311C90 (Zolmitriptan), a novel centrally and peripheral acting oral 5-hydroxytryptamine-1D agonist: a comparison of its absorption during a migraine attack and in a migraine-free period.

The oral absorption of a 10-mg oral dose of the novel 5-hydroxytryptamine (5HT1D) agonist, 311C90, was compared during a moderate or severe migraine headache and in a migraine-free period in an open, two-period study. The safety and efficacy of 311C90 in acute migraine were also assessed. Twenty patients attended the clinics during a moderate or severe migraine attack and 18 patients returned for a second dose in a migraine-free period. 311C90 was less rapidly absorbed during a migraine attack compared to the migraine-free period, consistent with gastric stasis during a migraine attach. The median area under the curve (AUC) was 15.7 ng/mlh lower during a migraine (median AUC: 18.4 ng/ml.h, range: 0-60.8 ng/ml.h) compared to the migraine-free period (median AUC: 33.4 ng/ml.h, range 9.4-79.5 ng/ml.h) (95% confidence interval: 6.9, 25.3) and the time to reach maximum plasma concentration was delayed (n = 18). Eleven out of 20 patients experienced a significant improvement in migraine headache intensity at 2 h post-dose. Plasma 311C90 concentrations were generally higher in those patients who responded to treatment with 311C90 in the plasma, but there was one patient with no quantifiable 311C90 in the plasma whose headache improved. Minor adverse experiences were reported in 11 out of 20 patients during a migraine attack and in 11 out of 18 patients outside an attack. They occurred shortly following drug administration and were of short duration, but their occurrence did not appear to be related to plasma 311C90 concentration. There were no clinically significant changes in blood pressure or 12-lead ECG during the assessment period.

Increased cerebrospinal fluid Met-enkephalin immunoreactivity in patients with chronic tension-type headache.

Cerebrospinal fluid (CSF) concentration of Met-enkephalin immunoreactivity (Met-enkephalin-ir) was determined by radioimmunoassay in 47 patients with chronic tension-type headache and in 47 headache-free control subjects. Thirty-nine of the controls were patients receiving spinal analgesia before surgery for diseases not associated with pain; 8 were healthy paid volunteers. Patients reporting migraine more than 1 day per month were excluded. Pericranial tenderness, nociceptive flexion reflex and thermal pain thresholds were determined in the majority of the patients. The median level of CSF Met-enkephalin-ir was significantly higher (115 pmol/l) (quartiles (107-134) pmol/l) in the headache patients than in the controls (median 79 pmol/l) (quartiles (73-87) pmol/l) (Mann-Whitney, P < 0.001). No indication of sex-difference or correlation with age with respect to CSF Met-enkephalin-ir was found. No correlation was found between CSF Met-enkephalin-ir and either pericranial tenderness, nociceptive flexion-reflex threshold, or thermal pain threshold. There was no indication of correlation between consumption of mild analgesics and CSF Met-enkephalin-ir. The higher levels of CSF Met-enkephalin-ir in the headache patients may be indicate activation of the enkephalinergic antinociceptive system at the spinal/trigeminal level, whereas the beta-endorphinergic system appears normal. This enkephalinergic activation may be caused by increased activity in the primary nociceptive afferents, or may be compensatory to decreased activity in other endogenous antinociceptive systems than the opioid.

Effect of sulpiride or paroxetine on cerebrospinal fluid neuropeptide concentrations in patients with chronic tension-type headache.

