Lars Bendtsen

Central sensitization in tension-type headache--possible pathophysiological mechanisms.

The aim of the present thesis was to investigate the pathophysiology of chronic tension-type headache with special reference to central mechanisms. Increased tenderness to palpation of pericranial myofascial tissues is the most apparent abnormality in patients with tension-type headache. A new piece of equipment, a so-called palpometer, that makes it possible to control the pressure intensity exerted during palpation, was developed. Thereafter, it was demonstrated that the measurement of tenderness could be compared between two observers if the palpation pressure was controlled, and that the Total Tenderness Scoring system was well suited for the scoring of tenderness during manual palpation. Subsequently, it was found that pressure pain detection and tolerance thresholds were significantly decreased in the finger and tended to be decreased in the temporal region in chronic tension-type headache patients compared with controls. In addition, the electrical pain threshold in the cephalic region was significantly decreased in patients. It was concluded that the central pain sensitivity was increased in the patients probably due to sensitization of supraspinal neurones. The stimulus-response function for palpation pressure vs. pain was found to be qualitatively altered in chronic tension-type headache patients compared with controls. The abnormality was related to the degree of tenderness and not to the diagnosis of tension-type headache. In support of this, the stimulus-response function was found to be qualitatively altered also in patients with fibromyalgia. It was concluded that the qualitatively altered nociception was probably due to central sensitization at the level of the spinal dorsal horn/trigeminal nucleus. Thereafter, the prophylactic effect of amitriptyline, a non-selective serotonin(5-HT) reuptake inhibitor, and of citalopram, a highly selective 5-HT reuptake inhibitor, was examined in patients with chronic tension-type headache. Amitriptyline reduced headache significantly more than placebo, while citalopram had only a slight and insignificant effect. It was concluded that the blockade of 5-HT reuptake could only partly explain the efficacy of amitriptyline in tension-type headache, and that also other actions of amitriptyline, e.g. reduction of central sensitization, were involved. Finally, the plasma 5-HT level, the platelet 5-HT level and the number of platelet 5-HT transporters were found to be normal in chronic tension-type headache. On the basis of the present and previous studies, a pathophysiological model for tension-type headache is presented. According to the model, the main problem in chronic tension-type headache is central sensitization at the level of the spinal dorsal horn/trigeminal nucleus due to prolonged nociceptive inputs from pericranial myofascial tissues. The increased nociceptive input to supraspinal structures may in turn result in supraspinal sensitization. The central neuroplastic changes may affect the regulation of peripheral mechanisms and thereby lead to, for example, increased pericranial muscle activity or release of neurotransmitters in the myofascial tissues. By such mechanisms the central sensitization may be maintained even after the initial eliciting factors have been normalized, resulting in the conversion of episodic into chronic tension-type headache. Future basic and clinical research should aim at identifying the source of peripheral nociception in order to prevent the development of central sensitization and at ways of reducing established sensitization. This may lead to a much needed improvement in the treatment of chronic tension-type headache and other chronic myofascial pain conditions.

Muscular factors are of importance in tension-type headache

Recent studies have indicated that muscular disorders may be of importance for the development of increased pain sensitivity in patients with chronic tension‐type headache. The objective of the present study was to investigate this hypothesis by examining the pain perception in tension‐type headache with and without muscular disorders defined as increased tenderness. We examined 28 patients with episodic tension‐type headache, 28 patients with chronic tension‐type headache, and 30 healthy controls. Pericranial myofascial tenderness was recorded with manual palpation, and pressure pain detection and tolerances in cephalic and extracephalic locations with an electronic pressure algometer. In addition, thermal pain sensitivity and electromyographic activity were recorded. The main result was significantly lower pressure pain detection thresholds and tolerances in all the examined locations in patients with chronic tension‐type headache with a muscular disorder compared to those without a muscular disorder. There were no such differences in any of the examined locations when the two subgroups of patients with episodic tension‐type headache were compared. Thermal pain sensitivity did not differ between patients with and without a muscular disorder, while electromyographic activity levels were significantly higher in patients with chronic tension‐type headache with than in those without a muscular disorder. Our results strongly indicate that prolonged nociceptive stimuli from the pericranial myofascial tissue sensitize the central nervous system and, thereby, lead to an increased general pain sensitivity. Muscular factors may, therefore, be of major importance for the conversion of episodic into chronic tension‐type headache. The present study complements the understanding of the important interactions between peripheral and central factors in tension‐type headache and may lead to a better prevention and treatment of the most prevalent type of headache.

