Prochlorperazine induces akathisia in emergency patients

TOXICOLOGY/ORIGINAL

CONTRIBUTION

l-'rochlorperazine Induces Akathisia in Emergency Patients

From the Department of Emergency Medicine, Madigan Army Medical Center, Tacoma, WA.

Daniel L Drotts, MD David R Vinson, MD

Received for publication July 7, 1998. Revisions received October 5, 1998;January 14, 1999; March 8, 1999; April 15, 1999; and May 4, 1999. Accepted for publication June 15, 1999. Presented at the annual meeting of the Society for Academic Emergency Medicine, Chicago, IL, May 1998. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense. Address for reprints: David R Vinson, MD, Department of Emergency Medicine, Kaiser Permanente Medical Center, 2025 Morse Avenue, Sacramento, CA 95825. Copyright 9 1999 by the American College of Emergency Physicians. 0196-0644/99/$8.00 + 0 47/1/100828

Study objective: Prochlorperazine (PCZ), a commonly used antiemetic and analgesic agent, is known to cause akathisia. The incidence of akathisia after a single 10-mg dose of intravenous PCZ has not been prospectively evaluated. We determined the incidence and severity of PCZ-induced akathisia at 1 hour and the incidence of delayed akathisic symptoms at 48 hours.

Methods: This prospective controlled study evaluated a convenience sample of 140 adult patients at a 400-bed, academic, tertiary-care medical center with an annual emergency department census of 95,000 patient visits. One hundred patients who received intravenous PCZ for the treatment of severe headache or vomiting constituted the PCZ group. Forty patients receiving nonakathisic intravenous therapy (eg, saline solution or antibiotics) served as control subjects. Patients were excluded if they had preexisting motor disorders (eg, restless-leg syndrome or Parkinson's disease) or if they recently had received any medication with extrapyramidal, anticholinergic, sedative, or antiakathisic properties. All patients underwent an akathisia assessment before and 1 hour after receiving their respective intravenous medications. An established scale was used to detect the presence of akathisia and grade its severity as mild, moderate, or severe. The delayed development of akathisic symptoms within 48 hours also was measured in the PCZ group. Results: Akathisia developed in 44 (44%) of the patients receiving PCZ within 1 hour (95% confidence interval, 34% to 54%). The akathisia was graded as mild, moderate, and severe in 14, 22, and 8 subjects, respectively. Delayed symptoms suggestive of akathisia developed in 3 other patients within 48 hours. None of the 40 control subjects developed akathisia. Conclusion: Single-dose intravenous PCZ frequently induced akathisia within 1 hour of administration. Acute akathisia was not observed in patients receiving intravenous saline solution

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or antibiotics. The delayed development of akathisia symptoms 48 hours after a single dose of intravenous PCZ was uncommon. [Drotts DL, Vinson DR: Prochlorperazine induces akathisia in emergency patients. Ann EmergMed October 1999;34:469-475.] INTRODUCTION Prochlorperazme (PCZ) is widely used in emergency medicine to treat headaches and nausea/vomiting. Although used as an antiemetic agent for more than 40 years,1 its application in the treatment o f headaches is more recent. 2-5 As a phenothiazine, PCZ displays extrapyramidal side effects. Broadly, these fall into 4 categories: acute dystonia, acute akathisia, parkinsonism, and chronic tardive dyskinesia. Akathisia, a peculiar state of mental and motor restlessness characterized by an intense desire to move in order to gain respite from overwhelming feelings of distress, was first observed with the use of dopamine antagonists in 1947. 6 Akathisic patients report restlessness and inner tension or discomfort, have an urge to constantly move their legs, and have difficulty in maintaining a posture for several minutes, such as sitting still in a chair or standing in one place. They display semipurposeful or purposeless limb movements and tend to repeatedly shift their bodily position while sitting and shift weight from foot to foot or pace while standing. 7 In its milder presentation, the disorder may resemble anxiety. Akathisia in patients taking psychotropic or antiemetic agents may be quite distressing, 8-11 perhaps even leading to violent behavior 12,13 and suicidal ideation. 14-1~ Akathisia is not restricted to patients taking daily oral medication but also occurs in those who receive a single dose of parenteral dopamine antagonists. Agents commonly used in emergency medicine include metoclopramide, promethazine, PCZ, haloperidol, and droperidol. The mental and motor manifestations of akathisia are well described in a fascinating report by an expert on drug-induced movement disorders who writes of his experience while a medical student after receiving a single dose ofhaloperidol for a research study. He explains that "the intensity of the dysphoria was striking.., and the sense of a foreign influence forcing me to move was dramatic." 18 Studies of the pharmacology of intravenous PCZ have been short-circuited because volunteers have withdrawn themselves from further participation because of the development of single-dose PCZ-induced akathisia. 19,20 On development of acute akathisia,