In lumbar cerebrospinal fluid (CSF) obtained from patients with chronic tension-type headache (CTH), the concentrations of beta-endorphin, met-enkephalin, dynorphin, cholecystokinin (CCK), calcitonin gene-related peptide (CGRP), and somatostatin were measured before and after 8 weeks of treatment with sulpiride or paroxetine. We previously reported higher than normal met-enkephalin concentrations in CTH. The present study reveals normal basal concentrations of CCK, CGRP and somatostatin and slightly decreased dynorphin in the same patients. Treatment with sulpiride or paroxetine did not change the concentration of any of the neuropeptides measured. These data suggest central changes in opioid systems but not in other peptide systems (CCK, CGRP, somatostatin) involved in nociceptive processing at the level of the spinal cord dorsal horn/nucleus caudalis of the trigeminal nerve in CTH. Such central changes might be pathophysiologically important or merely secondary to other more important occurrences. The lack of changes in neuropeptide concentrations during drug treatment makes planning of studies involving CSF analysis easier, but also limits the probability of obtaining information on specific neuropeptide systems through CSF analysis.

Sulpiride and paroxetine in the treatment of chronic tension-type headache. An explanatory double-blind trial.

Drugs influencing monoaminergic pathways are of potential use in the treatment of pain. A serotonin re-uptake inhibitor, paroxetine (20-30 mg daily), and a dopamine antagonist, sulpiride (200-400 mg daily) were compared in a randomized, double-blind, response-conditional cross-over pilot study in 50 non-depressed patients with chronic tension-type headache. Headache was scored daily on a 5-point verbal scale during 4-weeks baseline and during 8 weeks of treatment for each drug. A 5-point 'Global' assessment was obtained for each drug. In both treatment groups headache score decreased compared to baseline. Group comparison of 24 patients first treated with paroxetine and 24 patients first treated with sulpiride showed a non-significant trend in favor of sulpiride by 'Global' evaluation and by evaluation of the available diary records (18 paroxetine-treated and 19 sulpiride-treated). Cross-over analysis of 'Global' records from 20 patients treated with paroxetine followed by sulpiride and 17 patients treated in the reverse order showed better relief from sulpiride compared to paroxetine in patients having tested both drugs (P = .03). A similar difference was reflected in available headache scores (13 and 10 patients respectively; P = .03). Predominant side effects were sedation and depression, for paroxetine also nausea and head pain. None of the drugs improved headache more than one score-point on average. A placebo controlled trial of sulpiride may be warranted.

Decreased nociceptive flexion reflex threshold in chronic tension-type headache.

OBJECTIVE: To study nociceptive processing in chronic tension-type headache. DESIGN: Survey of the threshold for the nociceptive flexion reflex obtained by sural nerve stimulation in a convenience sample of 40 patients with chronic tension-type headache and in 29 sex- and age-matched healthy subjects. Muscular response was recorded from the biceps femoris muscle. For each stimulation, subjects recorded pain on a visual analogue scale. RESULTS: In seven subjects (four headache sufferers and three healthy subjects), no nociceptive flexion reflex response could be elicited. The median nociceptive flexion reflex threshold in the headache group was significantly lower (median, 10 mA) than in the control group (median, 20 mA). Pain tolerance thresholds were significantly lower in the headache group than in the control group. A high degree of correlation was found between nociceptive flexion reflex threshold and tolerated stimulus strength. The slopes of the stimulus intensity/visual analogue scale pain rating response curves were steeper in patients with headache than in control subjects. CONCLUSIONS: Chronic tension-type headache may represent a disorder of an endogenous antinociceptive system with a lowering of tone and recruitment of descending inhibitory systems.

Histamine receptors in the isolated human middle meningeal artery. A comparison with cerebral and temporal arteries.

The subtypes of histamine receptors mediating dilatation of human meningeal arteries have been tested in vitro, using "selective" antagonists, and compared with cerebral and temporal arteries previously examined. Dilatory responses were tested after preconstriction with prostaglandin F2 alpha. Both mepyramine and cimetidine caused a parallel shift to the right of the histamine concentration-response curve, suggesting the presence of both H1- and H2-receptors. Combined treatment with mepyramine and cimetidine caused further displacement of the concentration-response curve to the right. Schild analysis indicated pA2 values of 6.3 for cimetidine and 9.8 for mepyramine in situations of near complete blockade of either of the receptors. Both H1- and H2-receptors seem of importance for the histamine-induced dilatation in meningeal arteries and neither appear to dominate. The data considered in conjunction with our previous findings support the finding that experimental histamine-induced headache due to vasodilatation is intracranial of origin.

