Prophylactic Pharmacotherapy of Tension-Type Headache
Lars Bendtsen
Ninan T. Mathew
Prophylactic pharmacotherapy should be considered in patients with chronic tension-type headache (CTTH). Quality of life is substantially reduced in these patients and they are often difficult to treat. Simple analgesics are generally ineffective and medication-overuse may worsen the headache. Identification of a high intake of analgesics is essential as other treatments are ineffective in the presence of medication-overuse. Second, avoidance of risk factors such as unphysiological working positions or psychosocial stress is important.
Pharmacotherapy, behavioral modalities and physical medicine are effective for prophylaxis. Stress management, including relaxation therapy, physical exercise, and proper time-management strategies should go hand in hand with prophylactic pharmacotherapy. Significant comorbidities, e.g., anxiety or depression, should be treated concomitantly. In this respect, for example, a single medicine, such as tricyclic antidepressants to treat CTTH and comorbid depression, might be chosen. Medications that have been used for prophylaxis of CTTH include antidepressants, botulinum toxin, muscle relaxants, nonsteroidal antiinflammatory agents (NSAIDs), and miscellaneous agents.
ANTIDEPRESSANTS
Pharmacology of Antidepressants
The tricyclic antidepressant amitriptyline is the only drug that has proven to be effective in several controlled trials in tension-type headache (1). The general information on antidepressants will therefore mainly focus on amitriptyline. The tricyclic antidepressants all inhibit the presynaptic reuptake of serotonin (5-HT) and norepinephrine (NE) in the central nervous system, thus potentiating the activity of these neurotransmitters. Amitriptyline and doxepin mainly inhibit the reuptake of serotonin, whereas desipramine has its greatest effect on the inhibition of noradrenaline reuptake. However, the tricyclic antidepressants have numerous other actions. Amitriptyline is a potent blocker of muscarinic cholinergic receptors, H1-histamine receptors, α1-adrenergic receptors and several 5-HT receptors, e.g., 5-HT2A receptors, while the affinity for α2-adrenergic receptors is low (2,3). Moreover, amitriptyline potentiates the effect of endogenous opioids (4) and may act as a N-methyl-D-aspartate (NMDA) receptor antagonist (5). The selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, fluvoxamine, paroxetine and citalopram, have, as the name implies, a rather selective action on the serotonergic system, while novel antidepressants like mirtazapine and venlafaxine potentiate serotonin and noradrenaline neurotransmission.
Amitriptyline is lipid-soluble and rapidly absorbed after oral administration with peak concentrations achieved after 3-4 hours. The bioavailability is relatively low (45%) because of a large first-pass effect. Amitriptyline is mainly metabolized in the liver and its half-life ranges from 13-36 hours (6). Steady-state plasma concentrations are achieved within 7-10 days. Metabolism is slower in elderly patients, which may result in increased plasma concentrations. The pharmacokinetics of amitriptyline is characterized by large interpatient variability and there is no clear relationship between plasma concentrations and analgesic effect (6).
Mechanism of Action
The multiple actions exerted by amitriptyline makes it difficult to determine the exact mechanism(s) by which amitriptyline exerts its prophylactic effect in tension-type headache. The analgesic effect of amitriptyline seem unrelated to its antidepressant effect (7) and it cannot be ascribed solely to the inhibition of 5-HT reuptake (8,9). An effect on central pain pathways via inhibition of 5-HT
and NE reuptake, potentiation of endogenous opioids and attenuation of central sensitization via NMDA receptor antagonism are probably of importance (10,11), but the peripheral analgesic actions (12) of amitriptyline could also play a role. A recent study found that amitriptyline elicits its analgesic effect in CTTH by reducing the transmission of painful stimuli from myofascial tissues rather than by reducing overall pain sensitivity, and it was suggested that this effect could be caused by a segmental reduction of central sensitization in combination with a peripheral antinociceptive action (13). The efficacy of the noradrenergic and specific serotonergic antidepressant mirtazapine in tension-type headache (14) indicate that the analgesic effect of antidepressants is mediated through serotonergic, noradrenergic and opioid mechanisms (15).
and NE reuptake, potentiation of endogenous opioids and attenuation of central sensitization via NMDA receptor antagonism are probably of importance (10,11), but the peripheral analgesic actions (12) of amitriptyline could also play a role. A recent study found that amitriptyline elicits its analgesic effect in CTTH by reducing the transmission of painful stimuli from myofascial tissues rather than by reducing overall pain sensitivity, and it was suggested that this effect could be caused by a segmental reduction of central sensitization in combination with a peripheral antinociceptive action (13). The efficacy of the noradrenergic and specific serotonergic antidepressant mirtazapine in tension-type headache (14) indicate that the analgesic effect of antidepressants is mediated through serotonergic, noradrenergic and opioid mechanisms (15).
