Tender points are not sites of ongoing inflammation -in vivo evidence in patients with chronic tension-type headache

Increased muscle tenderness is the most prominent finding in patients with tension-type headache, and it has recently been shown that muscle blood flow is diminished in response to static exercise in tender points in these patients. Although tenderness has been ascribed to local inflammation and release of inflammatory mediators, the interstitial concentration of inflammatory mediators has not previously been studied in tender muscles of patients with tension-type headache. The aim of the present study was to investigate in vivo concentrations of prostaglandin E2 (PGE2), adenosine 5'-triphosphate (ATP), glutamate, bradykinin and other metabolites in a tender point of patients with chronic tension-type headache, in the resting state as well as in response to static exercise, and to compare findings with measurements in a matched non-tender point of healthy controls. We recruited 16 patients with chronic tension-type headache and 17 healthy control subjects. Two microdialysis catheters were inserted into the trapezius muscle and dialysates were collected at rest, 15 and 30 min after start of static exercise (10% of maximal force) and 15 and 30 min after end of exercise. All samples were coded and analysed blindly. There was no difference in resting concentration of any inflammatory mediators or metabolites between tender patients and non-tender controls (P > 0.05). We also found no difference in change in interstitial concentration of ATP, PGE2, glutamate, glucose, pyruvate and urea from baseline to exercise and post-exercise periods between patients and controls (P > 0.05). The present study provides in vivo evidence of normal interstitial levels of inflammatory mediators and metabolites in tender trapezius muscle in patients with chronic tension-type headache during both rest and static exercise. Thus, our data suggest that tender points in these patients are not sites of ongoing inflammation.     

Serotonin metabolism in chronic tension-type headache

Serotonergic neurons play a major role in the regulation of pain and may therefore also be involved in the pathophysiology of tension-type headache. Platelets are important in the regulation of the free serotonin level in plasma and may be a model of serotonergic neurons. The aim of the present study was to investigate the peripheral serotonin (5HT) metabolism in patients with chronic tension-type headache. The 5HT levels in platelets and in plasma, the beta-thromboglobulin (ß-TG) levels in plasma, and the urinary excretion of 5-hydroxyindoleacetic acid (5HIAA) were measured in 40 patients with chronic tension-type headache and in 40 healthy controls. The platelet uptake index was calculated as the ratio between platelet 5HT and plasma 5HT levels. There were, no significant differences in platelet 5HT, plasma 5HT ß-TG, or 5HIAA between patients and controls. The platelet uptake index was significantly lower in patients 243 (136–367) than in controls 352 (202–508), p =0.03. Our results indicate that the peripheral 5HT metabolism is largely normal in patients with chronic tension-type headache.     

Familial occurrence of chronic tension-type headache

Chronic tension-type headache (CTTH) assessed by proband report was evaluated in a family study of CTTH. A clinical interview of first-degree relatives by a physician was used as index of validity. Familial occurrence of CTTH in first-degree relatives was also investigated. Patterns of familial aggregation of CTTH were assessed by calculating the population relative risk. A neurological resident carried out all the interviews of probands and their first-degree relatives. The operational diagnostic criteria of the International Headache Society were used. The 122 probands had 377 first-degree relatives. Sensitivity, specificity, predictive values, and chance-corrected agreement rate for the diagnosis CTTH were 68%, 86%, 53% (PVpos), 92% (PVneg), and 0.48, respectively. The low sensitivity of CTTH assessed by proband report indicates that a clinical interview by a physician is necessary in family studies of CTTH. Clinically interviewed parents, siblings, and children had a 2.1 to 3.9-fold significantly increased risk of CTTH compared with the general population. The gender of the probands did not influence the risk of CTTH among first-degree relatives. The significantly increased familial risk of CTTH and no increased risk of CTTH in spouses suggest that a genetic factor is involved in CTTH.     

