Asymmetrical reduction of the nociceptive flexion reflex threshold in cluster headache

The nociceptive flexion reflex (NFR) of the lower limbs (RIII reflex) was examined bilaterally in 54 cluster headache (CH) patients suffering from episodic CH (ECH) and chronic CH (CCH). Fifteen ECH patients were examined in both remission and active phases. The RIII reflex threshold (Tr) and the threshold of pain sensation (Tp) were significantly reduced on the symptomatic side in patients with episodic CH during the bout. During the active phase of episodic CH an inverse correlation was found between the severity of CH (ratio: number of cluster periods/years of illness duration) and the Tp, which may suggest a role for secondary central sensitization in pain pathways. The lower Tr and Tp on the symptomatic side is in keeping with previous observations exploring pain mechanisms using different methods (i.e. corneal reflex, pain pressure threshold). On the whole, these data tie in with the view of an impairment of the pain control system, which parallels the periodicity of the disorder in the episodic form.     

Pupil responsiveness in cluster headache: A dynamic TV pupillometric evaluation

In this study the variations in pupil diameter induced by different stimuli (dark-light adaptation, light reflex, electric stimulation of the sural nerve) were investigated in episodic (in the active or remission phases) and in chronic cluster headache (CH) patients. Pupil size monitoring was performed with a monocular, infrared TV pupillometer, and sural nerve stimuli were applied after the pain threshold had been measured as the flexion reflex threshold of the biceps femoris muscle (RIII reflex). The results were compared with those obtained in patients with "peripheral" (third neuron) Horner's syndrome and in healthy sex- and age-matched controls. On the symptomatic side we found an impairment of pupil response to light flashes and nociceptive stimuli; similar findings were sometimes evident on the pain-free side, too. These results substantiate previous observations that in cluster headache a dysfunction of the integrative central nervous system pathways also exists intercritically and mostly bilaterally, involving both autonomic regulation and pain perception mechanisms.     

Impairment of corneal pain perception in cluster headache.

Despite many studies, the mechanisms underlying the pathogenesis of pain in cluster headache (CH) still remain obscure. An involvement of substance P (SP) containing neurons of the Gasserian ganglion and/or of the spinal trigeminal nucleus has recently been suggested, e.g., by impairment of inhibitory descending pathways on trigeminal nociceptive neurons. The electrically elicited corneal reflex was studied in 21 CH patients (15 in active phase, 6 in remission). This method allows simultaneous measurements of the trigemino-facial reflex and corneal pain perception. A significant reduction of pain thresholds (more evident on the pain side) was observed in CH during the active phase, while normal values were recorded during the remission phase. Ten out of 15 patients in the active phase showed a significantly reduced corneal pain threshold on the pain side, while tactile sensibility was normal. Moreover, latency, amplitude and duration of the corneal reflex were normal for both painful and painless stimulations during both phases. The threshold of the nociceptive muscular response in the active phase was significantly reduced, suggesting that the excitability of trigeminal nociceptive neurons or of the motor neurons is increased in CH. The results agree with the hypothesis that a reversible impairment of several integrative functions, including the activity of trigeminal pain control system, exists in CH during the active phase.     

The trigemino-pupillary response in cluster headache

Central impairment of the integrative neural systems controlling vegetative function and pain perception has been demonstrated in cluster headache (CH). Recently, we described the human pupillary response (trigeminal reflex) to quantified (painless and painful) corneal stimulation with a combined neurophysiological and pharmacological technique. In this study, the trigeminal reflex was evaluated in 26 subjects with episodic cluster headache. During the active phase of the disease, on the side of the pain we observed reduced mydriasis to electrical stimuli with an intensity equal to the corneal reflex threshold, and on both sides to stimuli with intensity that equalled the pain threshold. No difference was found when amplitude of the miotic phase was compared in the different groups. These suggest disordered pupillary activation in response to pain, probably sympathetic in origin, which is bilateral, detectable also during the remission phase and which cannot be explained simply by the antidromic release of pain-related peptides.     

Circadian variations of human flexion reflex

We investigated 8 healthy male volunteers, evaluating RII and RIII thresholds every 6 h starting from noon, for a 24-h period. Both reflex responses exhibited a circadian rhythmicity: the lowest values were found in the early morning (9.1 +/- 3.0 and 13.1 +/- 4.4 mA, respectively), while the highest values were observed at midnight (13.1 +/- 3.5 and 18.5 +/- 5.3 mA). Also mean cosinor analysis indicated the existence of a significant rhythm with acrophase at 20:12 for RII and 22:29 for RIII. In 4 subjects, beta-endorphin plasma (beta-EP) level was tested during the day. No correlation was observed between circadian changes of beta-EP and RIII threshold. Other factors are likely to be involved in the circadian variation of nociceptive flexion reflex in man.     

