Wang 1997 Headache IV droperidol ETC.pdf

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Droperidol Treatment of Status Migrainosus and Refractory Migraine

Shuu-Jiun Wang, MD; Stephen D. Silberstein, MD; William B. Young, MD

From the Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan (Dr.Wang) and the Comprehensive Headache Center, Germantown Hospital and Medical Center, Philadelphia,Penn (Drs. Silberstein and Young).

Address all correspondence to Dr. Stephen D. Silberstein, Germantown Hospital and Medical Center,Neurology, Wister Building, One Penn Boulevard, Second Flock, Philadelphia, PA 19144.

Accepted for publication September 21, 1996.

We conducted a pilot study of intravenous droperidol in 35 patients (32 women and 3 men; mean age 43years) with status migrainosus (n=25) or refractory migraine (n=10) in an ambulatory infusion center.Headache was graded as severe in 21 patients and moderate in 14. An intravenous line was started andkept open. Droperidol (2.5 mg) was given intravenously every 30 minutes until either three doses weregiven or the patient was completely or almost headache-free prior to the next dose.

Seven patients received one dose, 12 received two doses, and 16, three doses (mean 5.6 mg). Our success rate (headache-free or mild headache) was 88% (22 of 25) in patients with status migrainosus and100% (10 of 10) in patients with refractory migraine. The average time to headache improvement was 40minutes (n=35), to mild headache – 60 minutes (n=32), and to headache-free - 105 minutes (n=28). Nausea,vomiting, and light and sound sensitivity resolved in all but 5 patients. Four patients had an asymptomaticsystolic blood pressure drop ≥≥ 20 mm Hg. Most patients were sedated (34 of 35). Five patients developedakathisia and I dystonia. At follow-up 24 hours after discharge, the recurrence rate (headache intensityfrom none or mild to moderate or severe) was 23% in status migrainosus and 10% in refractory migraine.Twenty-one patients were sedated, while 19 had extrapyramidal symptoms, mainly restlessness.

Droperidol is effective and safe in treating status migrainosus or refractory migraine. Hypotension wasuncommon. Patients should be warned of sedation and akathisia.

Key words: droperidol, migraine, neuroleptics, status migrainosus

Abbreviations: IHS International Headache Society, DHE dihydroergotamine, ED emergency department,GHMC Germantown Hospital and Medical Center

(Headache 1997;37:377–382)

Status migrainosus is defined by the International Headache Society (IHS)1 criteria as an attack of migraine, theheadache phase of which lasts more than 72 hours, whether it is treated or not. The headache can be continuousthroughout the attack or interrupted by headache-free intervals lasting less than 4 hours. Relief during periods of sleep is disregarded. Headaches that last less than 72 hours are defined as migraine. For our purposes,headaches lasting between 24 to 72 hours and resistant to the usual aggressive headache treatment are definedas refractory migraine. The treatment of status migrainosus or refractory migraine is often a difficult problem for both the physician and the patient. There are no large series or double-blind treatment trials in status migrainosus.

Empirical treatments include dihydroergotamine (DHE),2–4 neuroleptics,2,4–5 corticosteroids,2,4 or narcotics.2

Neuroleptics are commonly and successfully used to treat acute migraine attacks. They are frequently used asan alternative to narcotics in emergency departments (EDs). Controlled studies have shown that intravenous (IV)

chlorpromazine,6,7 methotrimeprazine8 prochlorperazine,9,10 and prochlorperazine suppositories11 are effective in

controlling intractable headaches. Recently, Fisher 12 successfully treated six migraine patients with IV haloperidol(5 mg) in an ED. We designed this pilot study to evaluate the efficacy and safety of droperidol in patients withprolonged or intractable migraine. The patients we recruited had status migrainosus or refractory migraine attacks.

Droperidol, a butyrophenone with strong neuroleptic and antiemetic properties, is used to supplement

anesthesia.13 It is structurally and pharmacologically related to haloperidol with a more rapid onset but shorter

duration of action and a lower incidence of extrapyramidal symptoms.13,14 To our knowledge, it has never beenused for migraine treatment.

PATIENTS AND METHODS

Our open-label pilot study protocol was reviewed and approved by the Institutional Review Board at theGermantown Hospital and Medical Center (GHMC).

Patients.—We recruited patients with status mi-



grainosus (IHS code 1.6.1) or refractory migraine. We defined refractory migraine attacks as those lasting more than 1 day but lessthan 3 days, and unresponsive to an adequate clinical trial of at least one of the following treatments: DHE, sumatriptan, nonsteroidalanti-inflammatory drugs, butorphanol nasal spray, or other narcotics.