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patients undergoing preoperative evaluation have suddenly refused to have surgery for which they had previously consented. This disruption of medical care has been reported with both single-dose intravenous droperido121 and single-dose intravenous metoclopramide. 22 The effect of acute akathisia in emergency medicine has not been elucidated. To determine the influence of akathisia on patient care in the emergency department, an understanding of the incidence and severity of single-dose PCZ-induced akathisia must be available. The majority of the work on drug-induced akathisia is contained in the psychiatric literature and relates to long-term oral dosing with neuroleptic medications. Estimates of the incidence of akathisia in these studies vary widely (8% to 76%), 23,24 depending both on the medication and the diagnostic criteria used. A conservative estimate places the incidence between 20% and 30% .24 No less variable are the figures reported for the incidence of akathisia after a single intravenous dose of PCZ. The great disparity between the lowest figure of 0% 3 and the highest of 67% 19 maybe attributable, in part, to a misunderstanding of the essential characteristics of the disorder. Variations in the definition of akathisia allow for variations in its reported incidence. Because of the recent standardization of the diagnostic criteria of acute neuroleptic-induced akathisia (NIA),25 we undertook a prospective controlled study to determine the incidence and severity of single-dose PCZinduced akathisia i hour after the intravenous administration of 10 mg of the drug. We also evaluated the incidence of delayed symptoms of akathisia at 48 hours.

MATERIALS AND METHODS This prospective controlled study was undertaken between July 1997 and November 1997 at Madigan Army Medical Center, a 400-bed, academic, tertiary-care hospital located in Tacoma, WA, with an annual ED census of 95,000 patient visits. The study was approved by the institutional review board. We enrolled a convenience sample of 140 patients from the patient population seen by the 2 investigators during their customary shifts in the ED. All subjects provided informed consent. Patients aged 16 to 65 years with a clinical indication for PCZ (ie, severe headache or nausea/vomiting) were eligible for enrollment in the PCZ group. To be included, patients had to receive a single 10mg dose of intravenous PCZ administered by means of slow push (over 2 minutes) as recommended by the manufacturer. They could receive no other medications dur-

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ing the first 60 minutes of their ED care until the postadministration assessment was completed. Adult patients receiving nonakathisic medications (ie, normal saline solution and intravenous antibiotics) constituted the control group. Patients were excluded if they were pregnant or lactating or if they had preexisting motor disorders (eg, restless-leg syndrome or Parkinson's disease) that might masquerade as akathisia. They were also excluded ira disorder was present in which an anticholinergic medication might be contraindicated (eg, glaucoma, urinary retention, or bowel obstruction). The recent administration of medications with extrapyramidal, anticholinergic, sedative, or antiakathisic properties also disqualified patients from inclusion. Particularly, the patient could not have taken within 3 days of study entry any of the following medications: antiemetic agents, antihistamines, antipsychotic agents, antispasmodics, [3-blockers, or calcium channel blockers. Nor could they have taken within 2 weeks of study entry any of the following medications: antidepressants, lithium, barbiturates, benzodiazepines, other sedative-hypnotics, opioids, or illicit sympathomimetics. Before treatment, each subject underwent an assessment of akathisia using the akathisia scale (Table 1). The subject first was observed in the seated position over a 2minute span for the presence of 2 factors of restlessness. The frequency of each factor was rated numerically from 0 to 4 points. Once the objective measurement was made, the subjective aspect of the scale was administered. Three questions were asked of the patient, each requiring 1 of 4 responses on a 4-point scale numbered 0 through 3, ranging from absent to severe, respectively. The sum of the

Table 1.

