Nociception-specific blink reflex: pharmacology in healthy volunteers.

BACKGROUND: The physiology and pharmacology of activation or perception of activation of pain-coding trigeminovascular afferents in humans is fundamental to understanding the biology of headache and developing new treatments. METHODS: The blink reflex was elicited using a concentric electrode and recorded in four separate sessions, at baseline and two minutes after administration of ramped doses of diazepam (final dose 0.07 mg/kg), fentanyl (final dose 1.11 µg/kg), ketamine (final dose 0.084 mg/kg) and 0.9 % saline solution. The AUC (area under the curve, µV*ms) and the latency (ms) of the ipsi- and contralateral R2 component of the blink reflex were calculated by PC-based offline analysis. Immediately after each block of blink reflex recordings certain psychometric parameters were assessed. RESULTS: There was an effect due to DRUG on the ipsilateral (F 3,60 = 7.3, P < 0.001) AUC as well as on the contralateral (F 3,60 = 6.02, P < 0.001) AUC across the study. A significant decrement in comparison to placebo was observed only for diazepam, affecting the ipsilateral AUC. The scores of alertness, calmness, contentedness, reaction time and precision were not affected by the DRUG across the sessions. CONCLUSION: Previous studies suggest central, rather than peripheral changes in nociceptive trigeminal transmission in migraine. This study demonstrates a robust effect of benzodiazepine receptor modulation of the nociception specific blink reflex (nBR) without any µ-opiate or glutamate NMDA receptor component. The nociception specific blink reflex offers a reproducible, quantifiable method of assessment of trigeminal nociceptive system in humans that can be used to dissect pharmacology relevant to primary headache disorders.

Lateralized central facilitation of trigeminal nociception in cluster headache.

OBJECTIVE: To investigate whether central facilitation of trigeminal pain processing is part of the pathophysiology of cluster headache (CH). METHODS: Sixty-six patients with CH (18 episodic CH inside bout, 28 episodic CH outside bout, 20 chronic CH) according to the International Classification of Headache Disorders-II classification, as well as 30 healthy controls, were investigated in a case-control study using simultaneous recordings of the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP) following nociceptive electrical stimulation on both sides of the forehead (V1). RESULTS: nBR latency ratio (headache side/nonheadache side) was decreased in all CH patients independent from CH subtype compared with healthy controls indicating central facilitation at brainstem level. Area under the curve ratio was increased in patients with episodic CH inside bout only. PREP showed decreased N2 latency ratio in patients with chronic CH indicating central facilitation at supraspinal (thalamic or cortical) level. CONCLUSIONS: Asymmetric facilitation of trigeminal nociceptive processing predominantly on brainstem level was detected in patients with CH. This alteration is most pronounced in the acute pain phase of the disease, but appears to persist in remission periods. Only chronic CH patients show additional changes of PREP prompting to supraspinal changes of pain processing related to the chronic state of disease in regard to neuronal plasticity, which exceeds changes observed in episodic CH.

Effects of sub-perception threshold spinal cord stimulation in neuropathic pain: a randomized controlled double-blind crossover study.

BACKGROUND: Recent studies suggest that perception of the paraesthesia elicited by spinal cord stimulation (SCS) is not necessarily required for the pain relieving effect. OBJECTIVE: The purpose of the study was to determine the effect of sub-perception threshold SCS in patients with neuropathic pain. METHODS: Ten patients with implanted SCS systems underwent continuous sub-threshold stimulation and no stimulation in a blinded randomized crossover design. Pain scores under these treatment modalities were compared with usual supra-threshold stimulation. RESULTS: Sub-threshold stimulation elicited significantly lower pain relief than supra-perception threshold SCS. Mean pain scores were 3.6 [max 6.3, min 1.9, standard deviation (SD) 1.3] under supra-threshold stimulation, 5.6 (max 9.0, min 2.4, SD 1.9) under sub-threshold stimulation and 6.4 (max 10.0, min 4.0, SD 2.0) without stimulation. CONCLUSION: Sub-threshold stimulation under otherwise conventional stimulation parameters has a measurable but not clinically sufficient effect. Thus, the pain relieving effect elicited by SCS is not necessarily linked to the perceptibility of stimulation but may instead be attributed to the intensity of the electric field.

Intravenous aspirin (lysine acetylsalicylate) in the inpatient management of headache.

BACKGROUND: IV lysine acetylsalicylate (aspirin) has been shown to be effective in the treatment of acute migraine attacks, but little is known about its effectiveness and safety in patients hospitalized for management of severe headache, typically arising from abrupt withdrawal of other acute attack medications. METHODS: We present an audit of our use of IV aspirin in 168 patients in a tertiary referral setting. RESULTS: The findings demonstrate subjective approval of this medication by the patients and objective improvements in pain scores, a decrease of ≥3 points on a 10-point visual analog pain scale being seen on >25% occasions on which the medication was administered. Further, side effect rates were low (5.9%), with no serious adverse events. CONCLUSION: IV aspirin is safe, effective, and useful in the inpatient management of headache.

Electrically evoked nociceptive potentials for early detection of diabetic small-fiber neuropathy.