Bilateral pressure pain sensitivity mapping of the temporalis muscle in chronic tension-type headache

Purpose.— To analyze pressure pain sensitivity maps in chronic tension-type headache (CTTH) and healthy controls over nine locations covering the temporalis muscle.
Background.— Lower pressure pain thresholds (PPT) have been found in craniofacial muscles in patients with CTTH. Since the temporalis muscle can play a relevant role in the genesis or maintenance of headache, the determination of pressure pain sensitivity maps of this muscle is needed.
Methods.— A pressure algometer was used to measure PPT over 9 points of the temporalis muscle (3 points in the anterior part of the muscle, another 3 in the middle of the muscle, and the remaining 3 in the posterior part) in 15 females suffering from CTTH and 10 healthy women. A pressure pain sensitivity map of both dominant and nondominant sides in patients and controls was calculated.
Results.— Chronic tension-type headache patients showed lower PPT as compared with healthy subjects ( P  < .01). Further, PPT levels of the nondominant side were lower than those on the dominant side for controls ( P  < .01). Within the CTTH group, more bilaterally homogeneous pressure pain sensitivity maps with PPT decreased from the posterior to anterior column were found, whereas among controls, PPT distribution maps were inhomogeneous with side-to-side differences.
Conclusions.— Our data may provide preliminary new key information about muscle sensitivity, since it seems that pressure pain sensitivity maps could be different between CTTH patients and healthy subjects. Further studies with greater sample sizes and other headache populations are now required to confirm our results.     

Cervical muscle co-activation in isometric contractions is enhanced in chronic tension-type headache patients

The purpose of the study was to compare the co-activation of cervical agonist and antagonist muscles between people with chronic tension-type headache (CTTH) and healthy controls during brief isometric cervical flexion and extension contractions. Nine women with CTTH and 10 matched controls participated. Surface electromyographic (EMG) signals were detected from the sternocleidomastoid and splenius capitis muscles bilaterally during cervical flexion and extension contractions of linearly increasing force from 0% to 60% of the maximum voluntary contraction (MVC) in 3 s. Sternocleidomastoid and splenius capitis EMG average rectified values (ARV) were estimated at 10% MVC force increments. During cervical extension contraction, sternocleidomastoid (i.e. antagonist muscle) ARV was greater for patients than for controls in the force range 20–60% MVC ( P  = 0.029). During cervical flexion, the left splenius capitis (i.e. antagonist muscle) ARV was greater for CTTH patients regardless of the force level ( P  = 0.02). Maximum cervical flexion and extension force was lower for the CTTH patients compared with controls ( P  = 0.001). In conclusion, women with CTTH demonstrated greater co-activation of antagonist musculature during cervical extension and flexion contractions compared with healthy women. Increased co-activation of antagonist musculature may reflect reorganization of the motor control strategy in CTTH patients, potentially leading to muscle overload and increased nociception.     

Experimental induction of muscle tenderness and headache in tension-type headache patients

The aim of the present study was to investigate the impact of static contraction of the shoulder and neck muscles on muscle tenderness and headache in patients with tension-type headache. Twenty patients with frequent episodic tension-type headache and 20 healthy age- and sex-matched controls were examined using a placebo-controlled cross-over design. The subjects performed static contraction of the trapezius muscles (active procedure) or the anterior tibial muscles (placebo procedure) with 10% of maximal force for 30 min. Total tenderness score, local tenderness score and headache intensity were evaluated before and after the static work. Changes in headache intensity were followed for 24 h. Pericranial tenderness increased significantly more in patients than in controls after the active procedure (P = 0.04). The increase in pericranial tenderness tended to be higher after the active procedure than after the placebo procedure in patients (P = 0.08) and in controls (P = 0.07). Sixty per cent of the patients and 20% of the healthy controls developed headache after the active procedure. Fifty per cent of the patients and none of the controls developed headache after the placebo procedure. There was no significant difference in headache development between the active and the placebo procedure in patients or controls. These findings demonstrate that tension-type headache patients are more liable to develop shoulder and neck pain in response to static exercise than healthy controls.     

Plasma and cerebrospinal fluid beta-endorphin in chronic tension-type headache.

Previous studies have provided evidence of an increased sensitivity to pain, a decreased hypothalamic opioid tone, and decreased cerebrospinal fluid (CSF) beta-endorphin (beta-EP) concentration in patients with primary chronic headache. We applied separate specific radioimmunoassays for beta-EP in CSF and plasma on samples from age-matched controls and a group of 50 patients with chronic tension-type headache (CTH) fulfilling the diagnostic criteria set by the International Headache Society. Median CSF beta-EP concentrations (95% confidence limits) were 12.8 pmol/l (11.0-14.5) in CTH patients and 11.9 pmol/l (10.9-14.2) in the control group, which is not significantly different (P = 0.28). Plasma beta-EP concentrations did not differ either, being 3.1 pmol/l (2.4-3.7) and 3.3 pmol/l (1.8-4.0) in the patients with CTH and in controls, respectively (P = 0.88). Plasma and CSF beta-EP concentrations did not correlate. Reversed-phase high performance liquid chromatography (HPLC) of CSF pools from the headache patients and controls revealed similar profiles of beta-EP-immunoreactivity both when C-terminally and N-terminally directed antisera were used, suggesting a normal post-translational processing of the pro-opiomelanocortin gene in patients with CTH. beta-EP is not involved in the pathogenesis of CTH, or such a role is not reflected in CSF or plasma concentrations of the neuropeptide.     