Akathisia scale. Objective: Two-minute seated observation* ,Inability to remain seated (Is the patient shifting)? 9 Any semipurposeful or purposeless leg or foot movements? Subjective: Three questions* 9 Do you feel restless within or the urge to move, especially in the legs? 9 Are you unable to keep your legs still? 9 Are you unable to sit still or stand still? PCZ-inducedakathisia=Changein objective scale _>1point + change in subjective scale >_2 points (from pre-PCZto post-PCZassessment), *Objective scale: 0, Absent; 1, 25%; 2, 25% to 50%; 3, >50%; 4, continuously Percentages indicate the percentage of activity during the 2-minute observation period. *Subjective scale: 0. Absent; 1, mild and present some of the time; 2, moderate and present most of the time; 3, severe and present all of the time.

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objective score (range, 0 to 8) and the subjective score (range, 0 to 9) was calculated. After the initial measurements of akathisia were tabulated, an intravenous cannula was placed in the upper extremity. The control group received their intravenous therapy (eg, saline solution or antibiotics) according to their individual clinical needs. The PCZ group received 10 mg of intravenous PCZ. After 60 minutes, the investigator reassessed the patient. Again, the patient was asked to sit upright for a 2-minute period of observation and the objective score was noted. The 3 subjective questions of the akathisia scale then were asked of the patient. The preadministration assessment score and the postadministration assessment score were compared. Akathisia was diagnosed if both an increase in the objective scoring of 1 point or greater and an increase in the subj ective scoring of 2 points or greater were noted. Akathisia was considered mild if the akathisia score increased 3 to 7 points, moderate if the score increased 8 to 12 points, and severe if the score increased 13 to 17 points. Akathisia was deemed absent if the subject failed to meet diagnostic criteria. We chose to treat all patients in whom akathisia developed with 50 mg IV diphenhydramine, regardless of severity. Follow-up data were obtained by using stamped addressed postcards on which the subjective akathisia scale was printed. Patients were asked to circle their numerical answers 48 hours after discharge from the ED. If postcards were not obtained within 10 days, patients were contacted by phone, and the 3 questions were asked. Follow-up was completed in 94 of the 100 patients in the study group. Follow-up was not attempted with the 40 subjects in the control group. The unpaired t test and )~2 analysis were used as appropriate to test for significant differences between the groups. For all the analyses, a 2-tailed P value of less than .05 was considered to indicate statistical significance. Estimates of precision are displayed with 95% confidence intervals calculated with the exact binomial formula. We conducted data analysis by using StatView (version 4.5; SAS Institute, Inc, Cary, NC). RESULTS

One h u n d r e d forty patients were enrolled: 100 patients in the PCZ group and 40 patients in the control group. Seventy percent (951140) of the subjects were women. The mean age was 30_+10 years (range, 16 to 65 years). The 2 groups were comparable in age and sex (Table 2). The demographics of the PCZ group are

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summarized in Table 3 according to the presence or absence of akathisia. The incidence of akathisia within 1 hour of the administration of 10 mg of PCZ was 44% (95% confidence interval, 34% to 54%). The change in akathisia scores from preinfusion to postinfusion values for subjects in the PCZ group is shown in Figure 1. By using the grading categories of mild through severe (Table 4), the distribution of akathisia severity is illustrated in Figure 2. None of the control patients met the diagnostic criteria for akathisia. No subject whose change in akathisia score totaled 3 or greater failed to meet sufficient diagnostic criteria in both the subjective and objective components of the akathisia score; that is, no patient with a subjective score change of 2 or greater lacked a concomitant objective score change of 1 or greater. Some subjects had a negative total score change because their preinfusion level of illness-induced restlessness was mitigated by the treatment of their principal complaint; for example, a patient with acute gastroenteritis may feel less restless after PCZ resolves their nausea and vomiting and produces sedation.

