ^cDepartment of Emergency Medicine, Medical Faculty, Mersin University, 33079, Mersin, Turkey ^dDepartment of General Surgery, Medical Faculty, Pamukkale University, 20070, Denizli, Turkey

Received 14 June 2010; revised 28 September 2010; accepted 9 October 2010

Abstract

Study Objective: The study aimed to evaluate the effects of midazolam and diphenhydramine for the prevention of metoclopramide-induced akathisia.

Methods: This randomized, double-blind, and controlled trial aimed to investigate coadministered midazolam vs diphenhydramine in the prophylaxis of metoclopramide-induced akathisia. Patients 18 to 65 years of age who presented to the emergency department with primary or secondary complaints of nausea and/or moderate to severe vascular-type headache were eligible for this study. Patients were randomized to one of the fallowing 3 groups: (1) metoclopramide 10 mg + midazolam 1.5 mg; (2) metoclopramide 10 mg + diphenhydramine 20 mg; (3) metoclopramide 10 mg + placebo. Metoclopramide was administered as a 2-minute Bolus infusion. Midazolam, diphenhydramine, and normal saline solution were administered as a 15-minute slow infusion. The whole procedure was observed; and akathisia and sedation scores and vital changes were recorded.

Results: There were significant differences among groups with respect to akathisia (P = .016) and sedation (P b .001). The midazolam group showed the lowest mean akathisia score but the highest mean sedation score. Akathisia scores of the diphenhydramine group were not different from placebo. There were significant differences among groups in terms of changes in mean vital findings such as respiration rates, pulse rates, and systolic blood pressures (P b .05). There were no significant difference among groups in terms of changes in mean diastolic blood pressures (P = .09).

Conclusion: Coadministered midazolam reduced the incidence of akathisia induced by metoclopramide compared to placebo but increased the rate of sedation. No difference was detected from diphenhydramine. Routine coadministered 20 mg diphenhydramine did not prevent metoclopramide- induced akathisia.

(C) 2012

^? No conflict of interest to disclose.

* Corresponding author. Pamukkale Universitesi Tip Fakultesi Acil Tip AD, 20070, Kinikli- Denizli, Turkey. Tel.: +90 258 211 85 85 2004;

fax: +90 258 213 49 22.

E-mail address: [email protected] (B. Erdur).

Introduction

Metoclopramide is an extensively used agent in emergency departments (EDs) in the management of

0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2010.10.007

nausea, vomiting, vascular-type headache, and gastropar- esis [1,2]. Despite being effective in this role, it can cause acute extrapyramidal side effects, including akathisia, parkinsonism, acute dystonia, and tardive dyskinesia [1,2]. Akathisia is a common adverse effect of treatment with a single dose of parenteral metoclo- pramide [3]. This syndrome consists of subjective (feeling of inner restlessness and the urge to move) as well as objective components (rocking while standing or sitting, lifting feet as if marching on the spot, and crossing and uncrossing the legs while sitting) [4-6]. Mechanism of akathisia due to metoclopramide has not been sufficiently explained. It is postulated that it is due to an imbalance of acetylcholine and dopamine in the central nervous system (CNS). Metoclopramide increases the release of acetylcholine in the CNS and acts as a dopamine antagonist centrally. The results of this imbalance produce several of the CNS-related adverse reactions including akathisia [6].

The data obtained from the literature show a direct positive correlation between the serum concentration of metoclopramide and the development of akathisia [7,8]. The studies conducted so far show that akathisia appears when the serum concentration of metoclopramide only exceeds 100 ng/mL [8]. In this proposal, several strategies have emerged to prevent akathisia due to metoclopramide. An effective strategy to decrease the incidence of akathisia is to slow down the speed of infusion of metoclopramide [3,7,9-11]. Currently, the administration of metoclopramide as a slow infusion has been described as an effective way to decrease the frequency of its side effects in emergency medicine practice [3,6,9,12]. It has been found that administering metoclopramide slowly over 15 minutes reduces the severity and incidence of akathisia [2,3,9,10].

