A Randomized, Placebo-controlled Trial of Acetaminophen for Treatment of Migraine Headache

Mary Jane Prior, PhD, MPH; Joseph R. Codispoti, MD; Min Fu, MS

Headache. 2010;50(5):819-833.

Abstract and Introduction

Abstract

Objective.—To evaluate the efficacy and safety of acetaminophen 1000 mg for the treatment of episodic migraine headache.
Background.—While acetaminophen is commonly used to treat migraine, there have been limited published clinical trial efficacy results.
Design/Methods.—Ten investigators at 13 private, ambulatory, primary care sites in the United States enrolled and treated 346 outpatient adults 18–72 years of age with migraine headache of moderate to severe intensity into a randomized, placebo-controlled, double-blind clinical trial of 6 hours duration. Each patient was randomly assigned to a single dose of study medication of acetaminophen 1000 mg (n = 177) or placebo (n = 169). The percentage of patients with a reduction in baseline headache pain intensity from severe or moderate to mild or none 2 hours after treatment and the headache pain intensity difference from baseline at 2 hours were the primary efficacy measures. Other measures of pain relief, severity differences from baseline for migraine-associated symptoms of nausea, photophobia, phonophobia, and functional disability, and percentage of patients with migraine-associated symptoms reduced to none were also assessed.
Results.—Significantly (P = .001) more patients treated with acetaminophen 1000 mg reported mild to no pain after 2 hours (52.0%) compared with those treated with placebo (32.0%). The mean pain intensity difference from baseline measured at 2 hours was significantly (P < .001) greater for patients treated with acetaminophen 1000 mg (0.82) compared with those treated with placebo (0.46). A significant difference in favor of acetaminophen 1000 mg over placebo was also observed at 1 hour after treatment for the percentage of patients with mild to no pain and for mean pain intensity difference from baseline. Acetaminophen 1000 mg was significantly more effective than placebo for all but 1 (pain reduced to none at 2 hours) clinically important secondary pain relief outcomes. Mean severity changes from baseline in migraine-associated symptoms of nausea, photophobia, phonophobia, and functional disability at 2 and 6 hours were significantly (P < .001) in favor of acetaminophen over placebo; the percentage of patients with no symptoms at 2 and 6 hours statistically significantly favored acetaminophen in 6 of 8 comparisons. Adverse events, overall, and specifically for nausea, were reported more frequently in the placebo group.
Conclusions.—Acetaminophen 1000 mg, a nonprescription drug, is an effective and well-tolerated treatment for episodic and moderate migraine headache. In addition, acetaminophen generally provided a beneficial effect on associated symptoms of migraine including nausea, photophobia, phonophobia, and functional disability.

Introduction

Migraine is a common disabling primary headache disorder consisting of periodic episodes of painful headache sometimes preceded by aura and frequently accompanied by 1 or more of the following symptoms: nausea, photophobia, and phonophobia.^[1] Based on a national survey (American Migraine Study II) conducted in 1999 that included results from 13,869 households, migraine occurs frequently and recurrently in the United States with an estimated 28 million sufferers 12 years of age and older.^[2] Based on the American Migraine Prevalence and Prevention Study (AMPP), a national survey conducted in 2004 that included 162,576 participants, 17.1% of women and 5.6% of men have 1 or more migraines per year, and 77% of migraineurs report 1 or more migraines per month.^[3] The social and economic impact of migraine is considerable, resulting in days missed from work or school and interference with family and social activities. Functional impairment has been reported to occur in over 90% of migraineurs, ranging from some impairment (39%) to severe impairment/required bed rest (53%).^[2] Fifty-one percent of 29,727 migraineurs reported that work/school productivity was reduced by at least 50% during the previous 3 months.^[2] In addition, 31% reported missing at least 1 day of work/school in the previous 3 months.^[2] A study of families that included a migraineur indicated increased use by an employed parent of short-term disability days (5 per year), sick days (4 per year), and workman's compensation days (3 per year) when compared with employed parents of matched control nonmigraine families.^[4] The annual national direct cost associated with migraine in the United States has been estimated as $11 billion (2004 data) and the indirect cost as $12 billion (2002–03 data).^[5,6]

Use of nonprescription analgesics for the treatment of acute migraine is common. The AMPP indicated that 49% of migraineurs usually used only nonprescription drugs to treat migraine headaches, and that an additional 29% of migraineurs sometimes used nonprescription drugs and sometimes used prescription drugs to treat their migraines.^[3] Results of an earlier United States national survey (American Migraine Study II) indicated that 57% of migraineurs used only nonprescription drugs to treat their headaches.^[7] Randomized controlled trials have demonstrated a beneficial treatment effect for migraine headache for nonprescription drugs including acetaminophen,^[8–10] ibuprofen,^[11–13] and the combination of acetaminophen, aspirin, and caffeine.^[9,13,14] Despite published data to the contrary, some treatment recommendations indicate that insufficient data exist to recommend the use of acetaminophen for migraine headache treatment.