The insulin tolerance test and ovine corticotrophin-releasing-hormone test in episodic cluster headache II: comparison with low back pain patients

Hypothalamic involvement has been invoked to explain the periodicity of the cluster periods and rhythmicity of the pain attacks in cluster headache. To explore this hypothesis the ovine corticotrophin-releasing hormone (o-CRH) and the insulin tolerance test were administered to a group of episodic cluster headache sufferers during both cluster period and remission. A group of low back pain patients and healthy subjects comprised the control populations. For the o-CRH test, 7 healthy subjects, 7 low back pain patients, 6 cluster headache patients in remission, and 12 in cluster period were studied. Five healthy subjects, 7 low back pain patients, 6 cluster headache patients in remission, and 9 in cluster period were administered the insulin tolerance test. Significantly increased basal cortisol levels were found in cluster headache patients in both illness phases ( p < 0.0001), but not in low back pain patients. Significantly reduced cortisol response to the o-CRH test was observed in cluster headache patients in both phases compared to healthy controls ( p < 0.02.). A blunted ACTH and cortisol response ( p < 0.0001 and p < 0.003 respectively) to the insulin tolerance test was present in cluster headache patients in both phases of the illness compared to healthy subjects and low back pain patients. On the contrary, the ACTH surge after insulin induced hypoglycemia was significantly increased in the low back pain patient group ( p = 0.02). These results suggest that the altered hypothalamic-pituitary-adrenal axis responsiveness in cluster headache patients is not a consequence of the pain, and point to a central, probably hypothalamic derangement in this pathology.     

Facilitated temporal processing of pain and defective supraspinal control of pain in cluster headache

In cluster headache (CH), pathogenesis has been emphasized the role of the posterior hypothalamus. It is part of a supraspinal network involved in the descending control of pain, including the diffuse noxious inhibitory control (DNIC), which in turn modulates the pain processing. We hypothesized that CH during the active phase facilitated temporal pain processing supported by abnormal functioning of the DNIC. We studied the functional activity of the DNIC by evaluating the effect of the cold pressor test (CPT) on the temporal summation threshold (TST) of the nociceptive withdrawal reflex. Ten subjects with episodic CH (2 women, 8 men) and 10 healthy subjects were recruited. Each subject underwent neurophysiological evaluation (nociceptive withdrawal reflex TST and related painful sensation) at baseline, then before (control session), during (pain session), and 5 min after (aftereffect) the CPT (immersing hand in a 4 °C water bath for 4–5 min). Patients had been studied during both the active and remission phases. During the active phase, CH revealed a significant facilitation in temporal processing of pain stimuli (reduction of TST), which reverted during the remission phase. The CPT activating the DNIC did not produce any significant inhibitory effect of pain responses in CH during the active phase, whereas it induced a clear inhibition during the remission phase. We hypothesized that in CH, a dysfunction of the supraspinal control of pain related to the clinical activity of the disease, possibly supported by an abnormal hypothalamic function, leads to a facilitation in pain processing and a predisposition to pain attacks.     

Changes in Neutrophil Met-Enkephalin Containing Peptides in Episodic Cluster Headache

We have previously demonstrated an increase in plasma met-enkephalin levels during the pain attacks in episodic cluster headache. The present study was undertaken in order to clarify the source of the plasma met-enkephalin increase. Recent evidence has shown that peripheral blood polymorphonuclear cells contain peptides derived from the proenkephalin A system, which can be released by specific stimuli. We studied neutrophil met-enkephalin containing peptides (NMECP) in 27 episodic cluster headache patients: 24 in a cluster period (6 of them during a pain attack), and 3 in the remission period. Neutrophil met-enkephalin containing peptide levels (after sequential enzymatic digestion with trypsin and carboxypeptidase B) were determined by radioimmunoassay with specific antiserum. Neutrophil peptide concentration (pmol/mg prot) was lower (p less than 0.01) in patients during the pain attack (14.4 +/- 0.36) than after their pain had subsided (36.7 +/- 0.31) and lower than in the remission period patients (35.8 +/- 0.4). We conclude that neutrophil met-enkephalin containing peptides decrease during pain in episodic cluster headache, and that they may be involved in the concomitant plasma met-enkephalin increase.     