Qualitatively altered nociception in chronic myofascial pain

&NA; The aim of the present study was to investigate the stimulus‐response function for pressure versus pain in patients with myofascial pain. Forty patients with chronic tension‐type headache and 40 healthy controls were examined. Tenderness in 8 pericranial muscles and tendon insertions was evaluated by manual palpation with a standardized evaluated methodology. Thereafter, a highly tender muscle and a largely normal muscle were palpated with 7 different pressure intensities using a palpometer, and the induced pain was recorded by the subjects on a visual analogue scale blinded for the observer. Pericranial myofascial tenderness was considerably higher in patients than in controls (P < 0.00001). The stimulus‐response function recorded from normal muscle was well described by a power function. From highly tender muscle, the stimulus‐response function was displaced towards lower pressures and, more importantly, it was linear, i.e., qualitatively different from normal muscle. Our results demonstrate for the first time that nociceptive processes are qualitatively altered in patients with chronic myofascial pain and suggest that myofascial pain may be mediated by low‐threshold mechanosensitive afferents projecting to sensitized dorsal horn neurons. Further investigations of these mechanisms may lead to an increased understanding and better treatment of these common and often incapacitating pain disorders.

EFNS guideline on the treatment of tension‐type headache – Report of an EFNS task force

Background:  Tension‐type headache (TTH) is the most prevalent headache type and is causing a high degree of disability. Treatment of frequent TTH is often difficult.

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 ≤ 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.

Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomised crossover trial

BACKGROUND Studies in animals have shown that nitric oxide plays an important part in central sensitisation and that inhibitors of nitric oxide synthase (NOS) decrease sensitisation in models of persistent pain. The efficacy of inhibitors of NOS has not been tested in patients with tension-type chronic headache. We aimed to show whether N(G)-monomethyl-L-arginine hydrochloride (L-NMMA), an inhibitor of NOS, is effective in relieving pain in such patients. METHODS We undertook a randomised double-blind, crossover trial of 16 patients with chronic-tension-type headache. Patients were assigned intravenous infusion of 6 mg/kg L-NMMA or placebo on 2 days separated by at least 1 week in a randomised order. Headache intensity was measured on a 100 mm visual analogue scale, and on a verbal rating scale at baseline and at 30 min, 60 min, and 120 min after start of treatment. The primary endpoint was reduction of pain intensity on the visual analogue scale by the active treatment compared with placebo. FINDINGS L-NMMA reduced pain intensity on the visual analogue scale significantly more than placebo: 120 min after start of treatment, the mean pain score was decreased from 49 to 33 with L-NMMA and from 44 to 40 with placebo (p=0.01). Pain intensity on the verbal rating scale was also significantly lower for treatment with L-NMMA than for treatment with placebo (p=0.02). INTERPRETATION Inhibition of NOS had an analgesic effect in chronic tension-type headache. Further tests are required before clinical application.

Pressure-controlled palpation: a new technique which increases the reliability of manual palpation

The objective of the present study was to investigate whether the reliability of tenderness evaluation can be increased by using a new technique called “pressure-controlled palpation” (pcp). The technique has been made possible by a newly invented piece of equipment called a palpometer, with which a pressure-sensitive plastic film attached to the index finger records the pressure exerted. In 15 patients with chronic tension-type headache and in 15 healthy volunteers, 2 investigators studied myofascial tenderness using conventional palpation and pressure-controlled palpation. Tenderness was scored on a 4–point scale in each of the examined pericranial regions. The sum of tenderness scores recorded by two observers using conventional palpation differed significantly (p = 0.0003), while results did not differ between observers using pressure-controlled palpation (p = 0.89). During palpation with seven different pressure intensities a positive and linear relation between pressure and pain intensity was found (p = 0.00006). Pain intensity reported by the subjects correlated highly with tenderness scored by the observer (rs = 0.95, p < 0.0001). These results demonstrate for the first time that tenderness scores can be compared between observers if palpation pressure is controlled. Pressure-controlled palpation represents a major improvement on current palpation techniques and should be standard in future research on myofascial pain disorders.