The administration of adjuvant diphenhydramine has been used in some studies [2,13]. Whether diphenhydra- mine should be administered prophylactically with meto- clopramide is an unresolved issue [13]. In the study of Friedman et al [2], prophylactic diphenhydramine admin- istration did not decrease the rate of akathisia. However, for patients administered 20 mg of metoclopramide, prophylactic diphenhydramine may decrease only subjec- tive restlessness. It is yet to be studied whether the efficacy would have been enhanced with an alternate agent or a larger dose of diphenhydramine. Benzodiazepine (as midazolam) administration before metoclopramide may be another consideration [1,2]. There has not been any previous study about the administration of adjuvant benzodiazepine with metoclopramide.

The aim of this study was to compare the effects of midazolam and diphenhydramine for the prevention of metoclopramide-induced akathisia. To our knowledge, this is the first randomized controlled trial to compare the efficacy and side effects of these 2 medications in the prophylaxis against metoclopramide-induced akathisia.

Materials and methods

Study design

This was a prospective, randomized, double-blind, controlled trial to investigate prophylactic effects against metoclopramide-induced akathisia. Patients received medi- cation for nausea and/or moderate to severe vascular-type headache according to their random allocations. Diagnostic criteria for vascular headache included aura or anticipation of headache, nausea, vomiting, diarrhea, anorexia; Unilateral headache; photophobia or phonophobia; visual complaints; periodic headache; throbbing headache; childhood-onset headache; history of motion sickness; family history of headache; headache triggered by certain foods; and temporal association with menstruation. Prior headaches must have been resolved within 96 hours and should not have been associated with any Neurologic dysfunction. Patients with 4 or more positive items from this list were categorized as having vascular headache, as recommended by the vascular score criteria [14,15]. Randomization was achieved by using computer software to generate random numbers. Thus, patients were randomized to one of the following 3 groups: (group 1) metoclopramide 10 mg + midazolam (Dormicum Roche Ltd., Basel, Switzerland) 1.5 cm³ = 1.5 mg; (group 2) metoclopramide 10 mg + diphenhydramine 2 cm³ = 20 mg (Benison; Biosel, Istanbul, Turkey); (group 3) metoclopra- mide 10 mg + placebo 2 cm³ (normal saline solution). Metoclopramide (Primperan, Biofarma, Istanbul, Turkey) was administered as a 2-minute bolus infusion. Midazolam, diphenhydramine, and normal saline solution were inserted into a 150-cm³ bag of normal saline solution and concurrently administered as a 15-minute slow infusion for prevention of akathisia.

Setting

Permission from institutional review board of Pamukkale University Medical Faculty was obtained. The current study was conducted in the ED of the same university and completed between July 1, 2009, and November 1, 2009. Pamukkale University is an urban ED serving the commu- nities in and is located in the Aegean region, which is a relatively developed part of Turkey. This ED is visited by approximately 40 000 adults annually.

Selection of participants

Patients 18 through 65 years of age and 50 to 90 kg of weight who presented to the ED with primary or secondary complaints of nausea and/or moderate to severe vascular- type headache were eligible for this study. Participants were free of any respiratory problems. They all provided a written informed consent for the study. Patients who had liver and renal insufficiency, electrolyte imbalance, acute respiratory

symptoms, chronic obstructive pulmonary disease, blood pressure less than 90/60 mm Hg; who were uncooperative individuals, pregnant or lactating; who had a preexisting motor disorder, restless legs syndrome-Parkinson disease, organic brain disorder, (dementia, etc), epilepsy; admitted to the ED because of acute Psychiatric symptoms, advanced hearing loss, malnutrition, acute asthma attack; had serious physical illness, especially glaucoma, prostatic hypertrophy, or cardiac disease; had a contraindication to anticholinergic medications; within 3 days of study entry patients who had taken an antiemetic, antihistaminic, antipsychotic, antispas- modic, alpha-blocker, or Ca²⁺ channel blocker; or within

2 weeks of study entry patients who had taken an antidepressant, barbiturate, benzodiazepine, other sedative/ hypnotic, opioid, lithium, or illicit sympathomimetic agent were excluded [1].