Subchronic Cluster Headache

SYNOPSIS
A subgroup of 33 patients were distinguished from 59 other patients with episodic cluster headache by shorterremission periods, specifically of less than six months duration. This subgroup (subchronic cluster headache)was compared to episodic cluster headache patients and an additional 29 patients with chronic cluster headache,for differences in several clinical parameters.Results of this study demonstrated that the subchronic group was clinically similar to the chronic group andsignificantly different from episodic cluster headache patients. Thus, sub-chronic cluster headache wascharacterized by an increased frequency of treatment-resistance, headache attacks, drug abuse, hypochondriasisand prolonged cluster periods.Results of this study suggests that subchronic cluster headache, as defined by remission duration of sixmonths or less, may be a clinically relevant class of cluster headache. Distinction of this subgroup from thebroader "episodic" category may permit more accurate prognostic and therapeutic capabilities.     

Evaluation of β-Endorphin Secretion in Patients Suffering From Episodic Cluster Headache

In order to obtain data regarding peripheral levels of β-endorphin in head pain syndromes, we evaluated the plasma β-endorphin secretory pattern in 12 adult male patients suffering from cluster headache. Blood samples were drawn every 2 hours for a 24-hour period, and in addition at 30-minute intervals for 120 minutes during cluster attacks. The same sampling was repeated during an asymptomatic period. Cluster headache patients showed no significant β-endorphin circadian rhythm and a delayed acrophase during cluster periods compared with that recorded in the remission period and in normal subjects. Eighteen cluster headache attacks were recorded during the study day, 13 (72%) of which were followed by a significant increase in β-endorphin levels. No correlation was found between β-endorphin maximum net increase and intensity and/or duration of pain. These data suggest the hypothesis of a temporary alteration of β-endorphin circadian secretion, probably related to involvement of neural structures controlling biorhythm pacemakers.     

Neurophysiological Studies in Chronic Paroxysmal Hemicrania and Hemicrania Continua

SYNOPSIS
To explore the possible involvement of the pain control system, pain pressure threshold (PPT), nociceptive flexion reflex (RIll), blink and corneal reflexes have been studied for pain perception assessment in 12 patients with chronic paroxysmal hemicrania (CPH) and 12 patients with hemicrania continua (HC). PPT was found to be reduced in HC and CPH when separately compared to controls. In addition, a significant reduction of subjective pain perception (Tp) which was most marked on the symptomatic side, has been demonstrated after sural nerve stimulation in CPH. The RIll reflex threshold on the symptomatic side was significantly reduced when patients were compared to controls, No major differences between CPH and HC as regards blink reflex latencies were found; nor was any such difference observed when comparing the two headache groups to controls. The corneal reflex thresholds were found significantly reduced bilaterally in CPH, irrespective of whether the treatment was given or not.     

Abnormal 5-HT1D receptor function in cluster headache: a neuroendocrine study with sumatriptan

The purpose of this study was to assess the sensitivity of 5-HT(1D) receptors in patients with episodic cluster headache using sumatriptan as a pharmacological probe. The drug, a selective 5-HT(1B/1D) agonist, stimulates the secretion of growth hormone and inhibits the release of prolactin, adrenocorticotropic hormone (ACTH) and cortisol. These effects may be used to explore the function of serotonergic systems in vivo. We administered subcutaneous sumatriptan and placebo to 20 patients with cluster headache (10 in the active phase and 10 in the remission period) and to 12 controls. The sumatriptan-induced increase of growth hormone concentrations was significantly (P < 0.05) blunted in patients with active cluster headache. Prolactin and ACTH responses to the drug were significantly (P < 0.05) reduced in patients with cluster headache, both in the active and in the remission period. Our results suggest that cerebral serotonergic functions mediated by 5-HT(1D) receptors are altered in patients with episodic cluster headache.     

Pain pressure threshold in cluster headache patients

Pain perception threshold (PFT) in the head was assessed with a pressure algometer in 58 cluster headache (CH) patients (52M, 6F; 41 episodic and 17 chronic). Fourteen patients in cluster period were retested in remission. Thresholds were assessed at 10 symmetrical points on each side of the head and at the deltoid. Compared with controls ( n = 80), CH patients had lower PPT in the head and in the deltoid. PPT was lower on the symptomatic side than on the non-symptomatic side in patients with episodic CH during a cluster period ( p <0.001) and in patients with chronic CH ( p <0.05). This pattern was more evident during a cluster period than during remission ( p <0.05). A reduced PPT did not correlate with illness duration and pain side. The lowest PPT mean values were found at the anterior and intermediate levels of the temporal muscle on the symptomatic side. These results imply a central mechanism underlying the pathogenesis of CH.     