Acetaminophen is an effective, well-tolerated analgesic that has been available as a nonprescription medication for over 50 years. Acetaminophen is a nonopiate, centrally acting analgesic and antipyretic agent derived from para-aminophenol. Acetaminophen is approved for use for the temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, backache, for the minor pain of arthritis, for the pain of menstrual cramps, and for the reduction of fever. Current acetaminophen labeling in the United States directs consumers to take 1000 mg every 4 to 6 hours while symptoms last. Consumers are also directed not to take more than 8 tablets in 24 hours and not to use for more than 10 days unless directed by a doctor.

The current study was designed to compare the efficacy and safety of acetaminophen 1000 mg to placebo in treating moderate-to-severe episodic migraine headache.

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Abstract and Introduction
Methods
Results
Discussion
References
Sidebar

Table 1. Demographic Characteristics and Baseline Migraine Symptoms
Characteristic	Acetaminophen (N = 177)	Placebo (N = 169)	P*
Women, n (%)	143 (80.8)	145 (85.8)	.213
Race, n (%)			.069
Caucasian	154 (87.0)	145 (85.8)
African American	18 (10.2)	11 (6.5)
Other	5 (2.8)	13 (7.7)
Age, mean (SD), years	38.1(11.0)	39.8 (11.8)	.168
Pain intensity, n (%)			.970
Moderate	126 (71.2)	120 (71.0)
Severe	51 (28.8)	49 (29.0)
Aura, n (%)	38 (21.5)	38 (22.5)	.819
Nausea, n (%)			.361
None	76 (42.9)	72 (42.6)
Mild	64 (36.2)	50 (29.6)
Moderate	27 (15.3)	37 (21.9)
Severe	10 (5.6)	10 (5.9)
Sensitivity to noise, n (%)			.965
None	15 (8.5)	12 (7.1)
Mild	46 (26.0)	46 (27.2)
Moderate	88 (49.7)	85 (50.3)
Severe	28 (15.8)	26 (15.4)
Sensitivity to light, n (%)			.066
None	2 (1.1)	10 (5.9)
Mild	42 (23.7)	34 (20.1)
Moderate	95 (53.7)	96 (56.8)
Severe	38 (21.5)	29 (17.2)
Vomiting, n (%)	6 (3.4)	5 (3.0)	.819
Ability to work/function, n (%)			.535
Normal	9 (5.1)	5 (3.0)
Mildly impaired	48 (27.1)	54 (32.0)
Moderately impaired	97 (54.8)	85 (50.3)
Severely impaired	23 (13.0)	25 (14.8)

*Statistical comparisons of categorical variables were performed using a chi-square test; comparison of mean age performed with one-way analysis of variance.

Table 2. Baseline Migraine Episode Characteristics
Characteristic	Acetaminophen (N = 177)	Placebo (N = 169)	P *
Likeness of migraine, n (%)			.158
Typical of usual migraine	172 (97.2)	159 (94.1)
Atypical of usual migraine	5 (2.8)	10 (5.9)
Location of migraine, n (%)			.621
Entire head	15 (8.5)	16 (9.5)
Front	25 (14.1)	29 (17.2)
Back	10 (5.6)	10 (5.9)
One side	87 (49.2)	77 (45.6)
Both sides	15 (8.5)	8 (4.7)
One temple	10 (5.6)	16 (9.5)
Other	15 (8.5)	13 (7.7)
Quality of migraine, n (%)			.338
Sharp	102 (57.6)	101 (59.8)
Dull	64 (36.2)	57 (33.7)
Burning	5 (2.8)	9 (5.3)
Other	6 (3.4)	2 (1.2)
Character of migraine, n (%)			.838
Throbbing/pulsating	104 (58.8)	102 (60.4)
Boring/piercing/stabbing	28 (15.8)	21 (12.4)
Pressing/tightening	42 (23.7)	43 (25.4)
Other	3 (1.7)	3 (1.8)

*Statistical comparisons of categorical variables were performed using a chi-square test.

Table 3. Summary of the Primary Endpoints Overall and by Baseline Pain Intensity
Endpoint, at 2 hours	Acetaminophen	Placebo	P
Pain reduced to mild or none, n/N (%)	92/177 (52.0)	54/169 (32.0)	0.001*
Pain intensity difference, mean (SD) N	0.82 (0.83) 177	0.46 (0.88) 169	<0.001*
By baseline pain intensity
Pain reduced to mild or none, n/N (%)
Moderate	77/126 (61.1)	46/120 (38.3)	0.001
Severe	15/51 (29.4)	8/49 (16.3)	0.122
Pain intensity difference, mean (SD) N
Moderate	0.73 (0.83) 126	0.32 (0.79) 120	<0.001
Severe	1.02 (0.81) 51	0.80 (1.00) 49	0.351

*Statistical comparisons of acetaminophen vs placebo for pain reduced to mild or none were made using the Cochran-Mantel-Haenszel test of general association stratified by baseline level of pain intensity. A 3-way analysis of variance (treatment, baseline pain intensity, and investigator) was used in the analysis of pain intensity difference at 2 hours; pairwise treatment comparisons were made using the Fisher least significant difference.