Procedures and outcome measures

Study personnel (4 physicians and 8 nurses) were trained before the study. Nurses prepared and administered medica- tions according to the randomization protocol and monitored the patients. Physicians blinded to patient allocation were responsible for the evaluation of the sedation and akathisia scores, recording vital signs and adverse effects including hemodynamic instability. The Prince Henry Hospital Rating Scale of Akathisia was used to measure the level of objective, subjective, and total akathisia scores [16]. The modified Ramsay Sedation Scale (RSS) was used to measure the level of sedation [17] (Table 1A-B).

Data collection and processing

During the intervention, participants were monitored using a Spacelabs (SpO2, oxygen saturation), automatic sphygmomanometer (blood pressure), and rhythm monitor (heart rate and rhythms).

All medications used during the study were recorded. In addition, during the study, pulse, systolic blood pressure, diastolic blood pressure, respiration rate, and oxygen saturation (SpO2) were recorded at baseline (0th minute), 15th, 30th, and 60th minutes. Objective, subjective, and total akathisia scores were also recorded at baseline (0th min), 5th, 15th, 30th, and 60th minutes. The RSS score was recorded at baseline (0th minute), 5th, 15th, 30th, and 60th minutes. Adverse reactions (hemodynamic/respiratory compromise, etc) during the study were also recorded.

Primary data analysis

SPSS 17.0 for Windows (SPPS Inc, Chicago, Ill) was used for statistical analysis. Data were summarized as means (SDs) and percentages. ?2 and t tests were used for comparisons. Repeated-measure analysis of variance was used to compare the medications’ efficacy and side effects.

(A) The Prince Henry Hospital akathisia rating scale a

Objective ratings: (ratings by observer) I. Sitting Semipurposeful/purposeless leg/feet movement 0 1 2 3 Semipurposeful hand/arm movements 0 1 2 3 Shifting Body position in chair 0 1 2 3 Inability to remain seated 0 1 2 3 II. Standing Purposeless/semipurposeless leg/feet 0 1 2 3 movements Shifting weight from foot-to-foot and/or 0 1 2 3 walking on spot Inability to remain standing on one spot 0 1 2 3 (walking or pacing) Sum score Subjective ratings: (3 questions were asked) Do you feel restless, or urge to move, especially in 0 1 2 3 the legs? Are you unable to keep your legs still? 0 1 2 3 Are you unable to remain still, standing or sitting? 0 1 2 3 Key: 0-3: absent, mild, moderate, severe 0-absent 1-mild and present some of time 2-mild and present most of the time or severe and present some of the time 3-severe and present all the time Sum score Total score Global rating (by rater): 0-absent; 1-mild; 2-moderate; 3-severe. (B) Modified RSS: this scale has 6 levels b

Three for awake levels: 1-indicated patient anxious, agitated, or restless, 2-meant cooperative, oriented, and tranquil, 3-indicated response to verbal stimulus; and Three for asleep levels: 4-indicated a response to pain, 5-indicated a sluggish response to pain, 6-indicated no response.

a Biol Psychiatry. 1994;35:263-271. b Br Med J. 1974;2:656-659.

Ordinal data were also examined using nonparametric tests, which confirmed the statistical significance of findings. P values less than .05 were statistically significant.

Results

Table 1 Akathisia rating-modified RSS

Two hundred twenty-five participants were randomized into 3 groups according to their randomization scheme, and all of the randomized patients completed the trial (Fig. 1). Of 225, 162 (72%) were female; the mean (+-SD) age was 35

(13.6) years in the diphenhydramine group and 37.1 (14.3) years in the midazolam group. One hundred twenty-seven

Placebo Allocated to intervention and analyzed (n = 75)

Fig. 1 Patients enrolled by treatment groups.