Review of Clinical Trials of Antidepressants
The placebo effect must be taken into account in any study of treatment for headache. Therefore, only placebo-controlled trials and trials comparing a well-documented treatment with a new treatment allow definitive statements about efficacy in tension-type headache. Because of the limited number of placebo-controlled trials, however, controlled trials comparing two potentially active treatments are included. It should be kept in mind, however, that when both treatments are seemingly effective and no difference between studies can be detected the results may be falsely positive.
Placebo-Controlled Trials of Amitriptyline
In 1964, Lance and Curran (16) conducted a crossover trial of amitriptyline 10-25 mg three times daily in 27 patients with CTTH (Table 84-1). Twelve patients had no improvement during treatment with either amitriptyline or placebo, 12 patients reported a response only to amitriptyline and 3 patients responded to both treatments. These results were significantly in favor of amitriptyline. The response to treatment was not correlated with the presence or absence of depressive symptoms.
TABLE 84-1 Summary of Randomized, Double-Blind, Placebo-Controlled Studies of Antidepressants in Chronic Tension-Type Headache | ||||||||||||||||||||||||||||||||||||||||||||||||
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Diamond and Baltes (17) tested two different dosage ranges of amitriptyline, a lower one between 10 and 60 mg/d and a higher one between 25 and 150 mg/d (Table 84-1). All patients were also suffering from anxiety or depression. The results suggested that the lower dose range reduced headache more than placebo, while there was no significant effect of the higher dose range.
Göbel et al. (18) evaluated amitriptyline 75 mg/d (Table 84-1). Patients with depression were excluded. Compared with placebo, headache duration was reduced significantly in the last week of the 6-week study. Neither headache frequency nor headache intensity were presented. Nevertheless, as headache duration decreased consistently throughout all 6 weeks of active treatment but not throughout placebo treatment, the study is in favor of an effect of amitriptyline.
Pfaffenrath et al. (19) investigated amitriptyline 50 to 75 mg/d and amitriptylinoxide 60 to 90 mg/d (Table 84-1). No significant difference in headache reduction was found between active treatments and placebo. However, also the frequencies of side-effects were similar on amitriptyline and placebo. Usually, amitriptyline has marked side-effects and the inability to detect known side-effects suggests insensitivity of the trial for reasons which remain obscure.
Bendtsen et al. (8) evaluated amitriptyline 75 mg daily and the SSRI citalopram 20 mg daily (Table 84-1). The patients had been resistant to numerous previous treatments and were not suffering from depression. Amitriptyline reduced the area under the headache curve (calculated as headache duration times headache intensity) by 30%
compared with placebo, which was highly significant, while citalopram had only a slight (12%) and insignificant effect. Amitriptyline also significantly reduced the secondary efficacy parameters of headache duration, headache frequency and intake of analgesics. The majority of patients reported dry mouth and drowsiness during treatment with amitriptyline, but the number of dropouts was lowest during amitriptyline treatment.
compared with placebo, which was highly significant, while citalopram had only a slight (12%) and insignificant effect. Amitriptyline also significantly reduced the secondary efficacy parameters of headache duration, headache frequency and intake of analgesics. The majority of patients reported dry mouth and drowsiness during treatment with amitriptyline, but the number of dropouts was lowest during amitriptyline treatment.
Holroyd and colleagues (20) 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 (Table 84-1). After 6 months, all three treatments reduced headache index with approximately 30% more than placebo, which was highly significant. Patients with depression were not excluded and data on the relation between changes in mood and headache were not presented. This makes it unclear whether the beneficial effects were due to specific antiheadache effects or to antidepressant actions. However, in a subsequent correspondence regarding this question the authors wrote that reductions in depression scores did not differ between patients who received active drug and placebo (21). The study is important in demonstrating a long-lasting effect of amitriptyline in CTTH.
Placebo-Controlled Trials of Other Antidepressants
The tetracyclic antidepressant maprotiline 75 mg daily was reported effective by Fogelholm and Murros (22), while Langemark et al. (23) reported both the tricyclic antidepressant clomipramine 75-150 mg daily and the tetracyclic antidepressant mianserin 30-60 mg daily effective (Table 84-1). Bendtsen et al. (8) found no effect of the SSRI citalopram. Singh and Misra (24) reported reduced intake of analgesics but no effect on headache of the SSRI sertraline (Table 84-1). Bendtsen and Jensen (14) reported that the noradrenergic and specific serotonergic antidepressant mirtazapine reduced area under the headache curve by 34% more than placebo in difficult to treat patients including patients who had not responded to amitriptyline (Fig. 84-1). This response is similar to that previously obtained with amitriptyline by the same group (8). Mirtazapine was well-tolerated.
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