Lance and Curran [51] reported amitriptyline 10–25 mg three times daily to be effective, while Diamond and Baltes [52] found amitriptyline 10 mg/day but not 60 mg/day to be effective. Amitriptyline 75 mg/day was reported to reduce headache duration in the last week of a 6-week study [53], while no difference in effect size between amitriptyline 50–75 mg/day or amitriptylinoxide 60–90 mg/day and placebo was found in one study [54]. However, also the frequencies of side effects were similar on amitriptyline and placebo in the latter study. The inability to detect the well-known side effects of amitriptyline suggests insensitivity of the trial for reasons which remain obscure. Bendtsen et al. [55] found that amitriptyline 75 mg daily reduced the area-under-the-headache curve (calculated as headache duration times headache intensity) by 30 % compared with placebo, which was highly significant. Holroyd and colleagues [56] treated patients with antidepressants (83 % took amitriptyline median dose 75 mg daily and 17 % took nortriptyline median dose 50 mg daily) and compared this with stress management therapy and with a combination of stress management and antidepressant treatment. After 6 months, all three treatments reduced headache index with approximately 30 % more than placebo, which was highly significant. The effect tended to be greatest in the combined treatment group.

The tricyclic antidepressant clomipramine 75–150 mg daily [57] and the tetracyclic antidepressants maprotiline 75 mg daily [58] and mianserin 30–60 mg daily [57] have been reported more effective than placebo. Interestingly, some of the newer more selective antidepressants with action on serotonin and noradrenaline seem to be as effective as amitriptyline with the advantage that they are tolerated in doses needed for the treatment of a concomitant depression. Thus, the noradrenergic and specific serotonergic antidepressant mirtazapine 30 mg/day reduced headache index by 34 % more than placebo in difficult to treat patients without depression including patients who had not responded to amitriptyline [59]. The efficacy of mirtazapine was comparable to that of amitriptyline reported by the same group [55]. A systematic review concluded that the two treatments may be equally effective for the treatment of chronic TTH [60]. The serotonin and noradrenaline reuptake inhibitor venlafaxine 150 mg/day [61] reduced headache days from 15 to 12 per month in a mixed group of patients with either frequent episodic or chronic TTH. Low-dose mirtazapine 4.5 mg/day alone or in combination with ibuprofen 400 mg/day was not effective in chronic TTH. The selective serotonin reuptake inhibitors (SSRIs) citalopram [55] and sertraline [62] have not been found more effective than placebo. SSRIs have been compared with other antidepressants in six studies. These studies were reviewed in a Cochrane analysis that concluded that SSRIs are less efficacious than tricyclic antidepressants for the treatment of chronic TTH [63].

There have been conflicting results for treatment with the muscle relaxant tizanidine [58, 64], while the NMDA-antagonist memantine was not effective [65]. Botulinum toxin has been extensively studied [66–76]. It was concluded in a systematic review that botulinum toxin is likely to be ineffective or harmful for the treatment of chronic TTH [60]. The prophylactic effect of daily intake of simple analgesics has not been studied in trials that had this as the primary efficacy parameter, but explanatory analyses indicated that ibuprofen 400 mg/day was not effective in one study [77]. On the contrary, ibuprofen increased headache compared with placebo indicating a possible early onset of medication-overuse headache [77]. Topiramate [78] and buspirone [79] have been reported effective in open-label studies.

Amitriptyline has a clinically relevant prophylactic effect in patients with chronic TTH and should be drug of first choice (Fig. 9.1). Mirtazapine or venlafaxine are probably effective, while the older tricyclic and tetracyclic antidepressants clomipramine, maprotiline and mianserin may be effective. A recent systematic review [60] concluded that amitriptyline and mirtazapine are the only forms of treatment that can be considered proven beneficial for the treatment of chronic TTH. However, the last search was performed in 2007 before publication of the study on venlafaxine [61].

Amitriptyline should be started at low dosages (10–25 mg/day) and titrated by 10–25 mg weekly until the patient has either good therapeutic effect or side effects are encountered. It is important that patients are informed that this is an antidepressant agent but has an independent action on pain. The maintenance dose is usually 30–75 mg daily administered 1–2 h before bedtime to help to circumvent any sedative adverse effects. The effect is not related to the presence of depression [55]. A significant effect of amitriptyline may be observed already in the first week on the therapeutic dose [55]. It is therefore advisable to change to other prophylactic therapy, if the patient does not respond after 4–8 weeks on maintenance dose. The side effects of amitriptyline include dry mouth, drowsiness, dizziness, obstipation and weight gain. Mirtazapine, of which the major side effects are drowsiness and weight gain, or venlafaxine, of which the major side effects are vomiting, nausea, dizziness and loss of libido, should be considered if amitriptyline is not effective or not tolerated. Discontinuation should be attempted every 6–12 months. The physician should keep in mind that the efficacy of preventive drug therapy in TTH is often modest, and that the efficacy should outweigh the side effects.

Amitriptyline is drug of first choice for the prophylactic treatment of chronic TTH. Mirtazapine and venlafaxine are drugs of second choice.