Amitriptyline Is Effective in Chronic But Not in Episodic Tension-Type Headache: Pathogenetic Implications

The tricyclic antidepressant amitriptyline, is an effective drug for the treatment of chronic tension-type headache and for other chronic pain syndromes, but it is also effective in the prophylaxis of an episodic type of headache such as migraine. However, its efficacy in episodic tension-type headache has not yet been clarified. We compared the efficacy of amitriptyline (25 mg/day) in 82 nondepressed patients with either chronic or episodic tension-type headache in an open-label study. Amitriptyline significantly reduced ( P <0.05) frequency and duration of headache as well as analgesic consumption in chronic, but not in episodic, tension-type headache. Further placebo-controlled trials, possibly with higher doses of amitriptyline, might confirm if the different pattern of response to amitriptyline can be explained in terms of different involvement of central nociception and of peripheral myofascial factors in the chronic and in the episodic forms of tension-type headache.     

Amitriptyline reduces myofascial tenderness in patients with chronic tension-type headache

The tricyclic anti-depressant amitriptyline is widely used in the treatment of chronic tension-type headache. The aim of the present study was to investigate whether the analgesic effect is caused by a reduction of muscle pain or by a general reduction of pain sensitivity. Thirty-three non-depressed patients with chronic tension-type headache were treated with amitriptyline 75 mg/day and with the highly selective serotonin reuptake inhibitor citalopram 20 mg/day in a 32-week, double-blind, placebo-controlled, three-way crossover study. At the end of each treatment period, actual headache intensity and pericranial myofascial tenderness were recorded, pressure pain detection and tolerance thresholds were measured in the finger and in the temporal region and the electrical pain threshold was measured at the labial commissure. Amitriptyline reduced tenderness and headache intensity significantly more than placebo (P=0.01 and P=0.04, respectively). The reduction in tenderness could be ascribed solely to the group of patients who responded to amitriptyline treatment by at least 30% reduction in headache while tenderness was unchanged in non-responders. Amitriptyline did not affect pressure or electrical pain thresholds at any of the examined locations. Citalopram had no significant effect on any of the examined parameters. These findings indicate that amitriptyline elicits its analgesic effect in chronic myofascial pain by reducing the transmission of painful stimuli from myofascial tissues rather than by reducing overall pain sensitivity. We suggest that this effect is caused by a segmental reduction of central sensitization in combination with a peripheral anti-nociceptive action.     

Current and potential future drug therapies for tension-type headache

Tension-type headache is a common primary headache with tremendous socioeconomic impact. Establishment of an accurate diagnosis is important before initiation of any pharmacologic therapy. Simple analgesics and nonsteroidal anti-inflammatory drugs are the mainstays of treatment of episodic tension-type headache. The tricyclic antidepressant amitriptyline is the drug of choice in the preventive treatment of chronic tension-type headache. Progress in basic neuroscience has emphasized the importance of nitric oxide inhibition and N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid receptor antagonism in the treatment of chronic pain. It has been demonstrated that inhibition of nitric oxide is effective in chronic tension-type headache. These interesting data indicate that more specific and effective treatment possibilities will emerge in the future.     

Dynamic assessment of abnormalities in central pain transmission and modulation in tension-type headache sufferers

OBJECTIVE: To examine and compare central pain processing and modulation in young tension-type headache sufferers with that of matched healthy controls using an induced headache "challenge" paradigm. BACKGROUND: Recent research has suggested that abnormalities in central pain processing and descending pain modulation may contribute to chronic tension-type headache. These abnormalities, if they contribute to headache pathogenesis, should be present in young adult tension-type headache sufferers. Recent research using static measures of physiological variables, such as muscle tenderness and exteroceptive suppression, has identified chronic muscle tenderness as a characteristic of young tension-type headache sufferers, but other central nervous system functional abnormalities may require a dynamic "challenge" to be observed. METHODS: Twenty-four young women meeting the International Headache Society diagnostic criteria for tension-type headache (headache-prone) and a matched group of 24 healthy women who reported fewer than 10 problem headaches per year (control) participated in a double-blind, placebo-controlled, crossover study. Subjects completed jaw clenching and a placebo condition on different days in counterbalanced order. Pericranial muscle tenderness, pressure-pain thresholds on the temporalis, and exteroceptive suppression periods were assessed before and after each procedure. Head pain was recorded for 12 to16 hours following each condition. RESULTS: Headache-prone subjects were more likely than controls to experience headaches after both the jaw clenching and placebo procedures, but neither group was significantly more likely to experience headaches following jaw clenching than placebo. In pretreatment measurements, headache-prone subjects exhibited greater muscle tenderness than controls, but pressure-pain detection thresholds and exteroceptive suppression periods did not differ in the two groups. Control subjects showed increases in muscle tenderness and exteroceptive suppression periods following both the clenching and placebo procedures, whereas headache-prone subjects exhibited no significant changes in any of the physiological measures following either experimental manipulation. CONCLUSIONS: These results confirm previous findings indicating abnormally high pericranial muscle tenderness in young tension headache sufferers even in the headache-free state. In addition, the results suggest that the development of headaches following noxious stimulation is more strongly related to headache proneness and associated abnormalities in central pain transmission or modulation (indexed by pericranial muscle tenderness and exteroceptive suppression responses) than muscle strain induced by jaw clenching.     