Ineligible n = 684 (74%)

1. 397 investigators unavailable (58%)
2. 117 ED too busy (17%)
3. 96 presence of other exclusion criteria (14%)
4. 74 under 18 or above 65 years (11%)

Patients who received parenteral metoclopramide in the ED during the study period

(n = 920)

Not randomized (n = 11)

1. 6 refused
2. 5 logistical

Eligible (n = 236)

Diphenhydramine Allocated to intervention and analyzed (n = 75)

Randomized (n = 225)

127 received metoclopramide due to headache and 98 received metoclopramide due to nausea

Midazolam Allocated to intervention and analyzed (n = 75)

(56.4%) participants received metoclopramide because of headache and 98 (43.6%) received metoclopramide because of nausea. There were no significant baseline differences among groups in terms of patients’ demographic, hemody- namic characteristics, and baseline Ramsey sedation scores (Table 2).

There were significant differences among groups with respect to akathisia (P = .016 (P = .004, midazolam vs placebo; P = .20, diphenhydramine vs placebo; P = .09, midazolam vs diphenhydramine]) and sedation (P b .001 [P b .001, midazolam vs placebo; P = .003, diphenhy- dramine vs placebo; P b .001, midazolam vs diphenhy- dramine]) (Table 3). There were significant differences among groups in terms of changes in mean vital findings such as respiration rates, pulse rates, and systolic blood pressures during the study (all P b .001). There were no significant difference among groups in terms of changes in mean diastolic blood pressures (P = .09) (Fig. 2A-D). There were significant differences among groups in terms of changes in Ramsay sedation scores (P b .001), and mean RSS score in the first 15 minutes increased significantly in the midazolam group compared with that in the diphenhydramine and placebo groups (Fig. 3). None of the patients showed hemodynamic/respiratory compromise and returned to the ED with continued akathisia symptoms.

Discussion

Midazolam administration was effective in reducing the rate of metoclopramide-induced akathisia compared to placebo. However, midazolam generated more sedation than other groups. The current study also found that the effect of midazolam was not statistically different than diphenhydramine in reducing the rate of akathisia. In addition, coadministered diphenhydramine did not prevent metoclopramide-induced akathisia.

In this study, the rate of akathisia was found as 21.3%. Rates of metoclopramide-induced akathisia over 2 minutes without prophylaxis are similar to our findings [1-3,6,9,10,12,13,18-21]. Although the actual incidence remains unknown, the increased reporting of this adverse effect is likely because of the increasing awareness of akathisia as a side effect of metoclopramide as well as a better understanding of the phenomenon itself [9].

Diphenhydramine is classified as an antihistamine, antidyskinetic, antiemetic, antivertigo, and sedative/hypnotic [6]. Diphenhydramine’s significant anticholinergic activity results in the blockade of acetylcholine and its excitatory effects in the CNS, resulting in a restoration of balance between the dopaminergic and cholinergic activity [16]. Midazolam is classified as a short-acting benzodiazepine that treats akathisia more rapidly than diphenhydramine [1]. It

Sex (n [%])
Male (63 [28])	19 (25.3)	19 (25.3)	25 (33.3)	0.45
Female (162 [72])	56 (74.7)	56 (74.7)	50 (66.7)
Age
Mean (+-SD)	35 (13.6)	37.1 (14.3)	34.8 (12.4)	0.44
Weight
Mean (+-SD)	66.4 (14.3)	69.0 (15.0)	65.7 (14.1)	0.35
Respiration rate t0
Mean (+-SD)	18.7 (2.8)	18.9 (2.7)	18.6 (2.6)	0.80
Pulse Rate t0
Mean (+-SD)	86.8 (11.7)	83.7 (12.5)	84.5 (11.2)	0.26
Systolic blood pressure t0
Mean (+-SD)	128.3 (20.6)	127.3 (17.2)	129.3 (15.1)	0.79
Diastolic blood pressure t0
Mean (+-SD)	78.9 (13.5)	77.5 (11.5)	78.5 (11.4)	0.77
Ramsay sedation score t0
Mean (+-SD)	1.7 (0.4)	1.7 (0.5)	1.8 (0.4)	0.55
Reason for MTP (n [%])
Headache (127 [56.4])	41 (54.7)	45 (60.0)	41 (54.7)	0.75
Nausea (98 [43.6])	34 (45.3)	30 (40.0)	34 (45.3)
MTP indicates metoclopramide; t0, time 0. a P values from ?2 and analysis of variance.