Table 4. Summary of Migraine-Associated Symptom Mean Severity Differences From Baseline and Percentage of Patients With Migraine-Associated Symptom Severity Reduced to None at Two and Six Hours Postmedication in Those Patients With Each Symptom at Baseline
Endpoint	Acetaminophen	Placebo	P *
Severity difference from baseline at 2 hours, mean (SD) N
Nausea	0.64 (0.80)/101	0.19 (0.92)/97	<.001
Photophobia	0.69 (0.84)/175	0.37 (0.82)/159	<.001
Phonophobia	0.67 (0.84)/162	0.33 (0.78)/157	<.001
Functional disability	0.56 (0.78)/168	0.24 (0.88)/164	<.001
Severity difference from baseline at 6 hours, mean (SD) N
Nausea	0.72 (1.01)/101	0.30 (1.06)/97	<.001
Photophobia	0.95 (1.05)/175	0.47 (1.04)/159	<.001
Phonophobia	0.90 (1.12)/162	0.45 (1.03)/157	<.001
Functional disability	0.78 (1.05)/168	0.29 (1.08)/164	<.001
Reduced to none at 2 hours, n/N (%)
Nausea	42/101 (41.6)	19/97 (19.6)	.002
Photophobia	34/175 (19.4)	21/159 (13.2)	.124
Phonophobia	37/162 (22.8)	20/157 (12.7)	.012
Functional disability	30/168 (17.9)	20/164 (12.2)	.136
Reduced to none at 6 hours, n/N (%)
Nausea	54/101 (53.5)	28/97 (28.9)	.001
Photophobia	74/175 (42.3)	41/159 (25.8)	.001
Phonophobia	69/162 (42.6)	41/157 (26.1)	.002
Functional disability	66/168 (39.3)	39/164 (23.8)	.002

*Statistical comparisons of acetaminophen vs placebo for symptom severity reduced to none were made using the Cochran-Mantel-Haenszel test of general association stratified by baseline level of symptom severity. A 3-way analysis of variance (treatment, symptom severity, and investigator) was used in the analysis of symptom severity difference at 2 and 6 hours; treatment comparisons were made using the Fisher least significant difference.

Table 5. Summary of Secondary Efficacy Endpoints
Endpoint	Acetaminophen (N = 177)	Placebo (N = 169)	P *
Pain reduced to mild or none at 6 hours, n (%)	98 (55.4)	56 (33.1)	.001
PID at 6 hours, mean (SD)	1.05 (1.13)	0.48 (1.16)	<.001
Pain reduced to none at 2 hours, n (%)	24 (13.6)	14 (8.3)	.117
Pain reduced to none at 6 hours, n (%)	62 (35.0)	35 (20.7)	.003
Overall impression of medication, mean	1.33	0.82	.001
SPID, mean (SD)	5.06 (4.97)	2.38 (5.24)	<.001
TOTPAR, mean (SD)	10.6 (7.68)	6.57 (7.39)	<.001
Rescue rate at 6 hours, n (%)	60 (33.9)	88 (52.1)	.001
Vomiting within 6 hours, n (%)	4 (2.3)	11 (6.5)	.065

*Statistical comparisons of acetaminophen vs placebo using statistical test described in methods section.
PID = pain intensity difference from baseline; SPID = time-interval weighted sum of the pain intensity difference from baseline; TOTPAR = time-interval weighted sum of the pain relief scores.

Table 6. Summary of Adverse Events
Evaluation	Acetaminophen (N = 177)	Placebo (N = 169)	P*
Any adverse event, n (%)	60 (33.9)	77 (45.6)	.028
Drug-related† adverse event, n (%)	18 (10.2)	25 (14.8)	.198
Serious adverse event, n (%)	0 (0.0)	0 (0.0)
Withdrawals from treatment because of adverse events, n (%)	2 (1.1)	1 (0.6)	1.000
Adverse events reported in ≥1% of patients in any treatment group, n (%)
Abdominal pain	2 (1.1)	1 (0.6)	1.000
Asthenia	2 (1.1)	0 (0.0)	.499
Pain	1 (0.6)	2 (1.2)	.615
Migraine	4 (2.3)	6 (3.6)	.535
Dyspesia	2 (1.1)	3 (1.8)	.679
Nausea	26 (14.7)	44 (26.0)	.011
Vomiting	4 (2.3)	9 (5.3)	.163
Dizziness	2 (1.1)	2 (1.2)	1.000
Somnolence	1 (0.6)	2 (1.2)	.615
Hyperacusis	34 (19.2)	37 (21.9)	.595
Photophobia	28 (15.8)	32 (18.9)	.479

*Statistical comparison made using the Fisher exact test.
†Drug-related includes adverse events with relation to drug of "Certain,""Probable/Likely,""Possible,""Unlikely," or "Unknown."

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A Randomized, Placebo-controlled Trial of Acetaminophen for Treatment of Migraine Headache

Abstract and Introduction

Abstract

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