Table 2.

Characteristics of subjects by group.

Characteristic Age (y)* Range (y) Female (%)

Control Group (N=40)

PCZ Group (N=100)

31+11 17-59 16 (40)

29.6+10 16-62 71 (71)

PValue .49 .29

*Mean_+SD.

Delayed symptoms suggestive of akathisia occurred infrequently. Of the 94 patients contacted for follow-up, 32 received confounding discharge medications (eg, promethazine suppositories for recurrent vomiting or sedating medications for recurrent cephalgia) that would render the assessment of akathisia unreliable. However, 62 patients received no confounding medications during the 48 hours after initial assessment. Only 3 (5%) of these 62 reported the development of the subjective symptoms of mild akathisia after leaving the ED. Technically, we cannot equate these subjective symptoms with the formal diagnosis of akathisia because that diagnosis requires the presence of both objective and subjective criteria. Interestingly, akathisia developed in none of these 3 patients while in the ED.

DISCUSSION Acute NIA, of which PCZ-induced akathisia is a subset, had not until recently been systematically studied. The data on NIA first came into the medical literature from the psychiatric community. Their reports addressed this phenomenon among patients taking daily oral neuroleptic agents. Their figures on the incidence of multiple-dose NIA before the 1990s range from 8% to 76%. 23,24 Without standardization of the clinical characteristics of acute drug-induced akathisia, it is not surprising that the reported incidence of NIA is so broad. The figures vary depending on the medication, the quality of the study, and the different criteria used for diagnosis. During the 1980s, 8 rating scales existed that were specific for NIA, only 3 of which were supported by published reliability data. 26 The relative merits of the scales Figure 1.

Total change in akathisia scores in the PCZ group. Table 3.

Characteristics of the PCZ group. Akathisia Characteristic Age (y)* Range (y)

Female(%) Indication (%) Headache Nausea-vomiting

*Mean+SD.

472

Absent (N=56)

Present (N=44)

PValue

31+12 16-62

29+7 17-48

.34

38(68) 37(66) 19(34)

33(75) 25(57) 19(43)

.58 .49

25' No. of patients 20" 15._~ 10o'

l~m

I dl m,,nn,.,m.

m, ,n

. . . . . . . . .

-3

-1

1

9r-qAkathisia Akathisiaabsent present

3

5

7

. . . .

-,

9

11 13 15 17

Total change in akathisia score

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had never been addressed nor had research diagnostic criteria been estabhshed for the acute disorder. Several recent studies have remedied this. Building on the pioneering work of Braude et a127 on the clinical characteristics of akathisia, Sachdev 26 developed and standardized a reliable and valid rating scale for acute NIA. From this work, research diagnostic criteria were derived 25 and prospectively studied} 8 A conservative estimate places the incidence o f N IA between 20 % and 30 % during repeated-dose therapy. 24 Several prior publications mention the incidence of akathisia in patients receiving a single dose of intravenous PCZ. Taylor and Bateman 19 administered a single intravenous dose of either 6.25 or 12.5 mg of PCZ to 9 volunteers. Akathisia developed in 6 (67%). Jones et al 2 found no extrapyramidal reactions among'{2 patients who received 10 mg of intravenous PCZ for the treatment of acute headache. Saadah 29 also observed for adverse effects after administering both PCZ and dihydroergotamine of varying quantities in a study of their combined efficacy in aborting headaches. Akathisia was diagnosed in 2 (3%) of 65 subjects who received 3.5 mg of PCZ, 7 (28%) of 25 who received 5 mg, and 11 (25%) of 44 who received 10 mg. The PCZ was infused over 15 minutes. Thomas et al 3 report carefully monitoring (not otherwise described) for the adverse effects of PCZ in a comparative trial of rectal and intravenous PCZ. They observed no adverse effects (eg, dystonia or akathisia) among 23 patients receiving 10 mg of intravenous PCZ. Coppola et al 4 note in a study comparing 10 mg of intravenous PCZ with intravenous metoclopramide for ED treatment of migraine headache that either "dystonia or akathisia" developed in 2 of 22 patients. The aforementioned studies are too disparate to yield a unified estimate of the incidence of akathisia induced by a single dose of intravenous PCZ. The amount infused varied from 3.5 mg to 12.5 rag, and the rate o f infusion varies from 2 minutes to 15 minutes. The effect of both dose of

