Abstract: In the past few years there has been an increasing body of knowledge about etiological mechanisms of chronic tension type headache (CTTH), permitting a better understanding of this syndrome. It seems that CTTH diagnostic criteria should be modified to improve its differential diagnosis against migraine, since CTTH is a syndrome of "featureless" headaches characterized by nothing but pain in the head. It has been demonstrated that pressure pain hypersensitivity and pericranial muscle tenderness are both consequence and not causative factors of CTTH. An updated pain model has suggested that CTTH can be explained by referred pain from trigger points (TrPs) in the cranio-cervical muscles, mediated through the spinal cord and the trigeminal nerve nucleus caudalis. Different therapeutic strategies (pharmacological and non-pharmacological) are generally used for the management of these patients. CTTH is generally treated with non-steroidal anti-inflammatory drugs (NSAIDs), tricyclic antidepressants, and physical therapy, although the therapeutic efficacy of these approaches is controversial.

In this review we try to answer some of the most important questions regarding the pathogenesis and management of chronic tension-type headache (CTTH).

Can Chronic Tension-type Headache Be Considered as a Pathology or Just a Syndrome?

Tension-type headache is the most common form of headache (Andlin-Sobocki et al., 2005) and its chronic form (CTTH) is the most neglected and difficult headache to treat (Bendtsen & Jensen, 2006). CTTH is a syndrome of “featureless” headache characterized by nothing but pain in the head. This “tabula rasa” approach had the advantage of offering a single and accepted diagnosis, which should be submitted to further research, but the disadvantage of mixing in the same basket a number of head pain symptoms which have similar diagnostic criteria (Fumal & Schoenen, 2008). Since no clear diagnosis criteria for CTTH exist, there has been an increasingly strong opinion for considering CTTH as a syndrome. This assumption is supported by the fact that CTTH has common clinical, therapeutic, and pathophysiologic features with fibromyalgia syndrome, and both conditions are frequently co-morbid (Schoenen, 2004; Marcus et al., 2005; Kanaan et al., 2007).

Is Pressure Pain Hypersensitivity Cause or Consequence of CTTH?

Several studies had clearly demonstrated that the most prominent findings in CTTH are increased pericranial tenderness to palpation (Metsahonkala et al., 2006; Fernández-de-las-Peñas et al., 2007a) and a generalized pressure pain hypersensitivity (pressure pain thresholds, PPT) (Ashina et al., 2003a; Schmidt-Hansen et al., 2007). Nevertheless, whether mechanical pain sensitivity is a primary (cause) or a secondary (consequence) phenomenon to CTTH has been under debate. A 12-year follow-up longitudinal study has recently demonstrated that subjects who later would develop CTTH showed normal tenderness scores and PPT levels before the beginning of the symptoms, which suggests that the mechanical hypersensitivity is rather a consequence than a risk factor for the development of CTTH (Buchgreitz et al., 2008). The result from this study does not further support previous theories about the role of muscle tender tissues in CTTH.

New Concepts Related to Sensitization Mechanisms in CTTH

These hyperalgesic and allodynic responses support the role of both peripheral and central sensitization mechanisms in CTTH (Bendtsen, 2000; de Tommaso et al., 2003; Ashina et al., 2006; Filatova et al., 2008). A relevant finding was that patients with CTTH showed a significant decrease in gray matter in those structures involved in nociceptive pain processing, confirming a role of the brain stem in pain responses in these patients (Schmidt-Wilcke et al., 2005). However, since central sensitization is generated by prolonged peripheral nociceptive inputs (Mendell & Wall, 1965), and dynamically influenced by activity and location of these afferences (Herren-Gerber et al., 2004), the role of peripheral mechanisms in the patho-physiology of CTTH has been again described in the literature (Fernández-de-las-Peñas et al., 2009a).