All patients had physician-diagnosed migraine, with or without aura, (IHS criteria) for more than 1 year. All wele established patientsof the Comprehensive Headache Center at GHMC. The current headache characteristics had to fulfill the IHS migraine features, exceptthat the headache intensity had to be moderate or severe before entering the study. Pain intensity was measured on a 4-point severityscale (0 = no pain, 1 = mild, 2 = moderate, 3 = severe). Patients were excluded if they met any of the following criteria: were younger than 15 or older than 75 years; were pregnant or possibly pregnant; had chronic daily headache, analgesic, or ergotamine reboundheadache; a known history of allergy to droperidol; on current therapy with neuroleptics; had renal or hepatic impairment; or a bloodpressure lower than 80/55 mm Hg. Written informed consent was obtained from all patients before entering the study.

Treatment.—Patients had an IV line started and were pretreated with IV 5% dextrose water in one-fourth normal saline at a rate of

250 mL/hr. Patients then received droperidol (2.5 mg) IV push for I minute every 30 minutes until either a total of three doses had beengiven or patients became almost or completely headache-free prior to the next dose. The dosage was determined from our previousexperience. Diphenhydramine (50 mg IV) was available on an as-needed basis for akathisia or dystonia. All treatments were given at theoutpatient infusion center at GHMC.

Measurements.—Vital signs (blood pressure, pulse rate) were checked before (time = 0) and at 5 and 20 minutes after each dose

of droperidol.

Patients were asked to judge the intensity of their headaches using the 4-point headache scale at the time tile vital signs werechecked (0, 5, and 20 minutes) and every 30 minutes after the first dose of droperidol was given.

The symptoms of nausea, vomiting, sensitivity to light or sound, sedation, akathisia, and dystonia were rated as present or absent

every 30 minutes after the first dose of droperidol was given.

Patients were contacted by telephone 24 hours after discharge. They were asked about headache recurrence, nausea, vomiting,sedation, extrapyramidal symptoms, and the use of escape medicines. Patients were instructed before discharge to takediphenhydramine (Benadryl®) pills for extrapyramidal symptoms.

Treatment Success.—Treatment was considered successful if the patient's headache was either gone or mild in intensity. The

percentage of patients who were headache-free was also calculated.

Recurrence.—Headache recurrence was defined as a moderate to severe headache occurring within 24 hours in patients who had

mild or no headache after droperidol treatment. The percentage of recurrence of any headache within 24 hours in patients who wereheadache-free after treatment was also calculated.

We did not attempt to make statistical comparisons of the results between the two groups of patients.

RESULTS

Thirty-five patients (32 women, 3 men) were recruited and completed the study between October 1995 and March 1996. Twenty-fivepatients had status migrainosus, while 10 had refractory migraine (Table 1). Thirty-three (94%) were on at least one headachepreventive medication. None were overusing analgesics, ergotamine, or sumatriptan.

The mean dosage of droperidol was 5.6 mg in status migrainosus, and 5.7 mg in refractory migraine (Table 2). All patients improved(at least one point) after treatment (Table 2). Our success rate (headache-free or mild headache) was 88% (22 of 25) in patients withstatus migrainosus and 100% (10 of 10) in patients with refractory migraine. The average time to headache improvement (one pointbelow the original intensity) was 40 minutes, to mild headache – 1 hour, and to no headache – 1 1/2 to 2 hours. Figures 1 and 2 showheadache intensity over time following droperidol treatment.

Only five patients (14%), four patients with

Table 1.—Patient Characteristics

Status Refractory TotalMigrainosus Migraine

Feature Group (n=25) Group (n=10) (N=35)

Age, y* 42 ± 9 (16.58) 46 ± 13 (23–70) 43 ± 10

(16–70)Ratio of men to women 2:23 1:9 3:32History of migraine, y* 13 ± 12 (1.48) 20 ± 17 (2–42) 15 ± 14 (1–48)Prior migraine diagnosis, with/without 8/17 3/7 11/24auraCurrent migraine diagnosis, 4/21 2/8 6/29with/without auraPreventive medication 24 9 33Duration of current headache, d* 7.0 ± 3.5 (0–13) 1.4 ± 0.5 (1–2) 5.4 ± 3.9

(1–13)Headache intensity, moderate/severe 10/15 4/6 14/21Nausea 19 9 28Photophobia 12 7 19Phonophobia 13 7 20

*Values given as mean ± SD (range). All other values giver as number of patients.



Table 2.—Results of Droperidol Treatment

Status Migrainesus Refractory TotalMigraine

Group (n=25) Group (n=10) (N=35)

Droperidol use, No.