PCZ and rate of infusion on the development of akathisia have not been carefully evaluated. The weightiest element undermining the reliability of these figures, however, is the lack of uniform diagnostic criteria. None of the authors disclose the method by which their diagnosis of akathisia was established nor explicitly define their diagnostic criteria. Without uniformity in what constitutes akathisia and how it is detected, the aforementioned reports on the incidence ofPCZ-induced akathisia have little utility. Because none of these studies reports their diagnostic criteria for akathisia, we do not know whether the subjects were questioned about the characteristic symptoms of akathisia (Table 1). To make the diagnosis of akathisia, the patient must be asked about symptoms of restlessness. Inquiring about the disorder is critical to a proper estimation of its incidence because the diagnosis of akathisia may not be established unless it is pursued. Not only may the physician fail to inquire, but the patient may fail to volunteer the information without solicitation. A recently published survey supports this contention. Fleishman et al 3~ asked 24 patients with cancer receiving oral PCZ at home whether they had experienced any of a list of symptoms derived from previously validated akathisia scales. The diagnostic threshold was reached in 50% of these patients. Of these akathisic patients, fully 75% said that they would not have informed staff of these symptoms had they not been asked. Although asking about symptoms of restlessness is necessary for detection of the disorder, simply asking

Figure 2.

Grades of akathisia severity in the PCZ group.

No of patients 60 50 40

Table 4.

Grades of PCZ 4nduced akathisia.

30 20

Grade

Score

No. of Subjects

Mild Moderate Severe

3-7 8-12 13-17

14 22 8

PCZ Subjects at Indicated Grade or Higher (%) 44 mild-severe 30 moderate-severe 8 severeonly

95% Confidence Interval 34-54 21-40 4-16

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10 0 Absent

Mild

Moderate

Severe

(3radeof akathisia severity

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about akathisia does not appear to incite the disorder. All 40 subjects in our control group were asked about restless feelings both before and after treatment with intravenous fluids or antibiotics, but none of these met the diagnostic criteria for akathisia. The incidence of PCZ-induced akathisia is critically dependent on the diagnostic threshold of the akathisia score. We required at least a 1-point change in the objective score combined with a 2-point change in the subjective score. If the requirement of total point change is raised from 3 to 8 (our category of moderate akathisia), the incidence drops from 44% to 30%. If the diagnostic threshold were set to require that the patient become so disturbingly restless that he or she feels compelled to pace anxiously about the department and to demand premature discharge, then the incidence plummets to 8% (Figure 2). In fact, of those with severe akathisia, half were unable to remain still long enough for rescue diphenhydramine and eloped untreated from the ED. Our particular diagnostic criteria were selected because they conform closely to the definition of NIA used in the psychiatric literature. We selected a 2-point change in the subjective score as our diagnostic cutoff point because the subjective component of the Prince Henry Hospital Rating Scale of Akathisia,26 which we adopted verbatim, requires a minimum score of 2 to establish the diagnosis. The clinical data suggest that akathisia may be present to a mild degree with isolated subjective symptoms and no apparent objective features. 7,26 We adopted the more conservative diagnostic criteria, however, which require the presence of corroborating objective findings.31 Our criteria therefore necessitate at least 1 point of change in the objective score subsequent to the infusion of PCZ in addition to a change of 2 or more points in the subjective score. Additionally, rather than rely simply on an absolute point score measured only after the infusion of PCZ, we based our diagnostic criteria on the change in score from preinfusion to postinfusion levels. This controlled for any masquerading, akathisic-like manifestations of the patient's primary illness. Requiring an observed increase in the akathisia score also helped establish PCZ as the cause of the akathisia because it was the only medication that immediately preceded the acute development of the subjective and obj ective findings. Recognizing drug-induced akathisia is important for several reasons. Fundamentally, "it is the first order of any practitioner's business to be fully cognizant of all the disadvantages as well as the benefits of the medications that he [or she] employs."32 Acute akathisia is an unpleasant,