Transdermal Clonidine in the Prophylaxis of Episodic Cluster Headache: An Open Study

Transdermal clonidine has recently been reported to be efficacious in the prophylaxis of cluster headache. A 2-week course of transdermal clonidine (5 mg the first week, 7.5 mg the second week) prceded by a 5-day run-in period, was administered to 16 patients with episodic cluster headache in an active cluster period. In 5 patients, the painful attacks. disappeared after the seventh day of treatment. For the group as a whole, no significant variations in headache frequency. pain intensity, or attack duration were observed between the run-in period and the first and second weeks of treatment (ANOVA). Further studies are necessary to clarify the effectiveness of transdermal clonidine in the prophylaxis of episodic cluster headache.     

Laboratory pain perception and clinical pain in post-menopausal women and age-matched men with osteoarthritis: relationship to pain coping and hormonal status

The present study examined relationships between pain coping, hormone replacement therapy, and laboratory and clinical pain reports in post-menopausal women and age-matched men with osteoarthritis. Assessment of nociceptive flexion reflex threshold was followed by an assessment of electrocutaneous pain threshold and tolerance. Participants rated their arthritis pain using the Arthritis Impact Measurement Scales. To assess pain coping, participants completed measures of emotion-focused coping, problem-focused coping, and pain catastrophizing. Results indicated that women were more likely than men to report using emotion-focused pain strategies, and that emotion-focused coping was associated with more arthritic pain and lower electrocutaneous pain tolerance. Correlations between coping measures and pain reports revealed that catastrophizing was associated with greater arthritis pain and lower pain threshold and tolerance levels. However, catastrophizing was not related to nociceptive flexion reflex threshold, suggesting that the observed relationship between catastrophizing and subjective pain does not rely on elevated nociceptive input. A comparison of men (n=58), post-menopausal women receiving hormone replacement therapy (n=32), and post-menopausal women not receiving hormone replacement therapy (n=42) revealed no significant group differences in arthritis pain, electrocutaneous pain threshold or tolerance, or nociceptive flexion reflex threshold. Thus, older adults with osteoarthritis do not exhibit the pattern of sex differences in response to experimental pain procedures observed in prior studies, possibly due to the development of disease-related changes in pain coping strategies. Accordingly, individual differences in clinical and experimental pain may be better predicted by pain coping than by sex or hormonal differences.     

Ethnic differences in the nociceptive flexion reflex (NFR)

A substantial body of literature suggests that the experience of both clinical and experimental pain differs among ethnic groups, with African Americans generally reporting greater sensitivity to chronic and experimentally induced pain when compared to non-Hispanic whites. However, no studies to date have examined nociceptive processes that may underlie these differences. The nociceptive flexion reflex (NFR) is based on the measurement of stimulus-induced spinal reflexes. Prior research suggests that the NFR threshold, or RIII response, is highly correlated with subjective pain thresholds. The current study evaluated responses to the nociceptive flexion reflex in healthy young adults from two different ethnic groups: African Americans (n=29) and non-Hispanic whites (n=28). Perceptual responses (e.g., pain ratings) as well as physiological reflex responses (i.e., biceps femoris EMG) were assessed. Significant ethnic group differences were observed for NFR reflex threshold, with African Americans producing a reflex at lower stimulation intensities relative to non-Hispanic whites. Interestingly, verbal pain ratings at NFR threshold were not significantly different between the groups, suggesting that the lower stimulation intensities required to elicit a reflex in African-American versus non-Hispanic white participants were nonetheless perceived as similar. Psychological Involvement, Positive and Negative Mood, and Rumination were correlated with NFR threshold in a pattern that was consistent across both ethnic groups. These results extend previous research on ethnic differences in self-report measures of pain by demonstrating group differences in a nociceptive muscle reflex.     