One dose (2.5 mg) 5 2 7Two doses (5 mg) 9 3 12Three doses (7.5 mg) 11 5 16

Success rate, No. (%)

Headache ≤ 1 22 (88) 10 (100) 32 (91)Headache = 0 18 (72) 10 (100) 28 (80)

Mean time to improvement, min(range)

Some improvement* 35 (5–115), n= 25 40 (5–90), n=10 40 (5–120), n=35Mild headache 60 (5–240), n=22 65 (20–120), n=10 60 (5–240), n=32Headache-free 90 (30–150), n=18 125 (80–210), 105 (5–210), n=28

n=10Residual associated symptoms,No.

Nausea 1 0 1Photophobia 4 1 5

Phonophobia 1 0 1

*Headache decreased one point below the original intensity.

[FIG 1]

[FIG 2]

status migrainosus and one patient with refractory migraine, still had nausea (n=l) or light (n=5) and sound(n=1) sensitivity after treatment

Four patients had an asymptomatic systolic blood pressure drop ≥ 20 mm Hg and 2 hac transientasymptomatic hypertension up to 170 mm Hg. Asymptomatic tachycardia (heart rate > 100 beats per minute)was found in 3 patients No patients had respiratory difficulty during the trial. Most patients (34 of 35)

experienced sedation, which lasted on average 95 minutes (range: 30 to 165) after the last dose of droperidol. During treatment, 5 patients developed akathisia and 1 had dystonia. These side effectsresponded to IV diphenhydramine.

Telephone follow-up was obtained on all patients 24 hours after discharge (Table 3). The headacherecurrence rate was 23% in patients with status migrainosus and 10% in patients with refractory migraine. Inall, 72% of status migrainosus and 90% of refractory migraine patients remained headache-free or had mildheadache. Nine (32%) of 28 patients who were originally headache-free had some recurrent headache. Theaverage time for headache recurrence in these 9 patients was 8 ± 5 (4 to 18) hours. Five patients (20%) withstatus migrainosus and 1 patient (10%) with refractory migraine took escape medicines for headache relief within 24 hours. Six patients still had nausea, 1 had vomiting, 6 had sensitivity to light, and 4 sensitivity tosound. Twenty-one patients (60%) had some degree of drowsiness. Nineteen patients (54%) had akathisiaand 2 had dystonic reactions. Seventeen of these 19 patients took diphenhydramine tablets for symptomatic

relief. The occurrence of sedation (χ2=0.14, df=2, P=0.93) or extrapyramidal symptoms (χ2=1.62, df=2,



Table 3.—Results of Follow-up 24 Hours Postdischarge

Status Migrainosus Refractory Migraine TotalGroup (n=25) Group (n=10) (N=35)

No. (%) of Patients No. (%) of Patients No. (%) of Patients

Headache intensity

Headache 2–3 7 (28) 1 (10) 8 (23)Headache 1 5 (20) 2 (20) 7 (20)Headache 0 13 (52) 7 (70) 20 (57)

Headache recurrenceHeadache 0.1 5/22 (23) 1/10 (10) 6/32 (19)

→2,3

Headache 0 → >0 6/18 (33) 3/10 (30) 9/28 (32)Side effects

Sedation 13 (52) 7 (70) 21 (60) Akathisia 16 (64) 3 (30) 19 (54)Dystonia 2 (8) 0 2 (6)

Benadryl® 16/16 (100) 1/3 (33) 17/19 (89)Escape medicine 5 (20) 1 (10) 6 (17)

Table 4.—Results of Treatment With Droperidol Among Groups With DifferentDuration of Current Headaches

No. (%) of Patients No. (%) of Patients No. (%) of PatientsWith Refractory With Status With Status

Migraine Migrainosus Migrainosus1 to 3 Days 3 to 7 Days >7 Days

n=10 n=11 n=14

Success rate

Headache ≤1 10 (100) 11 (100) 11 (79)Headache 0 10 (100) 10 (91) 8 (57)

Success rate after 24hours

Headache ≤1 9 (90) 8 (73) 10 (71)Headache 0 7 (70) 7 (64) 6 (43)

P =0.44) was not dose related.

In order to evaluate the relationship between the treatment results and headache duration, we further divided the status migrainosus patients into two groups by their current headache duration (< 7 and ≥ 7 days)(Table 4). The success rates decreased as the duration of curreat headache increased, especially in thestatus migrainosus patients with duration ≥ 7 days. The trend remained for the follow-up results after 24hours.

COMMENTS

This open pilot study demonstrated the efficacy of droperidol in the treatment of status migrainosus andrefractory migraine attacks. The success rate (headache-free or mild headache) was 88% of statusmigrainosus patients and 100% of refractory migraine patients. About 72% of status migrainosus patients and100% of refractory migraine patients became headache-free. Droperidol was also very effective for theassociated symptoms of nausea, vomiting, and light or sound sensitivity. Most patients (72% of patients withstatus migrainosus and 90% of patients with refractory migraine) continued to do well after 24 hours; theywere either free of headache or had a mild headache. The recurrence rate in the patients with statusmigrainosus (23%) was higher than the patients with refractory migraine (10%). In status migrainosuspatients, the patients with duration shorter than 1 week did better than patients with duration longer than 1week. This suggests that the duration of the headache is of prognostic significance and that early aggressivetreatment may be more beneficial.