Clinical characteristics of migraine and episodic tension-type headache in relation to old and new diagnostic criteria.

Eighty-one patients were diagnosed as having migraine, tension headache or both according to previously used criteria. Then we performed a standardized interview to determine the frequency and severity of headache characteristics used in the new operational diagnostic criteria of the International Headache Society (IHS). In every patient the original diagnosis fulfilled also the IHS criteria, but in 9 patients the criteria were only fulfilled in half or less of the attacks, and applying the IHS criteria they also achieved an additional diagnosis. In one patient these attacks did not fulfill the pain criteria and in 8 (4 migraine, 4 tension headache) they did not fulfill the criteria for accompanying symptoms. Overall the IHS criteria are sensitive and specific, but they may possibly be improved with regard to accompanying symptoms. The present study suggests that recording of frequency and graded severity of characteristics using a headache diary may further improve the distinction between the different types of headache.

Temporal muscle blood flow in chronic tension-type headache.

Temporal muscle blood flow was measured with the xenon 133 clearance technique in 40 patients with chronic tension-type headache and in 13 control subjects. Pressure-pain threshold in the temporal region was determined with an algometer. Patients and control subjects did not differ in any of the blood flow parameters. Resting blood flow at the two sides was highly correlated (Spearman coefficient, r = .61) and no right/left differences could be demonstrated. In both patients and control subjects, blood flow increased approximately fivefold during isometric work (1/3 of a maximum surface electromyogram). Reactive hyperperfusion after isometric work was found in 8 patients and in 1 control subject. There was no definite correlation between the pressure-pain threshold and the corresponding blood flow. It is not likely that temporal muscle ischemia is the cause of muscle tenderness and pain in patients with chronic tension-type headache.

Clomipramine and mianserin in the treatment of chronic tension headache. A double-blind, controlled study.

114 patients with chronic tension headache (more than 10 days per month for at least 6 months) were treated with placebo, clomipramine or mianserin in a double blind parallel group comparison. Eighty-two patients completed the study. Headache pain was scored weekly on visual analogue scales for the 6 weeks of treatment. Observer-rating of headache was made at entry, after 3 weeks and after 6 weeks of treatment. In all groups, headache complaints decreased significantly compared to baseline. With the main parameter the decrease on both clomipramine and mianserin was significant compared to placebo. Although the trend was the same for the other parameters, the changes relative to placebo did not reach statistical significance.

Pressure pain thresholds and thermal nociceptive thresholds in chronic tension-type headache.

The nociceptive thresholds to mechanical and thermal stimuli in patients with chronic tension-type headache were compared. Palpation of pericranial tenderness was performed in 50 patients and a total tenderness score (TTS) was calculated. Palpation was repeated, and pressure pain thresholds (PPTs) were determined with a pressure algometer in the temporal and occipital regions. In 32 of the patients, pain thresholds for heat and cold and limens for detection of non-painful temperature changes were determined in the hands and the temporal regions. Twenty-four healthy volunteers served as controls. Scores obtained by manual palpation (TTS) at the first and second visit were positively correlated. A negative correlation between headache severity and PPT was found in the temporal region. A positive correlation between PPT in the temporal and occipital region was found, and PPT and TTS were negatively correlated. Thermal pain thresholds were consistently less extreme in patients compared to controls, and patients reporting severe headache on the examination day were those most sensitive to thermal pain. No difference was found between patients and controls with respect to detection of temperature changes. A correlation was found between PPT and the corresponding cold pain thresholds, but no correlation could be demonstrated between TTS and thermal pain thresholds. In conclusion, headache patients had decreased pain perception thresholds. Chronic tension-type headache might be a result of dysmodulation of nociceptive impulses, but it is likely that sensitized nociceptors also play a role.