Challenges of nonpharmacologic interventions in chronic tension-type headache

Interest in nonpharmacologic interventions for chronic tension-type headache has increased in recent years, with many professional organizations recommending behavioral treatments such as relaxation training, biofeedback, and cognitive-behavioral therapy alongside pharmacologic treatments. Although the efficacy of behavioral interventions is well-documented, several potential barriers in dissemination and implementation exist that have precluded more widespread adoption of behavioral treatments. This article briefly reviews the core components and efficacy of behavioral treatments for tension-type headache and outlines challenges to their broader clinical use as they occur at the levels of empirical research, treatment availability and delivery, and common clinical problems. Strategies for addressing these challenges are suggested, and directions for needed research are noted.     

Impairment of pain inhibition in chronic tension-type headache

Evidence has been accumulated suggesting that a dysfunction in pain inhibitory systems, i.e. in 'diffuse noxious inhibitory controls' (DNIC)-like mechanisms, might be-amongst other factors-responsible for the development of anatomically generalized chronic pain like fibromyalgia. The aim of the present study was to look for similar impairments in chronic tension-type headache (CTTH) as a regionally specific pain syndrome. Twenty-nine CTTH patients and 25 age- and sex-matched healthy control subjects participated in the study. After baseline assessment of electrical detection and pain thresholds, tonic heat stimuli were concurrently applied by a thermode to the thigh to induce DNIC-like pain inhibition. Tonic heat stimuli were applied either slightly above ('pain' condition) or slightly below ('heat' condition) pain threshold. For determination of electrical detection and pain thresholds, electrocutaneous stimuli were administered either to the forearm (extra-cranial site) or to the temple (cranial site), using a multiple staircase procedure. The increase in the electrical detection and pain thresholds induced by concurrent tonic heat stimulation was significantly smaller in the CTTH patients than in the control subjects. This group difference was present during the 'pain' as well as the 'heat' condition. Furthermore, the electrical detection and pain thresholds were affected in this group-specific manner both at the forearm and at the temple. These findings suggest that patients with CTTH suffer from deficient DNIC-like pain inhibitory mechanisms in a similar manner, as do patients with anatomically generalized chronic pain like fibromyalgia.     

Modified-release formulation of tizanidine in chronic tension-type headache

The efficacy of the modified-release formulation of tizanidine (Sirdalud) was compared with placebo in a randomized, double-blind, parallel-group study of 138 women and 47 men, aged 18 to 79 years, with a history of chronic tension-type headache (IHS categories 2.2 and 2.3). The treatment period was 6 weeks preceded by a 2-week prerandomization period. The patients were randomly assigned to receive 6-mg Sirdalud, 12-mg Sirdalud MR, or placebo. The study medication was taken once per day, orally in the evening. Efficacy was measured by visual analog scale, the number of headache-free days, the daily duration of headache, and the use of paracetamol. The primary end point was the severity of daily headache derived from visual analog scale scores covering the last 2 treatment weeks. One hundred sixty patients (56 in the 6-mg group, 49 in the 12-mg group, and 55 in the placebo group) completed the study. The severity of the headache decreased similarly in the treatment groups and the placebo group. The visual analog scale values decreased from the prerandomization values by 53% in the 6-mg group, 48% in the 12-mg group, and 52% in the placebo group. The modified-release formulation of tizanidine in doses up to 12 mg taken in the evening is not superior to placebo in the treatment of chronic tension-type headache. The placebo effect was unexpectedly strong in the present study, supporting the view that psychophysiological mechanisms are of considerable importance in sustaining chronic tension-type headache.     