Evidence for increased plasma levels of calcitonin gene-related peptide in migraine outside of attacks

&NA; Although calcitonin gene‐related peptide (CGRP) has been shown to be elevated in jugular venous blood of adult migraineurs during acute migraine attacks, it remains unknown whether CGRP is increased outside of attacks in jugular or cubital venous blood. The aim of the present study was to compare interictal plasma levels of CGRP in adult migraine patients and in healthy controls. Twenty patients with a diagnosis of migraine with or without aura and 20 healthy controls were included. In blood from the cubital vein, CGRP levels were significantly higher in patients (75±8 pmol/l (mean±SEM)) than in controls (49±3 pmol/l) (P=0.005). The subgroup of patients suffering exclusively from migraine without aura (n=14) also had significantly higher levels of CGRP (82±10 pmol/l) than controls (n=20; 49±3 pmol/l) (P=0.001). The findings could not be explained by confounding factors such as age, sex or use of contraceptive pills. We therefore conclude that CGRP is increased in cubital venous blood of migraineurs outside of attack. It is hypothesized that this finding may reflect a long‐lasting or permanent abnormal neurogenic vascular control in patients with migraine.

Muscle hardness in patients with chronic tension-type headache: relation to actual headache state.

It has recently been reported that the pericranial muscles in patients with chronic tension-type headache are harder, i.e. have a higher consistency, than in controls. The primary aim of the present study was to investigate whether muscle hardness is influenced by the presence or absence of actual headache and whether hardness is correlated to tenderness. The secondary aim was to compare muscle hardness between patients and healthy controls. Hardness of the trapezius muscle was measured with a hardness meter in 20 patients with chronic tension-type headache and in 20 healthy controls. The patients were examined on 2 days, 1 day with headache and 1 day without headache. Pericranial myofascial tenderness was recorded with manual palpation. In addition, muscle hardness was measured in another five patients out-side headache and in 30 healthy controls. The muscle hardness recorded in patients (n = 20) on days with headache, 98 +/- 26 kPa/cm, did not differ significantly from the muscle hardness recorded on days without headache, 100 +/- 21 kPa/cm, (P = 0.62). The muscle hardness was positively correlated to the local tenderness score recorded from the trapezius muscle both on days with headache (R = 0.52, P = 0.02) and on days without headache (R = 0.53, P = 0.02). The total tenderness score (TTS) recorded in patients on days with headache, 23 +/- 10, was significantly higher than the TTS recorded on days without headache, 15 +/- 11, (P = 0.0001). There was a significant difference between the TTS recorded in patients without headache, 15 +/- 11, and in controls, 4 +/- 4, (P = 0.002). The muscle hardness was significantly higher in patients on days without headache (n = 25), 97 +/- 20 kPa/cm, than in controls (n = 30), 87 +/- 16 kPa/cm (P = 0.03). On basis of previous and present results, we suggest that muscle hardness and muscle tenderness are permanently altered in chronic tension-type headache and not only a consequence of actual pain. In addition, the positive correlation between muscle hardness and tenderness supports the common clinical observation that tender muscles are harder than normal muscles.

Tension-type headache : the most common, but also the most neglected, headache disorder

Purpose of reviewTension-type headache is the most common type of headache and, in its chronic form, one of the most neglected and difficult types of headache to treat. Recently published data will be reviewed. Recent findingsThe prevalence of frequent tension-type headache increased significantly from 1989 to 2001, and several risk factors have been identified. The incidence decreases markedly with age. The prognosis is fairly favorable for the episodic forms. Chronic tension-type headache, coexisting migraine, sleep problems and not being married were identified as risk factors for a poor outcome. Previous reports of sensitization of the central nervous system in patients with chronic tension-type headache were confirmed by the findings of generalized pain hypersensitivity both in skin and in muscles, and of a decrease in the volume of gray matter in brain structures. A promising new animal model of tension-type headache has been developed. In addition, the efficacy of a prophylactic drug, mirtazapine, with fewer side-effects than the tricyclic antidepressants has been demonstrated. SummaryThe new data on the prevalence, incidence and prognosis of tension-type headache are valuable for health care planning and in daily clinical practice. The increased knowledge with regard to abnormal central pain modulation, together with the development of an animal model, hold promise for much-needed improvements in the understanding of pathophysiological mechanisms and treatment.