Venlafaxine extended release (XR) for the prophylaxis of migraine and tension-type headache: A retrospective study in a clinical setting

OBJECTIVE: To assess the efficacy of extended-release venlafaxine in the prophylaxis of migraine and chronic tension-type headache. BACKGROUND: Venlafaxine, a structurally novel antidepressant, is a selective serotonin-norepinephrine reuptake inhibitor. This study is the first to test the effects of extended-release venlafaxine on headaches. METHODS: Patients were evaluated on a retrospective basis. Fifty-six patients with chronic tension-type headache and 114 patients with migraine were prescribed extended-release venlafaxine. Nearly all the study subjects had been resistant to several previous preventive medications. Patients took venlafaxine for an average of 6 months with a median dose of 150 mg (range, 37.5 to 300 mg). RESULTS: The mean frequency of headaches in the group with chronic tension-type headache fell from 24.0 to 15.2 per month (P <.0001). The group with migraine showed a reduction from 16.1 to 11.1 headaches per month (P <.0001). The medicine was well tolerated. CONCLUSIONS: This trial indicates that extended-release venlafaxine has potential in headache prophylaxis based on its efficacy and safety profile. We recommend a double-blind, placebo-controlled study to further assess the role of extended-release venlafaxine in headache prevention.     

Behandlung chronischer Schmerzsyndrome mit Antidepressiva

During the 1960s, it was observed that the tricyclic antidepressant imipramine was effective in the treatment of neuralgia, myalgia, and pain in carcinoma. Similarly, in other studies, clomipramine was also found to have an analgesic effect. The sedative antidepressant amitriptyline has proved effective in migraine prophylaxis, chronic tension headache, and psychogenic musculoskeletal and neuralgic facial pain. Controlled studies have also shown pain-relief in patients with postherpetic neuralgia and diabetic neuralgia. In cases of predominantly psychogenic headache, idiopathic trigeminal neuralgia and chronic neck and back pain, the sedative and anxiolytic antidepressant doxepin has been found to be an effective analgesic. As chronic pain patients are typically restless, irritable, and emotionally labile, sedative antidepressants tend to be prescribed in preference to stimulating drugs. Consequently, the compounds amitriptyline and doxepin have attracted increasing scientific interest in the field of algology. Nevertheless, our knowledge regarding the usefulness of these substances in treating chronic pain syndromes is incomplete in many areas. The remaining tricyclic and the tetracyclic antidepressants have not been sufficiently well evaluated. This is also true of monoamine oxidase inhibitors, of which individual reports to date suggest are probably also effective as analgesics. A scientific investigation into the possible differences in the effectiveness of various antidepressants in specific chronic pain conditions is an important task for the future.     

Analgesic effect of amitriptyline in chronic tension-type headache is not directly related to serotonin reuptake inhibition

