RESEARCH BMJ: first published as 10.1136/bmj.c5222 on 20 October 2010. Downloaded from Tricyclic antidepressants and headaches: systematic review and meta-analysis Jeffrey L Jackson, director,4 William Shimeall, programme director,2 Laura Sessums, director,1 Kent J DeZee, programme director, general medicine fellowship,3 Dorothy Becher, research associate,1 Margretta Diemer, staff physician,1 Elizabeth Berbano, staff physician,1 Patrick G O’Malley, director, general internal medicine3 1General Medicine Division, Walter ABSTRACT between 8.4% and 18% worldwide.12 Tension-type Reed Army Medical Center, Objective To evaluate the efficacy and relative adverse headaches are even more common, occurring in 16- Washington, DC, USA 2 effects of tricyclic antidepressants in the treatment of 30% of people worldwide, with 3% having headaches Internal Medicine Residency, 2 National Naval Medical Center, migraine, tension-type, and mixed headaches. for more than 180 days a year. Migraine headaches Bethesda, MD, USA Design Meta-analysis. alone cost the United States $1bn (£0.64bn; €0.75bn) 3Uniformed Services University, Data sources Medline, Embase, the Cochrane Trials in medical costs and $13bn in lost productivity a year.3 Bethesda Registry, and PsycLIT. 4 Tricyclic antidepressants were first shown to be General Medicine Division, 4 Zablocki VA, 5000 W National Studies reviewed Randomised trials of adults receiving effective in preventing headaches in 1964 and have Avenue, Milwaukee, WI, 53295, tricyclics as only treatment for a minimum of four weeks. become a standard modality in headache USA Data extraction Frequency of headaches (number of prevention.5 Based on current standards for preventive Correspondence to: J L Jackson headache attacks for migraine and number of days with treatment in the United States, 43% of males and 34% [email protected] headache for tension-type headaches), intensity of of females who are candidates for such treatment are Cite this as: BMJ 2010;341:c5222 headache, and headache index. not receiving it.6 This may result from insufficient doi:10.1136/bmj.c5222 http://www.bmj.com/ Results 37 studies met the inclusion criteria. Tricyclics understanding of the magnitude of beneficial effects, significantly reduced the number of days with tension-type an overestimation of adverse effects, or the presump- headache and number of headache attacks from migraine tion that efficacy is only confined to migraine head- than placebo (average standardised mean difference aches. In a previous meta-analysis of antidepressants −1.29, 95% confidence interval −2.18 to −0.39 and −0.70, for headaches, we found that antidepressants were −0.93 to −0.48) but not compared with selective serotonin effective in preventing headaches, equally for ten- reuptake inhibitors (−0.80, −2.63 to 0.02 and −0.20, −0.60 sion-type headaches and migraine headaches.7 This to 0.19). The effect of tricyclics increased with longer meta-analysis was limited by the relatively small num- on 29 September 2021 by guest. Protected copyright. duration of treatment (β=−0.11, 95% confidence interval ber of available studies at the time. To expand on our −0.63 to −0.15; P<0.0005). Tricyclics were also more likely previous systematic review we assessed the efficacy to reduce the intensity of headaches by at least 50% than and tolerability of tricyclics in reducing the headache either placebo (tension-type: relative risk 1.41, 95% burden among adults with migraine or tension-type confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to headache. We also compared tricyclics with other 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 treatment modalities to assess whether the efficacy of to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely tricyclics varies by type of headache, dose, and dura- to cause adverse effects than placebo (1.53, 95% tion of treatment. confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry METHODS mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), This report closely adheres to the PRISMA method for and weight gain (P<0.001 for both), but did not increase reporting on systematic reviews. We searched, without dropout rates (placebo: 1.22, 0.83 to 1.80, selective language restrictions, Medline (1966-March 2010) and serotonin reuptake inhibitors: 1.16, 0.81 to 2.97). Embase (1974-March 2010) using the search strategy Conclusions Tricyclic antidepressants are effective in (antidepressive agents, tricyclic OR antidepressive$ preventing migraine and tension-type headaches and are OR tricyclic$ OR amitriptyline OR amoxapine OR more effective than selective serotonin reuptake clomipramine OR desipramine OR dibenzepin OR inhibitors, although with greater adverse effects. The dothiepin