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Tricyclic antidepressants and headaches: systematic review and meta-analysis

BMJ 2010; 341 doi: (Published 20 October 2010) Cite this as: BMJ 2010;341:c5222
  1. Jeffrey L Jackson, director4,
  2. William Shimeall, programme director2,
  3. Laura Sessums, director1,
  4. Kent J DeZee, programme director, general medicine fellowship3,
  5. Dorothy Becher, research associate1,
  6. Margretta Diemer, staff physician1,
  7. Elizabeth Berbano, staff physician1,
  8. Patrick G O’Malley, director, general internal medicine3
  1. 1General Medicine Division, Walter Reed Army Medical Center, Washington, DC, USA
  2. 2Internal Medicine Residency, National Naval Medical Center, Bethesda, MD, USA
  3. 3Uniformed Services University, Bethesda
  4. 4General Medicine Division, Zablocki VA, 5000 W National Avenue, Milwaukee, WI, 53295, USA
  1. Correspondence to: J L Jackson Jeffrey.jackson6{at}
  • Accepted 9 August 2010


Objective To evaluate the efficacy and relative adverse effects of tricyclic antidepressants in the treatment of migraine, tension-type, and mixed headaches.

Design Meta-analysis.

Data sources Medline, Embase, the Cochrane Trials Registry, and PsycLIT.

Studies reviewed Randomised trials of adults receiving tricyclics as only treatment for a minimum of four weeks.

Data extraction Frequency of headaches (number of headache attacks for migraine and number of days with headache for tension-type headaches), intensity of headache, and headache index.

Results 37 studies met the inclusion criteria. Tricyclics significantly reduced the number of days with tension-type headache and number of headache attacks from migraine than placebo (average standardised mean difference −1.29, 95% confidence interval −2.18 to −0.39 and −0.70, −0.93 to −0.48) but not compared with selective serotonin reuptake inhibitors (−0.80, −2.63 to 0.02 and −0.20, −0.60 to 0.19). The effect of tricyclics increased with longer duration of treatment (β=−0.11, 95% confidence interval −0.63 to −0.15; P<0.0005). Tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo (tension-type: relative risk 1.41, 95% confidence interval 1.02 to 1.89; migraine: 1.80, 1.24 to 2.62) or selective serotonin reuptake inhibitors (1.73, 1.34 to 2.22 and 1.72, 1.15 to 2.55). Tricyclics were more likely to cause adverse effects than placebo (1.53, 95% confidence interval 1.11 to 2.12) and selective serotonin reuptake inhibitors (2.22, 1.52 to 3.32), including dry mouth (P<0.0005 for both), drowsiness (P<0.0005 for both), and weight gain (P<0.001 for both), but did not increase dropout rates (placebo: 1.22, 0.83 to 1.80, selective serotonin reuptake inhibitors: 1.16, 0.81 to 2.97).

Conclusions Tricyclic antidepressants are effective in preventing migraine and tension-type headaches and are more effective than selective serotonin reuptake inhibitors, although with greater adverse effects. The effectiveness of tricyclics seems to increase over time.


  • Editorial, doi:10.1136/bmj.c4871
  • This paper is based on a Cochrane review first published in the Cochrane Library ( for information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms. The Cochrane Library should be consulted for the most recent version of the review. The results of a Cochrane review can be interpreted differently, depending on people’s perspectives and circumstances. Please consider the conclusions presented carefully. They are the opinions of review authors, and are not necessarily shared by the Cochrane Collaboration.

  • Contributors: JLJ had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. He is guarantor. All authors were involved in the study design and data collection, contributed to the writing and revision of the manuscript, and are able to take responsibility for its content. All authors were present at idea inception and were assigned various specific tasks in the process of creating this manuscript. All tasks were done in duplicate: LS and EB retrieved the articles, LS and MD selected the articles, WS and KJD abstracted the data, and JLJ and DB rated the articles for quality. JLJ and LS carried out the analysis. All the opinions in this article are those of the authors and should not be construed to reflect, in any way, those of the Department of the Army, Navy, the Department of Defense or the Department of Veterans Affairs.

  • Funding: This study received no external funding. Our institutional review board reviewed and approved this manuscript for publication.

  • Competing interests: All authors have completed the Unified Competing Interest form at ( (available on request from the corresponding author) and declare that (1) they have no relationships with companies that might have an interest in the submitted work; (2) their spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and (3) no authors have any non-financial interests that may be relevant to the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

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