Advances in the Pharmacologic Treatment of Tension-Type Headache Marcelo E. Bigal, MD, PhD, Alan M. Rapoport, MD, and Richard Hargreaves, PhD
Corresponding author Marcelo E. Bigal, MD, PhD Global Director for Scientific Affairs, Merck Research Laboratories, 1 Merck Drive, Whitehouse Station, NJ 08889, USA. E-mail:
[email protected] Current Pain and Headache Reports 2008, 12:442–446 Current Medicine Group LLC ISSN 1531-3433 Copyright © 2008 by Current Medicine Group LLC
Tension-type headache (TTH) is the most prevalent form of primary headache in the general population. We discuss advances in the treatment of TTH. We briefly review nonpharmacologic therapies and then focus on current pharmacologic strategies. For acute treatment, the most common interventions involve the use of simple analgesics and anti-inflammatory medications, often taken by the patient without a prescription. For preventive treatment, amitriptyline is the best-studied drug, but nortriptyline, mirtazapine, tizanidine, the selective serotonin reuptake inhibitors, and other medications can be used. We close by discussing potential future therapies, including calcitonin gene–related peptide receptor antagonism, as well as substance P and the nitric oxide pathways.
Introduction Tension-type headache (TTH) is the most common type of primary headache, with 1-year period prevalences ranging from 31% to 74% [1,2]. The fi rst edition of the International Classification of Headache Disorders (ICHD-I) distinguished two subtypes of TTH, episodic TTH (ETTH, < 15 days of headache/month) and chronic TTH (CTTH, ≥ 15 days/month) [3]. The ICHD-II (2004) distinguishes three subtypes: infrequent ETTH (headache episodes on < 1 day/month), frequent ETTH (headache episodes on 1–14 days/month), and CTTH (2.3; headache on ≥ 15 days/month) [4]. Table 1 presents the diagnostic criteria for TTH. In contrast with migraine, the main pain features of TTH are bilateral location, nonpulsating quality, mild to moderate intensity, and lack of aggravation by routine physical activity [4]. The pain cannot be accompanied
by nausea, although just one of photophobia or phonophobia does not exclude the diagnosis. CTTH invariably evolves from ETTH. A recently recognized disorder that often phenotypically resembles CTTH but is daily and unremitting from onset is separately classifi ed as new daily persistent headache [4]. TTH is very prevalent in the population. A Danish population study conducted in 1999 showed that the lifetime prevalence of ETTH was 79% (69% in men and 88% in women) [2]. Interestingly, when the same group replicated the study 12 years later, they found that the overall prevalence of TTH (87%), and especially of what they called frequent TTH (37%), had increased significantly [5••]. In the United States, a study conducted in 1995 showed that the overall 1-year prevalence of ETTH was 38.3% [1]. In the same study, the 1-year period prevalence of CTTH was 2.2%. The disability of ETTH is lower than the disability of episodic migraine [6,7]. Similarly, the disability of CTTH is lower than that of chronic migraine. Nonetheless, the burden of TTH is significant and well documented [6–8]. However, because the classification of TTH is based on what it is not (it is not migraine—it is not associated with nausea, it is not often unilateral, etc.), and because the burden of TTH is thought to be insignificant, clinical investigation of treatment options for TTH lags far behind that for migraine, in both number and impact. Accordingly, we discuss treatment options for TTH. We start by briefly reviewing the clinical phenotype of TTH. We then focus on the treatment of TTH, separately discussing the nonpharmacologic as well as acute and preventive pharmacologic treatments. We close by discussing future potential therapies for TTH.
The Clinical Phenotype of Tension-Type Headache The three subtypes of TTH differ in attack frequency, as mentioned earlier (Fig. 1) [4]. However, the clinical characteristics of the headaches are basically the same (Table 1). The criteria were designed to distinguish between TTH and migraine. TTH is characterized by two of the following four pain features: the pain is bilateral in location, nonthrobbing
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Table 1. Classification of tension-type headache according to the Second Edition of the International Classification of Headache Disorders Diagnostic criteria A. At least 10 episodes fulfilling criteria B–E; number of days with such headache < 1 day/month (episodic infrequent), from 1–14 (episodic frequent), or ≥ 15 (chronic) B. Headache lasting from 30 minutes to 7 days C. At least 2 of the following pain characteristics: 1. Pressing/tightening (nonpulsating) quality 2. Mild or moderate intensity (may inhibit, but does not prohibit activities) 3. Bilateral location 4. No aggravation by walking stairs or similar routine physical activity D. Both of the following: a. No nausea or vomiting (anorexia may occur) b. Photophobia and phonophobia are absent, or one but not the other may be present E. Not attributed to another disorder 2.X.1 Associated with pericranial tenderness* Diagnostic criteria A. Fulfills criteria for 2.X B. Increased tenderness on pericranial manual palpation 2.X.2 Not associated with pericranial tenderness* Diagnostic criteria A. Fulfills criteria for 2.X B. Not associated with increased pericranial tenderness *X means the correspondent digit of infrequent episodic (1), frequent episodic (2), or chronic (3).