Coping strategies in episodic and chronic tension-type headache

OBJECTIVE: To study the importance of coping with illness strategies in tension-type headache (TTH). BACKGROUND: The pathophysiology of TTH is complex, and coping with illness strategies might contribute to the transformation to a chronic form. METHODS: We examined 89 subjects (mean age, 45.6 +/- 14.8 years; range, 18 to 72 years) with episodic (n = 37) and chronic (n = 52) TTH. Patients were required to fill in a Freiburg Questionnaire of Coping with Illness (FQCI), a von Zerssen Depression Scale, quality-of-life questionnaires, and a headache home diary (over 4 weeks). In addition, pressure pain thresholds (temporal muscles) and total tenderness scores were obtained. RESULTS: Patients with chronic TTH exhibited poorer quality-of-life measures, slightly more depressive symptoms, and significantly stronger avoidance behavior and endurance strategies on FQCI scales F4 and F5 (P< .05). There was no difference between episodic and chronic TTH with respect to measures of muscle tenderness or pain thresholds. CONCLUSIONS: We conclude that disadvantageous coping with illness strategies might contribute to a transformation to chronic TTH.     

Genetic factors in migraine and chronic tension-type headache

Pathophysiological studies have dominated migraine research for several years. However, these studies are difficult to interpret because it is difficult to decide whether the observed phenomena are primary or secondary to the migraine attack. For that reason it is important that future migraine research focus on studies that concern migrain etiology. Migraine is a paroxysmal disorder. It is most likely and ion-channel disorder like familial hemiplegic migraine. The present paper focuses on genetic factors in migraine and chronic tension-type headache.     

Generalized hyperalgesia in patients with chronic tension-type headache

Increased pain sensitivity in the central nervous system may play an important role in the pathophysiology of chronic tension-type headache (CTTH). Previous studies using pain thresholds as a measure of central pain sensitivity have yielded inconsistent results and only a few studies have examined perception of muscle pain without involvement of adjacent tissues. It has been suggested that suprathreshold testing might be more sensitive than threshold measurements in evaluation of central hyperexcitability in CTTH. The aim of the study was to compare pain ratings to suprathreshold single and repetitive (2 Hz) electrical stimulation of muscle and skin in cephalic (temporal and trapezius) and extracephalic (anterior tibial) regions between patients with CTTH and healthy subjects. In addition, we aimed to examine gender differences in pain ratings to suprathreshold stimulation and degree of temporal summation of pain between patients and controls. Pain ratings to both single and repetitive suprathreshold stimulation were higher in patients than in controls in both skin and muscle in all examined cephalic and extracephalic regions (P < 0.04). Pain ratings to both single and repetitive suprathreshold electrical stimulation were significantly higher in female compared with male patients (P < 0.001) and in female compared with male controls (P < or = 0.001). The degree of temporal summation of muscular and cutaneous pain tended to be higher in patients than in controls but the differences were not statistically different. This study provides evidence for generalized increased pain sensitivity in CTTH and strongly suggests that pain processing in the central nervous system is abnormal in this disorder. Furthermore, it indicates that suprathreshold stimulation is more sensitive than recording of pain thresholds for evaluation of generalized pain perception.     

Transcranial Doppler ultrasonic features in chronic tension-type headache

We studied vascular features in patients suffering from chronic headache of the tension-type by means of transcranial Doppler ultrasound (TCD). Blood flow velocities of the basal cerebral arteries and the submandibular extracranial part of the internal carotid artery were compared between 20 chronic tension-type headache sufferers and the same number of age- and sex-matched control subjects. There were no significant differences of ultrasonic features between the groups. Changes in blood flow velocities do not seem to be involved in the pathogenetic mechanisms of chronic tension-type headache.     

Pericranial tenderness in chronic tension-type headache: the Akershus population-based study of chronic headache

Background

Most knowledge on chronic tension-type headache (CTTH) is based on data from selected clinic populations, while data from the general population is sparse. Since pericranial tenderness is found to be the most prominent finding in CTTH, we wanted to explore the relationship between CTTH and pericranial muscle tenderness in a population-based sample.

Methods

An age- and gender-stratified random sample of 30,000 persons aged 30-44 years from the general population received a mailed questionnaire. Those with a self-reported chronic headache were interviewed and examined by neurological residents. The questionnaire response rate was 71% and the interview participation rate was 74%. The International Classification of Headache Disorders II was used. Pericranial muscle tenderness was assessed by a total tenderness score (TTS) involving 8 pairs of muscles and tendon insertions. Cross-sectional data from the Danish general population using the same scoring system were used for comparison.