The tricyclic antidepressant amitriptyline is the only documented and most widely used prophylactic drug for chronic tension-type headache (CTTH). However, it is not fully clarified whether the serotonin (5-HT) reuptake inhibition plays a major role for the analgesic effect of amitriptyline. To explore the importance of 5-HT reuptake inhibition for mechanism of action of the analgesic effect of amitriptyline we investigated platelet 5-HT levels during preventive treatment of CTTH with amitriptyline, the selective serotonin reuptake inhibitor citalopram, and placebo. Thirty-four patients with CTTH were given preventive treatment with amitriptyline 75 mg/day, the selective 5-HT reuptake inhibitor citalopram 20 mg/day, and placebo in a 32-week, double-blind, placebo-controlled, three-way crossover trial. Blood samples were collected in the last week of each treatment period. Platelet 5-HT was used as a measure of 5-HT reuptake inhibition and determined by high performance liquid chromatography. Area under the headache curve was 308 (157-715) (median with quartiles in parentheses) with amitriptyline and significantly lower than 377 (158-1121) with citalopram (P = 0.04) and 441 (178-1408) with placebo (P = 0.002). There was no difference between citalopram and placebo (P = 0.23). Platelet 5-HT was 0.4 (0.3-0.7) x 10(-18)mol/platelet with citalopram, which was significantly lower than 1.7 (1.2-2.4) x 10(-18)mol/platelet with amitriptyline (P < 0.001), and 3.5 (2.8-4.3) x 10(-18)mol/platelet with placebo (P < 0.001). The lower platelet 5-HT during treatment with citalopram than amitriptyline indicates that 5-HT reuptake was most effectively inhibited by citalopram. In contrast, amitriptyline was most effective in reduction of headache. This suggests that the analgesic effect of amitriptyline in CTTH is not solely due to 5-HT reuptake inhibition and that other mechanisms such as norepinephrine reuptake inhibition, NMDA receptor antagonism, blockade of muscarinic receptors and ion channels should be addressed in the future research.     

Pressure pain threshold and needle acupuncture in chronic tension-type headache--a double-blind placebo-controlled study

In order to examine the role of muscular mechanisms in chronic tension-type headache a study with needle acupuncture was performed. Needle acupuncture could be of therapeutic value because it has shown some positive effects in myofascial pain syndromes. We performed a double-blind, placebo-controlled study with 39 patients (mean age 49.0 years, SD=14.8) fulfilling the International Headache Society criteria for chronic tension-type headaches. Participants were randomly assigned to verum or placebo condition. Six weeks after end of treatment no significant differences between placebo and verum could be observed with respect to visual analogue scale and frequency of headache attacks. Nevertheless, pressure pain thresholds significantly increased for the verum group. The findings of our study support the hypothesis that peripheral mechanisms - such as increased muscle tenderness - only play a minor role in the pathogenesis of chronic tension-type headache.     

An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache

OBJECTIVE: To assess effectiveness and safety of tizanidine hydrochloride tablets for the prophylaxis of chronic daily headache. BACKGROUND: Tizanidine hydrochloride is an alpha2-adrenergic agonist that inhibits the release and effectiveness of norepinephrine at both central sites (eg, the locus ceruleus) and the spinal cord. It acts as a central muscle relaxant and has antinociceptive effects. Preliminary research and retrospective analyses have suggested efficacy in treatment of both chronic tension-type headache and chronic daily headache with migrainous features. DESIGN: Thirty-nine patients with more than 15 headache days per month (33 with migraine, 5 migrainous, 1 chronic tension-type) completed a 4-week baseline, with 31 completing a planned 12 weeks of treatment with tizanidine. Dosing was titrated from 2 mg at bedtime to a median daily dose of 14 mg (mean, 13.5; SD, 4.3; range, 4 to 20, divided over three doses per day) by treatment week 4. RESULTS: The overall headache index through week 12 (headache frequency x average intensity x duration) declined significantly (P<.00000002), with a corresponding increase in mean percentage improvement from 49% for weeks 1 through 4, to 65% for weeks 5 through 8, and 64% for weeks 9 through 12 (P<.0182). During weeks 9 through 12, 67% had improved more than 50% compared to baseline. Overall headache frequency declined from 22.83 to 15.83 days per month (P<.00001), with frequency of severe headaches dropping from 7.52 to 3.58 days per month (P<.000035). Average headache intensity dropped from 1.83 to 1.07 (1-to-5 scale), peak intensity declined from 2.37 to 1.40, and mean duration was reduced from 6.96 to 4.00 hours per headache (P<.00001). Improvement also occurred on visual analog scales of overall headache status, mood, sleep, quality of life (P<.00001), and sexual function (P<.0075); as well as the Beck Depression Inventory-II (P<.00073). Mild-to-moderate adverse events reported by more than 10% of the patients included somnolence, asthenia, and dry mouth. Only 3 patients discontinued treatment due to adverse events: somnolence and dry mouth alone (n = 1), or in combination with either hyperkinesis (n = 1) or constipation (n = 1). One patient had elevated liver enzymes that returned to normal after the drug was discontinued. CONCLUSIONS: The results provide preliminary support for the efficacy, safety, and tolerability of tizanidine in the prophylaxis of chronic daily headache.     