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dysphoric phenomenon, the presence of which will likely have a negative effect on patient comfort and satisfaction, z, 11.18,23,27,3o Also, acute akathisia may diminish a patient's compliance with further medical care, as illustrated by the subjects who withdrew from clinical studies because of their akathisia, 19,2~the cases of refusal of surgery, 21,22 and our 4 cases of premature ED departure. The true impact of PCZ-induced akathisia on refusal of further evaluation and therapy and premature discharge from the ED has yet to be elucidated. Akathisia also has been reported to lead to violence 12,13 and suicidal ideation, 14-17 serious sequelae from what is considered routine pharmacotherapy. Finally, diagnosis of akathisia in the ED is critical because treatment cannot be provided for akathisia until the disorder is first detected. We chose a priori to offer diphenhydramine treatment to all patients whose akathisia score met our diagnostic threshold. Only 2 patients, both with mild akathisia (total scores of 5 and 7, respectively), who were offered treatment for akathisia declined treatment. One of these patients said she was able to tolerate the restlessness; the other refused to receive further medications, fearful of further adverse effects. Although the natural history of acute NIA after the administration of single-dose intravenous dopamine antagonists has not been extensively studied, it appears to be a self-limited phenomenon. One study evaluated the clinical pharmacology of single-dose intravenous PCZ in healthy males.2~ By using a visual analog scale of restlessness, which they measured serially over time, Isah et a[2~ observed peak akathisic symptoms between I and 2 hours, which resolved by 8 hours. Saadah 29 observed that the effects of PCZ-induced akathisia lasted up to 24 hours. Such findings are consistent with prior observations. 19 Because this appears to be a self-limited disorder, some patients may not require treatment. Without data defining which patients with akathisia can comfortably forego treatment, we selected a conservatively low treatment threshold and offered diphenhydramine to all patients in whom akathisia was diagnosed. Our study has several weaknesses of method. The foremost shortcoming is the lack of blinding. The investigators knew which patients received PCZ and which patients did not. This could have introduced bias. A second weakness of our study design is that the 40 control patients were dissimilar to the PCZ group regarding chief complaint. All 100 in the PCZ arm had a clinical indication for PCZ; all 40 in the control arm had a chief complaint by definition other than nausea/vomiting or headache. It could be argued that the symptoms of nausea

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and headache in some way contributed to the development of akathisia. However, akathisia induced by intravenous PCZ is known to develop in healthy volunteers without any complaints. 19 Another limitation deserving comment is the arbitrary selection of a treatment threshold. Although we equated the diagnostic threshold with our treatment threshold, data demonstrating that this is the best approach are lacking. "Antiemetic-induced akathisia is a prevalent problem that causes much patient suffering and deserves greater study.'3~ Given the high incidence of PCZ-induced akathisia at 1 hour, as demonstrated in this study, we are investigating methods of akathisia prevention. We have recently shown that adjuvant diphenhydramine reduces the incidence of PCZ-induced akathisia. 33 Decreasing the rate of infusion from 2 minutes to 15 minutes also is beneficial (DR Vinson and AFA Migala; unpublished data, 1999). We thank Steve Pace, MD, for his assistance with the design and implementation of this project. The contributions of Drs J TebyVandenberg, Nate Rudman, and Dan Mcllmail in critiquing an earlier version of this manuscript are also greatly appreciated. Troy Patience, medical statistician, provided the statistical analysis.