Clomipramine and mianserin in chronic idiopathic pain syndrome. A placebo controlled study.

The reduction of pain by two antidepressants, clomipramine and mianserin, was, in this study on 253 patients with chronic idiopathic pain syndrome, found to be not better than a placebo when all patients were compared independently of the classification of pain. The improvement rate was around 40% after 6 weeks of treatment when using a 50% or better reduction in pain level. However, in patients who fulfilled a checklist definition of minor to major depression (30% of the total patient material) clomipramine was superior to mianserin and placebo with an improvement rate of 75% after 6 weeks. Using pain curves over time as outcome measure in the various clinical pain categories it was found that both mianserin and clomipramine seemed superior to placebo in patients with tension headache, but in patients with low back pain syndrome placebo was superior to the two antidepressants. No difference among the three treatments was found in patients with burning mouth syndrome or in patients with abdominal pain. These differences underline the importance of studying specific pain syndromes rather than composite groups of patients with idiopathic pain. The clinical significance of these pain curves needs further placebo controlled investigations.

Platelet 3H-imipramine binding in psychogenic pain patients.

High-affinity binding of 3H-imipramine was analyzed in platelet membranes from patients with chronic psychogenic pain. The patients who in addition to the pain also showed affective symptoms such as depression and anxiety had lower binding than the pain patients without these symptoms.

Pericranial tenderness in tension headache. A blind, controlled study.

Forty patients with tension headache and 40 healthy comparable control persons were palpated by the same "blinded" observer. Tenderness in 10 pericranial muscles on each side was rated on a four-point scale. A Total Tenderness Score was calculated for each individual by adding the scores from all palpated areas. Headache patients had significantly higher scores than controls and also significantly higher tenderness in each point separately. Median normal values and confidence limits for tenderness are given. Among 23 patients with daily headache a correlation was found between headache intensity and Total Tenderness Score. It is likely that the pathologic tenderness in patients with tension headache is the source of nociception, but pain mechanisms are more complex, as evidenced by discrepancy between tenderness and pain in some patients. Pathologic tenderness should be a contributing criterion to the diagnosis of tension headache (muscle contraction headache).

Discomfort or disability in patients with chronic pain syndrome.

In the present study of 253 patients with chronic pain syndrome we have made a multidimensional approach. All patients have been included in the study independent of coexisting states of anxiety or depression. We included criteria for diagnosis, duration, generability and intensity of pain, anxiety and depression, psychosocial stressors and social functioning. Using this system we have evaluated the antipain effectiveness of clomipramine and mianserin in a double-blind, placebo-controlled trial. By use of the Melancholia Scale 16 patients (6%) had a major depression, and by use of the Hamilton Anxiety Scale, 72 patients (28%) had a generalized anxiety disorder. The results showed no statistically significant difference between the three treatments, when using a visual analogue scale (VAS 10 cm with cut-off score 2 cm) for severity of pains as outcome criteria or the results of VAS and Global Clinical Impression Scale using the criteria of reduction of 50% or more between the pretreatment and posttreatment scores. By use of all the assessments it is possible to make an improvement curve for each patient expressed by the area under the curve, and not even there we found a difference between the three treatments. Clomipramine and mianserin were significantly superior to placebo in the topographical pain subgroup with headache using area under the improvement curves as criteria (p less than 0.05). When the 60-item General Health Questionnaire was used to identify minor psychiatric morbidity 44% was found. We can use this as a measure of quality of life. Our results have indicated that placebo-controlled studies are still needed in this field of research.

The pharmacokinetics of the individual constituents of an aspirin-metoclopramide combination ('Migravess').

A study was carried out in 10 healthy volunteers, aged between 22 and 28 years, to investigate the pharmacokinetics of an aspirin-metoclopramide combined preparation compared with those of the individual components given alone. Blood levels were determined before and after administration of a single dose of the three medications given at weekly intervals. No significant difference was found in the bioavailability of either the aspirin or metoclopramide from the combination as compared to the individual components.