OR doxepin OR imipramine OR lofepra- effectiveness of tricyclics seems to increase over time. mine OR nortriptyline OR opipramol OR protripty- line OR trimipramine) AND (headache or headache INTRODUCTION disorders or headache$ OR migrain$ OR tension$ Headaches are common and cause distress and disabil- OR cephalgi$ OR cephalalgi$). We also searched ity. The prevalence of migraine headaches ranges CRISP and FEDRIP databases for unpublished BMJ | ONLINE FIRST | bmj.com page 1 of 13 RESEARCH literature. In addition we searched the Cochrane Pain, headache. Studies reporting less than 50% improve- BMJ: first published as 10.1136/bmj.c5222 on 20 October 2010. Downloaded from Palliative and Supportive Care Trials Register; the ment were not abstracted. We assessed article quality Cochrane Central Register of Controlled Trials; Psy- independently and in duplicate (DB, JLJ) using the risk cLIT (1974-2002); and PsycINFO (1974-March 2010), of bias assessment tool developed by the Cochrane and carried out a review of the bibliographies of all collaboration,12 with good inter-rater agreement articles retrieved. The last search date was 25 March (Cochrane: κ=0.83). Disagreements were resolved by 2010. The search was supplemented by searches car- consensus. ried out by medical librarians at our institution as well as the Cochrane clinical research group. Statistical analysis We included published, randomised clinical trials Because reported measures for headache varied, a that evaluated the efficacy of tricyclic antidepressants priori we preferentially abstracted and pooled data in reducing the frequency or severity of migraine or on headache measures in this order: frequency of head- tension-type headaches. Treatment groups were ache, intensity of headache, and headache index, per required to receive a tricyclic regularly at any dosing the recommendations of the reviewers of our schedule as a single intervention for at least four weeks. Cochrane protocol. For frequency we used the number Tricyclics could not be combined with other drugs of headache attacks for migraines and number of days with possible prophylactic benefit or effect augmenta- with headache for tension-type headaches. Intensity tion. Comparison groups could receive placebo or a was abstracted in the scale used by each study; some specified alternative drug or non-drug treatment. studies used visual analogue scales, others used other Additional inclusion criteria required studies to continuous measures of intensity. Many studies used a include only adults (>18 years) with migraine or ten- “headache index” to sum aspects of the burden of sion-type headache (frequent episodic or chronic) that headache, usually derived by multiplying the fre- could reasonably be defined on the basis of diagnostic quency of the headache by intensity. In addition we criteria described in 1988 by the International Head- pooled analgesic use. Because of differences in mea- ache Society8 or earlier.910 We excluded secondary surement of headache burden between studies, we headaches, such as those related to drug overuse, con- pooled standardised differences between studies, a cussion, or lumbar puncture. Because the classification measure also known as an effect size. By convention, of headache has changed over time, two authors inde- effect sizes greater than 0.8 are considered as large, pendently reviewed each included article’s definition those between 0.6 and 0.8 as moderate, and those of headache and, where possible, classified it according between 0.2 and 0.6 as small.13 http://www.bmj.com/ to the most recent criteria of the International Head- For studies with more than one arm, we pooled the ache Society.8 data for all arms into one group; if this was not possible we reduced the sample size for each arm by 50% to Study selection and data abstraction prevent overweighting studies. We pooled data using We selected articles for inclusion in two stages. In the the DerSimonian and Laird random effects model.14 first stage two researchers (PGO’M, KJD) indepen- Regardless of headache type, we pooled all studies dently reviewed titles and abstracts to select full text with stratified analysis to provide estimates for each articles for retrieval. A priori we decided to include subgroup, and used metaregression to test for differ- on 29 September 2021 by guest. Protected copyright. all articles recommended by either reviewer for full ences between these groups. Heterogeneity was text retrieval. Agreement was only modest during this assessed visually using Galbraith plots15 and the I2 stage (κ=0.66). During the second stage two other statistic.16 For continuous data (such as headache fre- researchers (LS, MD) independently applied inclusion quency and