Patrick G. O’Malley, MD, MPH Jeffrey L. Jackson, MD, MPH James Santoro, MD, MPH Glen Tomkins, MD, MPH Erin Balden, MD, MPH Kurt Kroenke, MD Washington, DC; Bethesda, Maryland; El Paso, Texas; and Indianapolis, Indiana Submitted, revised, July 15, 1999. From the Department of Medicine (P.G.O., G.T., E.B.), Walter Reed Army Medical Center, Washington, DC; Uniformed Services University of the Health Sciences (J.L.J), Bethesda; William Beaumont Army Medical Center (J.S.), El Paso; and the Regenstrief Institute for Health Care and Indiana University School of Medicine (K.K.), Indianapolis. The opinions and assertions in this paper are the private views of the authors and should not be interpreted to reflect the views of the Department of the Army or the Department of Defense.Reprint requests should be addressed to Patrick G. O’Malley, MD, MPH, Division of General Internal Medicine, Walter Reed Army Medical Center, 6800 Georgia Avenue, Washington, DC 20307. E-mail: pgomalley@msn.com.
References
Data Abstracted
We abstracted information about the type of syndrome, setting, treatment (including dosage and duration of treatment, active or placebo control, and follow-up), demographics and number of participants enrolled, assessment of comorbid psychiatric disease (and if so, the instrument used), adverse effects, outcomes, and statistical analysis of results reported.
Meta-Analysis
We performed a meta-analysis on only the placebo-controlled studies from which data was extractable. We used the random effects model for combining data proposed by DerSimonian and Laird,12 and the tests used by Begg and Mazumdar13 and Egger and coworkers14 for the assessment of publication bias in placebo-controlled studies. To assess the number of studies necessary to render the effect size insignificant, we used the “file drawer” method of Rosenthal.15
Results
There were 392 articles identified by our search strategy of which 94 were included for review. Reasons for exclusion were as follows: review articles (115), observational studies (61), lack of placebo or nonantidepressant controls (50), neuropathic pain (diabetes, postherpetic or traumatic neuralgia, cancer or degenerative joint pain; 24 studies), pediatric patient population (21), duplicate reporting of data (20), and letters (7).
The 6 symptom syndromes in the included studies were: headache (migraine, tension, mixed); fibromyalgia; functional gastrointestinal (GI) disorders (irritable bowel syndrome, functional dyspepsia, idiopathic esophageal contraction abnormalities); idiopathic pain (psychogenic, facial, chest, musculoskeletal, pelvic); tinnitus; and chronic fatigue. The number of trials for each individual syndrome and the general characteristics of these studies are presented in Table 1. The only symptom in our search for which studies of antidepressants could not be found was dyspnea.
Characteristics of Included Studies
We included 94 studies that involved a total of 6595 patients.1,16-109 In describing all trials as a whole, the median number of patients in each included trial was 50 (range 7 to 698), and the majority of the patients in the trials were women (76% pooled from all the trials, ranging from 42% in the tinnitus trials to 92% in the fibromyalgia trials). Most of the trials were undertaken in referral clinics (87%) rather than a primary care setting (12%). Eighty-two percent of the trials were done after 1980, and most were done in Europe (only 28% were done in the United States). Almost half of the trials were industry sponsored (45%).
The duration of the trials was short (median = 9 weeks) relative to the chronicity of the symptoms (74% of the trial populations had a median duration of symptoms greater than 3 years), and the dropout rate was high—40% of the trials had dropout rates greater than 20% (ranging from 18% in functional GI trials to 67% in idiopathic pain trials).
Quality of Studies
Overall, the quality of the studies was fair. The principal characteristics responsible for the deficits in quality were appropriateness of randomization (16% of the trials), appropriateness of blinding (35%), and description of the assessment of adverse effects (37%). The descriptions of withdrawals and dropouts (71%), statistical analysis (79%), and inclusion criteria (78%) were considerably better. Intention-to-treat analysis, an item that was not included in the quality assessment tool, was either explicitly stated (or implicitly done when there were no withdrawals) in only 13 of the 55 (24%) parallel-design placebo-controlled studies.
The overall mean quality score was 4.8, ranging from 4.0 in chronic fatigue and tinnitus studies (only 2 studies each), to 5.8 in fibromyalgia studies (Table 2).
Specific Symptom Syndromes
The details of the individual syndromes by antidepressants used, proportion of studies showing benefit, quality scores, correlation with effect on depression, and effect size are presented in Table 2. The dosing and titration of antidepressants in these trials were variable and dependent on the agent used. Generally, doses were titrated, and therapeutic doses were lower than those used in treating depression, except in SSRI trials where the antidepressant doses were typically used without titration.
Chronic Headache. The differences in relative efficacy and general study characteristics were negligible between trials of migraine headache compared with trials of tension headache. We grouped all of these trials under the general term of chronic headache.
There were 50 headache trials of which 22 studied antiserotonin antidepressants (pizotifen, mianserin, and ritanserin);16-36,65 19 studied a tricyclic antidepressant (TCA);37-44;50-60 7 studied an SSRI;45-49 one studied both a TCA and an antiserotonin antidepressant,61 and one studied both a TCA and an SSRI.62
Antiserotonin agents are not available in the United States and have been used predominantly in Europe for migraine prophylaxis and depression. They have been demonstrated to have antidepressive effects in placebo-controlled studies.110,111 Although all of the 7 antiserotonin studies (all pizotifen)26-28,31-34 that used active nonantidepressive controls (calcium channel blockers, metoprolol, and naproxen) did not find pizotifen to be more efficacious than other treatments, all 16 of the antiserotonin placebo-controlled trials (12 pizotifen, 3 mianserin, 1 ritanserin)16-25,29,30,35,36,61,65 demonstrated superior efficacy to placebo.