Trait- and Frequency-Dependent Dysfunctional Habituation to Trigeminal Nociceptive Stimulation in Trigeminal Autonomic Cephalalgias

We investigated whether the stimulation frequency (SF), the pain phases, and different diagnoses of trigeminal autonomic cephalalgias (TACs) may influence the habituation to pain. We studied the habituation of the nociceptive blink reflex R2 responses at different SFs (.05, .1, .2, .3, .5, and 1?Hz), in 28 episodic cluster headache (ECH) patients, 16 during and 12 outside the bout; they were compared with 16 episodic paroxysmal hemicrania (EPH) during the bout and 21 healthy subjects. We delivered 26 electrical stimuli and subdivided stimuli 2 to 26 in 5 blocks of 5 responses for each SF. Habituation values for each SF were expressed as the percentages of the mean area value of second through fifth blocks with respect to the first one. A significant lower mean percentage decrease of the R2 area across all blocks was found at .2 to 1?Hz SF during ECH, outside of the ECH, and EPH compared with healthy subjects. We showed a common frequency-dependent deficit of habituation of trigeminal nociceptive responses at higher SFs in ECH and EPH patients, independently from the disease phase. This abnormal temporal pattern of pain processing may suggest a trait-dependent dysfunction of some underlying pain-related subcortical structures, rather than a state-dependent functional abnormality due to the recurrence of the headache attacks during the active period.

Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients

The aim of this study was to evaluate the function of pain modulating systems subserving diffuse noxious inhibitory controls (DNICs) in primary headaches. DNICs were examined in 24 migraineurs, 17 patients with chronic tension-type headache (CTTH) and 20 healthy subjects by means of nociceptive flexion RIII reflex and the cold pressor test (CPT) as heterotopic noxious conditioning stimulation (HNCS). The subjective pain thresholds (Tp) and the RIII reflex threshold (Tr) were significantly lower in CTTH vs. controls. In controls a significant inhibition of the RIII reflex was observed during the CPT (-30%, P < 0.05). Conversely, migraine and CTTH patients showed facilitation (+31%, P < 0.05 and +40%, P < 0.01, respectively) of the RIII reflex during the HNCS. This study demonstrates a dysfunction in systems subserving DNICs in both migraine and CTTH. Impairment of endogenous supraspinal pain modulation systems may contribute to the development and/or maintenance of central sensitization in primary headaches.     

Trigemino-cervical reflex abnormalities in patients with migraine and cluster headache

BACKGROUND: Head pain arises within the trigeminal nociceptive system. Current theories propose that the trigeminal system is intimately involved in the pathogenesis of migraine. Short-latency responses can be recorded in sternocleidomastoid muscles after stimulation of the trigeminal nerve (trigemino-cervical reflex). This brainstem reflex could be a suitable method to evaluate the trigeminal system in migraine and CH. OBJECTIVE: The aim of the present study was to further elucidate the pathophysiology of migraine and cluster headache (CH) with special reference to the involvement of the central trigeminal system in the different forms of primary headache. METHODS: The trigemino-cervical reflex was investigated in 15 healthy subjects, in 15 patients having migraine with aura, in 15 patients with migraine without aura, and in 10 patients with CH. RESULTS: Significant abnormalities were observed in a great number of patients with both types of migraine and CH during the headache attacks, but only in migraine patients during the interictal period. The alterations are bilateral in migraine, unilateral in CH. CONCLUSIONS: Our results further support the relevance of brainstem mechanisms in the pathogenesis of migraine rather than of CH. These data, taken together with that from experimental head pain and functional imaging studies, demonstrate that primary headache syndromes may be distinguished on a functional basis by areas of activation specific to the clinical syndrome.     

Comparative study of perceived pain and nociceptive flexion reflex in man

The purpose of this study was to compare the amplitude of the flexion reflex of the biceps femoris muscle (BF) with the intensity of the painful sensation elicited by a nociceptive stimulation resulting from application of a constant-current either on the sural nerve or on the skin in its distal receptive field. Experiments were carried out on 15 normal volunteers.It was observed that: (1) Stimulation of the sural nerve (either on or through the skin) elicits two different reflex responses in the BF: the first (RII) is of short latency, low threshold and corresponds to a tactile reflex. The second (RIII) is of longer latency and higher threshold, and corresponds to a nociceptive reflex. The threshold of RIII was found to be the threshold of a pain sensation. (2) Stimulation of the skin elicits only a late nociceptive (RIII) response in the BF. The threshold of this response was also found to be that of pain. (3) The thresholds of both pain and RIII were found to be higher for sural nerve stimulation (10 mA) than for cutaneous stimulation (5 mA).It was suggested that the large diameter cutaneous fibers could have an inhibitory effect on both pain and the nociceptive reflex. This was supported by the results obtained during a selective ischemic block of the largest diameter fibers in the sural nerve, when a 10 mA stimulation was applied to the nerve. In this case, a decrease of the RII reflex was observed in BF, together with an increase of both RIII and pain sensation. Functional implications of these results are discussed.