Chronic Tension-Type Headache, Mood Depression and Serotonin: Therapeutic Effects of Fluvoxamine and Mianserine

SYNOPSIS
Forty out-patients affected by chronic tension-type headache were selected according to the diagnostic criteria of International Headache Society (IHS) Headache Classification Committee. In a controlled trial patients received placebo for a four-week baseline period, then they were randomized in double-blind fashion to therapy with mianserine (30-60 mg/day) or fluvoxamine (50-100 mg/day) for another eight-week period. Frequency of headache, pain severity and analgesic consumption were evaluated using a self-monitoring system. Mood depression was evaluated at 0, 4 and 8 weeks by using Zung'ss Self-Rating Depression Scale and Hamilton Rating Scale for Depression. Both drugs were beneficial in the treatment of chronic tension-type headache. Non-depressed subjects with more severe headache responded best to fluvoxamine, whereas mianserine was more effective in the treatment of depressed patients with moderate headache. These results suggest that central serotoninergic neurotransmission can play a role in the pathophysiology of chronic tension-type headache also in non-depressed patients.     

Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial

Although amitriptyline relieves pain in many patients with painful diabetic neuropathy, side effects often preclude effective treatment. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressants. We compared a 6 week course of desipramine (mean dose, 201 mg/day) to active placebo in 20 patients with painful diabetic neuropathy in a double-blind crossover trial. Pain relief with desipramine was statistically significant in weeks 5 and 6. Eleven patients reported at least moderate relief with desipramine, compared to 2 with placebo. Pain relief tended to be greater in depressed patients, but relief was also observed in patients who did not show an antidepressant effect. We conclude that desipramine relieves pain in many patients with painful diabetic neuropathy, offering an alternative for patients unable to tolerate amitriptyline. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressants proven effective in neuropathic pain, may mediate this analgesic effect.     

Dextroamphetamine pilot crossover trials and n of 1 trials in patients with chronic tension-type and migraine headache

OBJECTIVE: To examine the preventive effects of dextroamphetamine in select small groups of patients with chronic tension-type and migraine headache. BACKGROUND: Neither amphetamine nor methylphenidate is used as a headache preventive. This study was undertaken after a chance observation led one of us to prescribe dextroamphetamine with apparent successes in specific patients with chronic tension-type or migraine headaches. METHODS: Two pilot trials were done. Trial 1 tested patients who were taking dextroamphetamine, while Trial 2 tested patients who had never taken this drug. Each trial obtained full data on eight subjects with chronic tension-type headache and eight subjects with migraine headache. A randomized, double-blinded, controlled, multiple-crossover design was used. Subjects took capsules containing dextroamphetamine or equi-stimulatory caffeine (the control) during four alternating 20-day periods. Trial 1 subjects took their pretrial dextroamphetamine dose at breakfast and lunch. Trial 2 subjects took 10 mg at these times. Subjects recorded the integer from 0 to 3 that represented their headache intensity during the previous 24 hours. The subject's data were the average daily headache grade for the two dextroamphetamine periods and for the two caffeine periods. The differential effect of amphetamine and caffeine on each group of eight subjects and on each individual was analyzed by t-tests. RESULTS: In both trials, the tension-type and migraine groups had lower mean daily headache grades in the amphetamine than in the caffeine periods. P values for these differences indicated that there were real drug effects, on the average, in the migraine groups (P<.05) and suggestive but inconclusive effects in the tension-type groups (P<.10). The individual n of 1 analyses showed that five tension-type and three migraine subjects in Trial 1 and three tension-type and three migraine subjects in Trial 2 had considerably lower mean daily headache grades on amphetamine with P values indicating, at various levels of significance (from P<.05 to P<.001), real amphetamine effects. Twelve of the remaining 18 patients had lower, albeit not significant, mean daily grades with amphetamine. No subject in either trial had a significantly lower mean daily headache grade on caffeine. CONCLUSIONS: Dextroamphetamine had real preventive effects on chronic tension-type and migraine headaches in some subjects. These results should encourage other investigators to study its effects on these headaches.     