Results

The tenderness scores were significantly higher in women than men in all muscle groups. The TTS was significantly higher in those with co-occurrence of migraine compared with those without; 19.3 vs. 16.8, p = 0.02. Those with bilateral CTTH had a significantly higher TTS than those with unilateral CTTH. The TTS decreased significantly with age. People with CTTH had a significantly higher TTS compared to the general population.

Conclusions

People with CTTH have increased pericranial tenderness. Elevated tenderness scores are associated with co-occurrence of migraine, bilateral headache and low age.Whether the increased muscle tenderness is primary or secondary to the headache should be addressed by future studies.     

Impaired nutritive skeletal muscle blood flow in patients with chronic renal failure

1. The possibility that abnormalities of skeletal muscle may limit the exercise tolerance of patients with chronic renal failure was investigated in patients undergoing regular haemodialysis. 2. Blood flow to the calf, a vascular bed consisting predominantly of skeletal muscle, was measured in six patients before and after exercise and compared with values obtained from 12 control subjects. 3. The patients were limited on exertion and had an abnormal response of calf blood flow to bicycle exercise. Resting calf blood flow was similar in patients and control subjects, but the mean increase in calf blood flow in response to submaximal exercise was 0.55 (SEM 0.12) ml min-1 100 ml-1 in the patients and 1.43 (SEM 0.17) ml min-1 100 ml-1 in the control subjects. The increase after symptom-limited maximal exercise was 1.50 (SEM 0.80) ml min-1 100 ml-1 in the patients and 4.20 (SEM 0.40) ml min-1 100 ml-1 in the control subjects. 4. Skeletal muscle biopsies from eight haemodialysis patients were studied by histochemistry and electron microscopy. 5. Oxidative enzyme activity was increased and there were large subsarcolemmal aggregates of structurally normal mitochondria. Necrotic capillaries were observed as empty basement membrane tubes containing fragments of degenerating endothelium. 6. The changes were compatible with a response to a chronic reduction in skeletal muscle blood flow.     

Cephalic and extracephalic pressure pain thresholds in chronic tension-type headache.

Pressure pain thresholds were assessed with an algometer (Somedic Inc.), over the forehead, temple and suboccipital region as well as over the Achilles tendon. A group of 32 patients suffering from chronic tension-type headache was compared to 20 healthy controls and to 10 migraineurs without aura. Although individual values were widely scattered, pressure pain thresholds were on average significantly lower in chronic tension-type headache, not only at pericranial sites but also over the Achilles tendon. Only 50% of these patients had one or more pericranial thresholds 1.5 S.D. below the mean of controls. After muscular biofeedback therapy, all pain thresholds were on average increased. Along with results obtained previously, the present data support the hypothesis that diffuse disruption of central pain-modulating systems, possibly due to a modified limbic input to the brain-stem, is pivotal in the pathophysiology of chronic tension-type headache.     

Possible mechanisms of glyceryl-trinitrate-induced immediate headache in patients with chronic tension-type headache

Nitric oxide (NO) plays an important role in the pathophysiology of primary headaches including chronic tension-type headache (CTTH). Thus, a NO synthase inhibitor reduces headache and muscle hardness while the NO donor glyceryl trinitrate (GTN) causes more headache in patients than in healthy controls. Sensitization of myofascial pain pathways is important in CTTH, and the aim of the present study was to investigate if such mechanisms may also explain GTN-induced immediate headache in patients with CTTH. In a randomized, double-blind, crossover study 16 patients with CTTH and 16 healthy subjects received intravenous infusion of GTN (0.5 microg/kg per min for 20 min) or placebo on two headache-free days separated by at least 1 week. Muscle hardness, myofascial tenderness, mechanical and heat pain thresholds were measured at baseline and at 60 min and 120 min after start of infusion. In patients, GTN infusion resulted in a biphasic response with immediate headache and more pronounced delayed headache. A similar but less pronounced response was seen in controls. There was no difference between GTN and placebo regarding muscle hardness, myofascial tenderness or pressure and heat pain thresholds in either patients or controls (P>0.05). The unchanged sensitivity of pericranial myofascial pain pathways indicates that peripheral and central sensitization is not involved in the mechanisms of GTN-induced immediate headache.