in quality, mild to moderate in intensity, and not aggravated by physical activity. In addition, the pain is not associated with nausea, although the presence of just one of photophobia or phonophobia does not exclude the diagnosis. Patients usually describe their pain as a “dull,” “nonpulsating” headache; some patients refer to a “band” or “cap” compressing their head, whereas others mention a big “weight” over their head and/or shoulders. A pulsating character occurs “seldom” or “never” in 80% to 86% of the patients from clinical populations [7,9]. Thus, the most frequent pain quality in TTH is nonpulsating and pressing, although it may be experienced as periodically pulsating during severe pain episodes. Pericranial tenderness recorded by manual palpation is a significant abnormal fi nding in some patients with TTH, to the point that TTH is subdivided into “with” or “without” this pericranial tenderness [10,11]. When present, it is associated with the intensity and frequency of headache and may be exacerbated during headache attacks. Electromyogram and pressure algometry have limited clinical diagnostic value in TTH [11]. In migraine, the burden of disease is determined not only by the pain, but also by the associated symptoms (eg, aura, nausea, photophobia, and phonophobia) [12]. Because TTH lacks associated symptoms, the burden is determined mainly by the severity of pain (which is often
Episodic
Infrequent episodic TTH
Frequent episodic TTH
Chronic
Chronic TTH
1/month 15/month Frequency of attacks Figure 1. The subdivision of tension-type headache (TTH) based on the frequency of attacks.
not severe) and the frequency of attacks (which may be very frequent). Accordingly, although ETTH can often be treated by simple analgesics, CTTH sufferers often benefit from nonpharmacologic treatment strategies, as well as from prevention. Herein we discuss separately these forms of treatment.
Treatment of Tension-Type Headache Nonpharmacologic techniques Nonpharmacologic treatment, which is widely used for TTH, is rarely evidence based. Physical therapy is the most common form and includes relaxation and exercise
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programs, improvement of posture, hot and cold packs, ultrasound, and electrical stimulation. Most of these modalities have not been properly evaluated [13,14]. A recent controlled study reported a modest effect of a standardized 8-week physiotherapy program that included relaxation techniques, smooth stretching, and daily muscle exercise at home [14]. Spinal manipulation has also been extensively used, but the amount of evidence is insufficient for fi nal conclusions [15]. Patients with frequent attacks of TTH, especially CTTH, are often referred for acupuncture [15]. The evidence to support this treatment modality is weak. A recent randomized, controlled, multicenter, patient-and-observerblinded trial investigated 409 patients with TTH from German clinics [16•]. All had more than 10 headache days per month. Interventions were verum acupuncture according to the practice of traditional Chinese medicine or sham acupuncture, consisting of superficial needling at nonacupuncture points. Response was defined as more than 50% reduction in headache days/month at 6 months and no use of excluded concomitant medication or other therapies. In the intent-to-treat analysis, 33% of verum patients and 27% of sham controls (P = 0.18) were classified as responders. Accordingly, the magnitude of the effect was small and, as in most trials of migraine, verum acupuncture was no more effective than sham acupuncture [17]. Biofeedback and relaxation training are self-regulation strategies that aim to provide patients who have significant stress with the ability to consciously reduce the muscle tension and general arousal that precipitate headaches [18]. The ultimate goal is to reduce the emotional and physiologic arousal that can trigger and exacerbate headache; it typically includes relaxation training, cognitive restructuring, and problem-solving methods [19,20]. A well-conducted placebo-controlled study demonstrated significant and comparable efficacy of stress management therapy and amitriptyline, with a tendency to greater improvement when the two treatments were combined [19].