Several methodology issues need to be addressed: (1) This study was not placebocontrolled. In clinical

trials of acute migraine drugs, the placebo effects are around 30% to 50%.8,11 However, the placebo effectsfor status migrainosus and refractory migraine are unknown, especially in patients who have failed prior acutetreatment of the current headache. (2) Most clinical trials for migraine abortive



treatment recruited patients with episodic attacks. In these studies, some patients also fulfilled the criteria of status

migrainosus.15 For our study, we recruited only intractabe pretreated patients. (3) All of our patients came from aheadache center and most (94%) were on headache preventive agents. Thus, these patients differ from those inthe community- or ED-based studies. The effects of preventive agents on abortive treatment are not known. (4) Noclear distinction is made between status migrainosus and transformed migraine, as no upper time limit is given to

status migrainosus15 Abortive medication overuse is a well-known cause of transformed migraine. None of thepatients in our study overused analgesics, ergotamine, or sumatriptan, which might impair the effect of both acute

and prophylactic medication. Our patients' headaches were "breakthrough" rather than rebound headaches.

The main side effects of droperidol treatment included sedation, akathisia, and dystonia. Sedation andextrapyramidal symptoms were not dose related, perhaps because even smaller doses of this potent neurolepticare equivalent to higher doses of other phenothiazines. Akathisia, and to a much less extent, dystonia, occurred inalmost half of patients after discharge. However, these extrapyramidal symptoms were more annoying than severeand were successfully controlled with oral diphenhydramine. A drop in blood pressure (≥ 20 mm Hg) was found infour patients (11%); however, none were symptomatic.

Previous placebo-controlled ED-based studies showed that neuroleptics are effective in the treatment of acutemigraine attacks. The study designs and the efficacy parameters used varied considerably among trials, making itdifficult to compare the results and to judge their clinical relevance. The success rates (adequate or complete

headache relief) ranged from 72% to 100%.7–9,11 The percentage of patients who used escape medicine or

returned to EDs for help ranged from 0% to 30%.3,9,10 In two comparative studies, chlorpromazine was more

effective than DHE6 or meperidine with dimenhydrinate.7 Our study showed high success rates (88% to 100%) of droperidol treatment in patients with either status migrainosus or refractory migraine. The success rates of droperidol are comparable to those of previous studies using phenothiazines, although both our patients and studydesign differed. Recently, haloperidol (another butyro-phenone) was shown to be effective in acute migraine

treatment in an open case series.12 In addition to dopamine receptor-blocking properties, droperidol has affinity for

à-adrenergic and 5-hydroxytryptamine receptors.16 The mechanisms for the beneficial effect of droperidol, as wellas other neuroleptics in migraine, remains unknown.

Status migrainosus patients did not do as well as refractory migraine patients, especially in the patients withduration longer than 1 week. Whether this is due to the self-limited nature of migraine attacks which were caughtbefore they had run their course or due to the benefit of early intervention is uncertain. Droperidol can beconsidered for the acute treatment of refractory headache when ergotamine, DHE, sumatriptan, or corticosteroidshave failed (or cannot be used), and when escape or secondary medications such as analgesics, with or without

narcotics, and oral or suppository neuroleptics have failed. In our experience, patients have fewer troublesome sideeffects and better relief than with prochlorperazine. We find the sedation useful. We now give all patients oraldiphenhydramine for possible restlessness.

In conclusion, droperidol is effective in treating status migrainosus or refractory migraine with a safe side effectprofile. It could be used as an alternative or if usual empirical treatments fail. Placebo-controlled trials of droperidolas an abortive treatment for migraine are warranted in the future.

REFERENCES

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criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8(suppl 7):1–96.2. Couch JR Jr, Diamond S. Status migrainosus: causative and therapeutic aspects. Headache.1983:23:94–101.

3. Jauslin P, Goadsby PJ, Lance JW. The hospital management of severe migrainous headache. Headache.1991;31:658–660.

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5. Gallagher RM. Emergency treatment of intractable migraine. Headache. 1986;26:74–75.6. Bell R, Montoya D, Shuaib A, Lee MA. A comparative trial of three agents in the treatment of acute

migraine headache. Ann Emerg Med. 1990;19:1079–1082.7. Lane PL, McLellan BA, Baggoley CJ. Comparative efficacy of chlorpromazine and meperidine with

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Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York: PergamonPress; 1990:285–310.14. Resnick M, Burton BT. Droperidol vs. haloperidol in the initial management of acutely agitated

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