A previous pain model hypothesized that the central sensitization seen in CTTH is provoked by peripheral nociception initiated in tender muscle tissues (Bendtsen, 2000). However, a posterior study did not confirm that tender muscle tissues elicit peripheral nociception (Ashina et al., 2003b). Posterior studies found that active trigger points (TrPs), those TrPs which referred pain pattern reproduced headache symptoms (Simons et al., 1999), are responsible for peripheral nociception not only locally (Shah et al., 2005), but also in distant pain-free regions (Shah et al., 2008). Additionally, a number of studies (Fernández-de-las-Peñas et al., 2009b) conducted by our group have demonstrated that CTTH is associated with active TrPs in the suboccipital (Fernández-de-las-Peñas et al., 2006a), upper trapezius (Fernández-de-las-Peñas et al., 2007b), superior oblique (Fernández-de-las-Peñas et al., 2005), sternocleidomastoid (Fernández-de-las-Peñas et al., 2006b), temporalis (Fernández-de-las-Peñas et al., 2007c), and lateral rectus muscles (Fernández-de-las-Peñas et al., 2009c; Fernández-de-las-Peñas et al., 2007d). With these findings, Fernández-de-las-Peñas et al. (2007e) formulated an updated pain model for CTTH involving both peripheral sensitization of nociceptors by active muscle TrPs and central sensitization: active muscle TrPs located in the muscles innervated by C1-C3 segments and by the trigeminal nerve are responsible for peripheral nociception and may produce a continuous afferent barrage into the trigeminal nucleus caudalis, sensitizing the central nervous system. In this model, muscle tenderness is the consequence whereas muscle TrP referred pain is one of the main causes (but not the only one) of CTTH (Fernández-de-las-Peñas et al., 2007e; 2009d).

How Can Clinicians Treat CTTH with Pharmacological Drugs?

Pharmacological treatment is divided into acute (or symptomatic) treatment and preventive treatment (or prophylaxis). Many studies of simple analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) have been conducted in CTTH patients. At present time, ibuprofen (800 mg) can be considered the first choice for headache followed by naproxen sodium (825 mg) because of the all-over better gastrointestinal tolerability (Fumal & Schoenen, 2008). Unfortunately, few novel drugs have been developed.

The tricyclic antidepressants are the most used first-line prophylactic therapeutic agent for CTTH. In a meta-analysis of preventive drugs for tension type headache, only marginal efficacy emerged for tricyclic antidepressants (Verhagen et al., 2008). Among antidepressants inhibiting reuptake of serotonin and noradrenaline (norepinephrine), mirtazapine was found effective in treating CTTH at 15-30mg per day (Bendtsen & Jensen, 2004). Finally, in an open study, topiramate, an anticonvulsant effective in migraine prophylaxis, was also effective in CTTH at 100mg/d (Lampl et al., 2006).

How Can Clinicians Treat CTTH with Non-pharmacological Interventions?

A recent meta-analysis of 53 trials found medium-to-large effects (d = 0.73; 95% CI 0.61 - 0.84) for relaxation and EMG biofeedback therapies in the management of CTTH (Nestoriuc et al., 2008). Among non-pharmacological interventions proposed for the treatment of CTTH, physical therapy is the most commonly used (Eisenberg et al., 1998). Systematic reviews analyzing the effects of physical therapy in CTTH concluded that there is insufficient evidence to support or refute the efficacy of physical therapy for the management of CTTH (Lenssinck et al., 2004; Biondi, 2005; Fernández-de-las-Peñas et al., 2006c). Posterior studies reported that physical therapy can be effective in reducing headache frequency, intensity, and duration in CTTH patients (Torelli et al., 2004; Söderberg et al., 2006; Van Ettekoven et al., 2006). Nevertheless, clinicians know that not all patients benefit in the same degree of a specific intervention. Perhaps identifying the clinical features of CTTH patients who will likely to benefit from a specific treatment (clinical prediction rules) prior to carrying out of a randomized clinical trial might lead to a stronger efficacy. A preliminary clinical prediction rule to identify patients with CTTH who experience a short-term success with a muscle TrP therapy approach has been developed (Fernández-de-las-Peñas et al., 2008). A clinical rule with 4 variables for immediate short-term (headache duration < 8.5 hour/day, headache frequency < 5.5 days/week, bodily pain < 47, vitality < 47.5) and 2 variables for 1-month (headache frequency < 5.5 days/week and bodily pain < 47) follow-up was identified (Fernández-de-las-Peñas et al., 2008).

Future Research

It is clear that future studies investigating the diagnostic criteria for CTTH and the different therapeutic strategies are urgently needed. These studies should incorporate sub-groups of CTTH patients identified in clinical prediction rules in order to increase the clinical effect of the interventions.

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