has been postulated that ?-aminobutyric acid agonists are effective in treating conditions that are caused by blockade of dopamine receptors. However, this recommendation is largely anecdotal or derived from open studies.

Table 2 Distribution of the baseline characteristics between the study groups

Variables

Medications

Midazolam n = 75

P a

Diphenhydramine n = 75

Placebo n = 75

Given that akathisia is a common side effect of metoclopramide that is disturbing and not altogether preventable, an effective treatment with benzodiazepines or anticholinergic would be welcome. Benzodiazepines and anticholinergic medication agonists have been used tradi- tionally to treat drug-induced acute akathisia [22,23]. The effectiveness of these medications is unclear. Use of benzodiazepines to treat akathisia has met with variable results. Some advocate the use of benzodiazepines before the administration of metoclopramide to decrease the incidence

Table 3 Distribution of akathisia and sedation between the study groups

Variables

Medications

Midazolam n = 75

P a

OR (%95 CI)

Diphenhydramine n = 75

Placebo n = 75

of akathisia [12]. Schroeder et al [20] reported that intravenous 1 mg of midazolam completely reversed of all metoclopramide-induced extrapyramidal side effects in their series of patients. Hirose and Ashby [24] studied patients with neuroleptic-induced acute akathisia during treatment with antipsychotic medication, and they suggest that intravenous diazepam can be used in the treatment of patients with severely distressing akathisia who require immediate relief. In addition, in our previous study, we found that midazolam can correct the symptoms of metoclopramide-induced akathisia faster than diphenhydramine [1].

The rationale for pretreatment with benzodiazepines is logical but currently based on anecdotal evidence. LaGorio et al [12] and Barnes et al [25] reported that anxiety or

Akathisia n (%)	4 (5.3)	10 (13.3)	16 (21.3)	.016
			Midazolam vs placebo	.004	0.21 (0.07-0.66)
			Midazolam vs diphenhydramine	.09	0.37 (0.11-1.23)
			Diphenhydramine vs Placebo	.20	0.57 (0.24-1.35)
Sedation n (%)	60 (80)	38 (50.7)	20 (26.7)	.000
			Midazolam vs placebo	.000	11 (5.13-23.60)
			Midazolam vs diphenhydramine	.000	3.9 (1.89-8.04)
			Diphenhydramine vs placebo	.003	2.83 (1.43-5.60)
CI indicates confidence interval. a P values from ?2 test and analysis of variance.

Fig. 2 Mean vital findings of the study groups.

restlessness was reduced when a sedative or anxiolytic medication was coadministered with metoclopramide. Cohen et al [21] assume that even small doses of sedative drugs given for cesarean delivery perioperatively elevate the threshold for the development of akathisia. They indicated that, potentially, with small doses of midazolam, it may prevent the occurrence of this side effect. Although benzodiazepines may represent a safe and familiar Treatment modality, the evidence to support their efficacy (specifically from studies using diazepam, lorazepam, and clonazepam) in acute akathisia is largely anecdotal or derived from open studies. There is not enough work for adjuvant activity of benzodiazepines with metoclopramide-induced akathisia in the literature, and more research is needed to support the use of benzodiazepines for akathisia [1]. In our study,

akathisia developed in 4 (5.3%) patients in the midazolam- applied group and this was statistically significant. This is an effective strategy for reducing the development of akathisia incidence.