16. Drake RE, Ehrlich J: Suicide attempts associated with akathisia. Am J Psychiatry 1985;142:499-501. 17. Shear MK, FrancesA, Weiden P: Suicide associated with akathisia and depot fluphenazine treatment. J Clin Psychopharmaco11983;3:235-235. 18. Kendler KS: A medical student's experience with akathisia. Am J Psychiatry1976;133:454455. 19. Taylor WB. Bateman DN: Preliminary studies of the pharmacokinetics and pharmacadynamics of prochlorperazinein healthy volunteers. BrJ C/in Pharmaco/1987;23:137-142. 20. Isah AO, Rawlins D, Bateman DN: Clinical pharmacology of prechlorperazine in healthy young males. Br J Clin Pharmaco11991;32:677-684. 21. Lee C, Yeakel A: Patient refusal of surgery following Innovar premedication. Anesth Analg 1975;54:224-226. 22. LaGorioJ, ThompsonVA, Sternberg D, et al: Akathisia and anesthesia: refusal of surgery after the administration of meteclepramide. Anesth Analg 1998;87:224-227. 23. Adler LA, Angrist B, Reiter S, et al: Neureleptic-induced akathisia: A review. Psychopharmacology1989;97:1-11. 24. Sachdev P: The epidemiolegy of drug-induced akathisia: Part I. Acute akathisia. Schizophr Bull 1995;21:431-449. 25. Sachdev P: Researchdiagnostic criteria for drug-induced akathisia: Conceptualization, rationale and proposal. Psychopharmacology(Berl)1994;114:181-186. 26. Sachdev P: A rating scale for acute drug-induced akathisia: Development, reliability, and validity. Biol Psychiatry1994;35:263-271. 27. Braude WM, Barnes TR, Gore SM: Clinical characteristics of akathisia: A systematic investigation of acute psychiatric inpatient admissions. Br J Psychiatry1983;143:139-150. 28. Sachdev P, Kruk J: Clinical characteristics and predisposing factors in acute drug-induced akathisia. Arch Gen Psychiatry1994;51:963-974.

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29. Saadah HA: Abortive headache therapy in the office with intravenous dihydreergotamine plus prochlorperazine.Headache1992;32:143-146. 30. Fleishman SB, Lavin MR, Sattler M, et al: Antiemetic-induced akathisia in cancer patients receiving chemotherapy. Am J Psychiatry1994;151:763-765. 31. Mazure CM, Cellar JS, Bowers MB, et al: Assessment of extrapyramidal symptoms during acute neureleptic treatment. Clin Psychiatry1995;56:94-1OO. 32. Nelson NM: Severe neurologic reactions to antiemetics. N EnglJ Med 1959;260:1296-1298. 33. Vinson DR, Dretts DL: Diphenhydramine prevents akathisia induced by intravenous prochlerperazine: A randomized controlled trial [abstract 491]. AcadEmergMed1999;6:533.

5. Seim MB, March JA, Dunn KA: Intravenous ketorolac vs. intravenous prochlorperazinefor the treatment of migraine headaches.Acad EmergMed 1998;5:573-576. 6. Sigwald J, GressiordA, Duriel P, et al: Le traitement de la maladie de Parkinsenet des manifestations extrapyramidalles par le diethylaminoethyl n-thiephyenylamine (2987RP):resultants d'une anee d'applicatien. Rev Neuro11947;79:683-687. 7. Sachdev P: Akathisia. Cambridge: Cambridge University Press, 1995. 8. Bakheit A: The syndrome of motor restlessness--A treatable but unrecognizeddisorder. PostgradMed J 1997;73:529-530. 9. ChungWSD, Chiu HFK: Drug-induced akathisia revisited. BrJCfin Prac 1996;50:270-278. 10. Miller I_6, Jankovic J: Neurologic approach to drug-induced movement disorders. South Med J 1990;83:525-532. 11. FriedmanJH, Wagner RL: Akathisia: The syndrome of motor restlessness. Am/:am Physician 1987;35:145-149. 12. Keckich WA: Neuroleptics. Violence as a manifestation of akathisia. JAMA 1978;240:2185. 13. Crowner ML, Douyon R, Convit A, et al: Akathisia and violence. PsychopharmacolBull 1990;26:115-117. 14. Chow LY, Chung D, LeungV, et al: Suicide attempt due to metoclopramide-induced akathisia. Int J Clin Pract1997;51:330-331. 15. Rothschild AJ, LockeCA: Reexposureto fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry1991;52:491-493.

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