Pharmacologic treatment Acute treatment The pharmacologic treatment of the acute episode of TTH is most often done with simple analgesics (aspirin and acetaminophen), as well as with anti-inflammatory medications [21,22]. In well-controlled trials, both aspirin (500 and 1000 mg) and acetaminophen (1000 but not 500 mg) were superior to placebo in the treatment of TTH [23]. There is no evidence that specific anti-inflammatory medications are better choices for TTH [24]. Patients who have infrequent TTH attacks and respond well to over-the-counter drugs only rarely seek medical care. When attacks are frequent, preventive medications are warranted (see following text). More difficult decisions involve the treatment of patients with ETTH who are not responsive to simple analgesics. Frequent intake of simple analgesics or NSAIDs (eg, ≥ 10 days/month) and
use of combination analgesics should generally be avoided because of the risk of medication-overuse headache [25], and patients should be thoroughly informed about this. The triptans do not have a clinically relevant effect in patients with pure ETTH [26]. However, it has been suggested that triptans may be effective in treating TTH in individuals who also have migraine [27]. Accordingly, triptans are sometimes used in the treatment of TTH. Opioids or sedative hypnotics should not be used routinely to treat TTH because they impair alertness and are common causes of overuse and dependence syndromes [25]. As a rule, if patients need opiates, they should be put on preventive treatment. Preventive treatment Preventive pharmacotherapy should be considered in all patients with CTTH, in those with ETTH and frequent attacks ( > eight headache days/month), and in those with disability. Since 1964, the tricyclic antidepressant amitriptyline has been the mainstay in treatment of patients with CTTH, and several subsequent studies have supported its use [28–31]. Although amitriptyline generally is fairly well tolerated, most patients experience some side effects, especially weight gain. Other tricyclic and tetracyclic antidepressants may also be effective, but there is insufficient evidence for this. More recently, mirtazapine, a relatively new noradrenergic and specific serotonergic antidepressant with a better tolerability profile than the tricyclic antidepressants, was reported to be effective in CTTH [32]. Mirtazapine, 15 to 30 mg/day, had an effect similar to amitriptyline when compared with placebo in nondepressed, difficult-to-treat patients with CTTH [32]. Muscle relaxants have often been used in TTH, but only the centrally acting drug tizanidine has been tested (with conflicting results) [33–35]. Antiepileptic drugs, such as topiramate, have been tested only in open-label trials [36], and evidence is limited. In an open-label study assessing the efficacy of this drug in CTTH, headache frequency declined from 23.50 ± 5.32 days (baseline, mean, SD) to 12.58 ± 6.28 days at weeks 13 to 24 (P < 0.0001), with frequency of severe headaches dropping from 8.18 to 3.14 days (P < 0.0001) [36]. Botulinum type A toxin (BoNT-A) is sometimes used in patients with CTTH. However, most studies are negative for the primary end point [37]. The guidelines for botulinum toxin use in neurologic disorders state that BoNT-A is probably ineffective in episodic migraine and CTTH (level B) [38]. The usual goals of preventive treatment are a reduction in the frequency and intensity of headache and improved response to abortive treatment. The optimal duration of preventive treatment is unknown. In the absence of evidence, a reasonable practice is to continue a successful preventive regimen for 6 months and then slowly reduce the dose while observing headache frequency.
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Future Targets In the past 10 years, there has been increasing interest in the role of central factors in TTH [39]. For example, thresholds for pain and mechanical stimuli are decreased in CTTH sufferers [40,41]. Furthermore, it has been suggested that the central sensitization and thereby the chronic pain state in patients with CTTH may be due to sensitization at the level of the spinal dorsal horn or trigeminal nucleus, or both, induced by prolonged nociceptive input from pericranial myofascial tissues. Supporting these points, recent studies have demonstrated sustained facilitation of brainstem nociception due to noxious neck muscle input evoked by nerve growth factor or α,β-methylene ATP in mice [42]. Calcitonin gene–related peptide (CGRP) has emerged as a key neuropeptide in the pathophysiology of migraine [43]. Up to 40% of trigeminal neurons express CGRP [44]. Increased CGRP is also detected between migraine attacks in susceptible patients [45], and CGRP levels correlate with the degree of headache pain [46]. CGRP is implicated in several processes relevant to pain transmission overall, not just migraine. It has been suggested to play a role in regional pain syndromes [47] and in chronic neuropathy [48]. CGRP receptor antagonists are promising therapies for migraine and may have a role in the treatment of CTTH, pending demonstration by wellconducted clinical studies. Similarly, the neuropeptide substance P may be a future target as well. Substance P colocalizes with CGRP in trigeminal ganglia neurons (in only 18% of these neurons, however) [49]. Nociceptive effects of substance P are mediated by its binding to the G-protein–coupled NK1 receptor [50]. However, the exact impact, if any, of substance P in TTH remains unclear. Finally, the antinociceptive effect of nitric oxide synthase (NOS) inhibitors [40,41] and the nociceptive effect of NO donors were investigated in patients with CTTH. The NOS inhibitor NG-monomethyl-L-arginine hydrochloride was found to reduce headache and pericranial myofascial tenderness and hardness in patients. Furthermore, the NO donor glyceryl trinitrate induced TTH in these patients. Accordingly, inhibition of NOS may become a novel principle in the treatment of this disorder. Many other targets may be suggested based on their importance in pain modulation. They include N-methyl-Daspartate/glutamate, adenosine, orexins, and targeting the endocannabinoid system. However, their roles in the future treatment of TTH remain purely speculative at this time.
Conclusions Considering its prevalence, therapeutic options for TTH are poorly studied. For acute treatment, the most common interventions involve the use of simple analgesics and anti-inflammatory medications, often taken by the patient without a prescription. For preventive treatment,
the best studied drug is amitriptyline, but nortriptyline, mirtazapine, tizanidine, the selective serotonin reuptake inhibitors, and other medications may be used. Future therapies should encompass the new status of knowledge in the pathophysiology of this disorder and may include CGRP receptor antagonism, as well as substance P and the nitric oxide pathways.
Disclosures Dr. Bigal is a full-time employee of Merck Research Laboratories. He owns stock and has stock options. Dr. Rapoport has been a speaker for GlaxoSmithKline, Merck, Valeant, Endo, and Pfi zer. He has served on the advisory board for Pfi zer and Endo. Dr. Hargreaves is the Vice President, Worldwide Head Basic Neuroscience Merck Research Laboratories. He owns stock and has stock options.
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