Anticholinergics are perhaps the oldest of the treatments for drug-induced akathisia. Centrally acting anticholinergics such as diphenhydramine presumably restore the relative balance between dopaminergic and cholinergic activity [12]. Vinson and Drotts [26] compared akathisia rates in patients who received prochlorperazine with and without an accompanying dose of diphenhydramine. They represent that adjuvant diphenhydramine greatly reduces (62%) the incidence of akathisia induced by prochlorperazine. Pro- chlorperazine administered over 2 minutes with diphenhy- dramine caused akathisia in 14% of subjects [27]. In another

Fig. 3 Ramsey sedation scores between the study groups.

study, akathisia rate was 8% when administered with diphenhydramine as a 15-minute infusion. It has been shown that concurrent administration of diphenhydramine along with prochlorperazine substantially decreases the rate of akathisia [26,27].

Whether diphenhydramine should be administered pro- phylactically with metoclopramide is an unresolved issue, and this uncertainty is reflected by practice variability in US EDs. Hurtado et al [19] tried to prevent the development of akathisia by coadministering diphenhydramine with the metoclopramide, although this is an off-label use. One study of 20 mg metoclopramide, infused over 15 minutes, along with diphenhydramine in a population of ED migraine patients resulted in an akathisia rate of 5% [13]. In another randomized, double-blind, controlled study, 38 of 77 patients with acute migraine attack received concomitantly 20 mg metoclopramide and 25 mg diphenhydramine infusion in

20 minutes. Those patients showed 5% akathisia [13]. Because of those findings, we believe that prophylactic usage of diphenhydramine might be more effective when used with 2-minute infusion of metoclopramide.

Friedman et al [2] investigated whether concomitant administration of diphenhydramine decreased the rate of development of akathisia after administration of 10 or 20 mg of intravenous metoclopramide over 15 minutes. In this randomized, double-blind, and controlled clinical trial, they found that prophylaxis with diphenhydramine to prevent akathisia is unwarranted when intravenous metoclopramide is administered over 15 minutes. For patients administered 20 mg of metoclopramide, prophylactic diphenhydramine may decrease subjective restlessness. The use of prophylac- tic diphenhydramine is not necessary when metoclopramide is given as an infusion over 15 minutes. In our study, akathisia developed in 10 (13.3%) patients in the prophy- lactic diphenhydramine-applied group. Diphenhydramine reduced the rate of akathisia compared to placebo (21.3%), but this was not statistically significant. Our result is similar with all of the above-mentioned studies.

This study has a number of limitations. First, patients given metoclopramide must be monitored for akathisia that can develop at any time over 48 hours post administration [28]. We did not reassess patients after ED discharge. Therefore, we cannot comment on the late development of akathisia and other extrapyramidal effects associated with metoclopramide. Especially, late-development dystonias (torticollis, opisthotonus, blepharospasms, and ocular crises) can lead to life-threatening situations because of respiratory and swallowing problems [7]. Dystonic symptoms frequent- ly start within 24 hours after administration of a dopamine antagonist and these symptoms occur within 72 hours [29]. However, none of the patients returned to the ED with any akathisia symptoms or other late-development extrapyrami- dal side effects. Second, the usual dosage of diphenhydra- mine for the treatment of akathisia recommended is between

25 and 50 mg per dose. However, the only available formulation for this medication in Turkey is 20 mg. Because of logistic concerns, we used one flacon (2 mL = 20 mg) for patients in our study. This borderline dosage may also affect the results. Nevertheless, we found an akathisia rate of concurrent diphendydramine group similar to that in another study using diphenhydramine at a dosage of 25 mg [2]. Furthermore, there is no universally accepted dosage for the prophylactic use of diphenhydramine and midazolam to prevent metoclopramide-induced akathisia.

Conclusion

Coadministered midazolam reduced the incidence of akathisia induced by metoclopramide compared to placebo but increased the rate of sedation. No difference was detected from diphenhydramine. Routine coadministered 20 mg diphen- hydramine did not prevent metoclopramide-induced akathisia.

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