Desipramine enhances opiate postoperative analgesia

In a double-blind, placebo-controlled study the analgesic efficacy of the combination of a tricyclic antidepressant and morphine was investigated. One of two tricyclic antidepressants (either amitriptyline, a relatively selective serotonin uptake inhibitor or desipramine, a relatively selective noradrenaline uptake inhibitor) or a placebo, was given for 1 week prior to surgery, followed by a single postoperative dose of morphine. Desipramine, but not amitriptyline, both increased and prolonged morphine analgesia. Neither tricyclic antidepressant reduced dental postoperative pain in the absence of morphine. We propose that desipramine enhances opiate analgesia by enhancing a noradrenergic component that contributes to endogenous opioid-mediated analgesia systems.     

Frequent migraine and migraine status without tension-type headaches: an unusual presentation of rebound headaches

Rebound headaches usually present as daily or almost daily, prolonged, generalized tension-type headaches with superimposed migraine-like attacks. The latter are more frequent, more intense, and longer than any episodic migraine that the patient might have experienced prior to the development of the chronic daily headaches. Rebound presenting as migraine without tension-type pain has been mentioned in a few previous articles on chronic daily headache, but there have been no previous articles stressing that frequent migraine might relate to the analgesics that are being used. These case histories are presented to illustrate that frequent migraine and migraine status without tension-type headaches may be manifestations of rebound and improve when the offending analgesic agents are stopped. If the clinician fails to recognize this unusual presentation of rebound headache, the patient might be placed on unnecessary and often ineffective medications for prophylaxis instead of stopping the offending pain relief medications.     

Chronic daily headache prophylaxis with tizanidine: a double-blind,placebo-controlled,multicenter outcome study

OBJECTIVE: To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). BACKGROUND: Tizanidine is an alpha2-adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. METHODS: Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. RESULTS: Tizanidine was shown to be superior to placebo in reducing the overall headache index (P =.0025), as well as mean headache days per week (P =.0193), severe headache days per week (P =.0211), average headache intensity (P =.0108), peak headache intensity (P =.0020), and mean headache duration (P =.0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P =.0144), 55% versus 21% for severe headache days (P =.0331), 35% versus 19% for headache duration (P =.0142), 35% versus 20% for peak headache intensity (P =.0106), 33% versus 20% for average headache intensity (P =.0281), and 30% versus 22% for total headache days (P =.0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P =.0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. CONCLUSIONS: The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.     

Specificity and Sensitivity of Temporalis ES2 Measurements in the Diagnosis of Chronic Primary Headaches

We have evaluated the specificity and sensitivity of temporalis ES2 measurements for the diagnosis of primary headaches. Ninety-four outpatients diagnosed according to IHS criteria were prospectively included: 25 had chronic tension-type headache (code 2.2.), 15 episodic tension-type headache (code 2.1.), 20 migraine without aura (code 1.1.) and 34 chronic daily headaches with daily analgesics/ergotamine abuse (code 8.2.). In chronic tension-type, the sensitivity of the ES2 test was 84% at the 0.1 and the 0.5 Hz, but only 56% at the 2Hz stimulation rates. Its specificity was 100% at 0.1Hz, 90% at 0.5Hz and 95% at 2Hz compared to migraine; positive predictive values were at similar levels. Sensitivity of ES2 at 0.1 Hz was 67% in episodic tension-type headache, but its positive predictive value versus migraine was excellent. Comparing chronic tension-type headache and analgesic abusers, the specificity and positive predictive value of the ES2 test for diagnosing chronic tension-type headache were less satisfactory (60%) while the negative predictive values, however, remained good (83% at 0.1Hz).
The results confirm that the temporalis ES2 test has a higher diagnostic sensitivity in chronic and episodic tension-type headache, but that it has a high negative predictive value for both types of tension-type headache compared to other primary headaches. For diagnostic purposes, the 0.1Hz stimulation rate seems optimal. The 2Hz stimulation rate is the least sensitive, although it may induce total disappearance of ES2 in up to 40% of patients. ES2 is of limited usefulness for separating chronic tension-type headache and chronic drug-abuse headache, possibly because the latter group comprises both tension-type headache and migraine patients.     

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.     

Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain

This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and tolerability of lamotrigine added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic in patients whose neuropathic pain was inadequately controlled with these medications. Patients with neuropathic pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy, who had a mean weekly pain score > or =4 on an 11-point numerical rating scale, were randomized to receive a flexible dose of lamotrigine 200, 300, or 400mg daily (n=111) or placebo (n=109) for up to 14 weeks (including eight weeks of dose escalation) in addition to their prestudy regimen of gabapentin, a tricyclic antidepressant, or a nonopioid analgesic. No statistically significant difference in the mean change in pain-intensity score from baseline to Week 14 (primary endpoint) was detected between lamotrigine and placebo (P=0.67). Differences between lamotrigine and placebo were not statistically significant for secondary efficacy assessments, including mean changes from baseline in the Short-Form McGill Pain Questionnaire, the Neuropathic Pain Scale, rescue medication use, and the percentages of patients rated as much improved or very much improved at the end of treatment on the Clinician Global Impression of Change scale and the Patient Global Impression of Change scale. Lamotrigine was generally well tolerated. Lamotrigine (up to 400 mg/day) added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic did not demonstrate efficacy as an adjunctive treatment of neuropathic pain but was generally safe and well tolerated.     

American Headache Society members' assessment of headache diagnostic criteria

OBJECTIVE: We assessed the views of physicians interested in headache as to the diagnosis of the most commonly occurring and currently controversial headaches. BACKGROUND: The International Headache Society (IHS) classification system has received wide professional endorsement and considerable empirical support, but in the United States, their adoption by clinicians may be proceeding more slowly. Questions remain, including what diagnostic criteria for migraine and tension-type headache clinicians may continue to favor over those outlined by the IHS, to what extent is the "transformed migraine" diagnosis used in clinical practice, and how is analgesic rebound headache diagnosed with regard to the various quantitative measures of analgesic use. METHODS: Members of the American Headache Society rated the importance of IHS and non-IHS diagnostic criteria for migraine and tension-type headache and for analgesic rebound headache. Respondents also described their use of the proposed transformed migraine diagnosis. RESULTS: Two-thirds (67.3%) of the respondents reported use of the IHS criteria or the IHS criteria in conjunction with clinical judgment. For migraine and tension-type headache, IHS criteria were rated with high importance, but some respondents reported using additional non-IHS diagnostic criteria and de-emphasizing certain IHS criteria. For chronic headache, almost two-thirds (63%) of respondents reported using the transformed migraine diagnosis. For analgesic rebound headache, respondents preferred to make the diagnosis based on medication consumption that is lower than amounts stipulated in the IHS classification system. CONCLUSIONS: There remains a number of physicians interested in headache who do not use the IHS classification system, who modify the IHS criteria in practice, and who use the "transformed migraine" diagnosis for patients with chronic daily headache.     

2000 Wolfe Award. Sumatriptan for the range of headaches in migraine sufferers: results of the Spectrum Study

BACKGROUND: Migraineurs experience a spectrum of headaches: migraine, migrainous, and episodic tension-type as defined by the International Headache Society (IHS). OBJECTIVE: To evaluate the effectiveness of sumatriptan, 50-mg tablets, in treating the spectrum of headaches in IHS-diagnosed migraineurs. DESIGN/METHODS: Migraineurs with severe disability (Headache Impact Questionnaire score 250 or greater) were enrolled in a randomized, double-blind, placebo-controlled, crossover study. Patients treated up to 10 headaches with sumatriptan, 50 mg, or placebo (4:1). Headache features, recorded prior to treatment, were used to classify each headache using IHS criteria. Headache response (moderate or severe pain reduced to mild or no pain) and pain-free response were recorded at 2 and 4 hours postdose (primary endpoint). Because patients treated multiple attacks, statistical methods controlling for within-subject correlation were used. RESULTS: Two hundred forty-nine migraineurs treated 1576 moderate or severe headaches: migraine (n = 1110), migrainous (n = 103), and tension-type (n = 363). Sumatriptan was superior to placebo for headache response 4 hours postdose (primary endpoint) across all headache types (migraine, 66% versus 48%; P<.001; migrainous, 71% versus 39%; P<.01; tension-type, 78% versus 50%, P<.001). Sumatriptan was also superior to placebo for pain-free response 4 hours postdose for migraine (41% versus 24%, P<.001) and tension-type headaches (56% versus 36%, P =.001). Sumatriptan provided superior pain-free response 2 hours postdose for migraine (18% versus 7%, P<.0001) and tension-type headache (28% versus 14%, P =.0005) compared with placebo. CONCLUSION: Sumatriptan, 50-mg tablets, are effective for the full spectrum of headaches experienced by patients with disabling migraine due to a sumatriptan-responsive mechanism.