BACKGROUND AND PURPOSE: This study investigated the utility of pain-related evoked potentials (PREP's) elicited by a nociceptive electrical stimulation of the skin (= electrically evoked nociceptive potentials) in early detection of diabetic small-fiber neuropathy. METHODS: We studied 36 'young' (19-35 years) and 24 'older' (36-65 years) healthy subjects as well as 35 patients (35-64 years) with diabetes and neuropathic symptoms and 22 patients (34-64 years) with diabetes without neuropathic symptoms. Only patients with normal standard nerve conduction testing were included. RESULTS: In patients with neuropathic symptoms, we found a significant increase in PREP latencies and decrease of amplitudes elicited from both, upper and lower limbs. In non-symptomatic diabetic patients, we observed PREP abnormalities from lower limbs only. CONCLUSIONS: These data suggest that the method of pain-related evoked potentials elicited by a nociceptive electrical stimulation of the skin may contribute to the early detection of diabetic sensory neuropathy.

Effects of topiramate on migraine frequency and cortical excitability in patients with frequent migraine.

We studied the excitability of the visual and motor cortex in 36 patients with frequent migraine without aura (30 women, mean age 38.6 +/- 10.0 years) before and after treatment with topiramate (100 mg/day) using transcranial magnetic stimulation. Treatment with topiramate resulted in reduction of both headache frequency (12.0 +/- 1.3 to 5.8 +/- 3.2 migraine days per month; P = 0.004) and cortical excitability: motor cortex thresholds increased on the right side from 43.8 +/- 7.5% to 47.7 +/- 9.2% (P = 0.049) and on the left side from 43.4 +/- 7.0% to 47.2 +/- 9.6% (P = 0.047), and phosphene thresholds increased from 58.9 +/- 11.1% to 71.2 +/- 11.2% (P = 0.0001). Reduction of headache frequency correlated inversely with an increase of visual thresholds and did not correlate with motor thresholds. The effect of topiramate in migraine prevention is complex and can not be explained simply by inhibition of cortical excitability.

Evaluation and proposal for optimalization of neurophysiological tests in migraine: part 1--electrophysiological tests.

Neurophysiological testing has become a valuable tool for investigating brain excitability and nociceptive systems in headache disorders. Previous reviews have suggested that most neurophysiological tests have limited value for headache diagnosis, but a vast potential for exploring the pathophysiology of headaches, the central effects of certain pharmacological treatments and phenotype-genotype correlations. Many protocols, however, lack standardization. This meta-analytical review of neurophysiological methods in migraine was initiated by a task force within the EUROHEAD project (EU Strep LSHM-CT-2004-5044837-Workpackage 9). Most of the neurophysiological approaches that have been used in headache patients are reviewed, i.e. evoked potentials, nociception-specific blink reflex, single-fibre electromyography, neuroimaging methods (functional MRI, PET, and voxel-based morphometry) and the nitroglycerin attack-provoking test. For each of them, we summarize the results, analyse the methodological limitations and propose recommendations for improved methodology and standardization of research protocols. The first part is devoted to electrophysiological methods, the second to neuroimaging techniques and the NTG test.

Evaluation and proposal for optimization of neurophysiological tests in migraine: part 2--neuroimaging and the nitroglycerin test.

Neuroimaging methods have been widely used in headache and migraine research. They have provided invaluable information on brain perfusion, metabolism and structure during and outside of migraine attacks, contributing to an improved understanding of the pathophysiology of the disorder. Human models of migraine attacks are indispensable tools in pathophysiological and therapeutic research. This review of neuroimaging methods and the attack-provoking nitroglycerin test is part an initiative by a task force within the EUROHEAD project (EU Strep LSHM-CT-2004-5044837-Workpackage 9) with the objective of critically evaluating neurophysiological tests used in migraine. The first part, presented in a companion paper, is devoted to electrophysiological methods, this second part to neuroimaging methods such as functional magnetic resonance imaging, positron emission tomography and voxel-based morphometry, as well as the nitroglycerin test. For each of these methods, we summarize the results, analyse the methodological limitations and propose recommendations for improved methodology and standardization of research protocols.

Occipital nerve blockade in chronic cluster headache patients and functional connectivity between trigeminal and occipital nerves.

Headache syndromes often involve occipital and neck symptoms, suggesting a functional connectivity between nociceptive trigeminal and cervical afferents. Although reports regarding effective occipital nerve blockades in cluster headache exist, the reason for the improvement of the clinical symptoms is not known. Using occipital nerve blockade and nociceptive blink reflexes, we were able to demonstrate functional connectivity between trigeminal and occipital nerves in healthy volunteers. The R2 components of the nociceptive blink reflex and the clinical outcome in 15 chronic cluster headache patients were examined before and after unilateral nerve blockade of the greater occipital nerve with 5 ml prilocain (1%) on the headache side. In contrast to recent placebo-controlled studies, only nine of the 15 cluster patients reported some minor improvement in their headache. Six patients did not report any clinical change. Exclusively on the injection side, the R2 response areas decreased and R2 latencies increased significantly after the nerve blockade. These neurophysiological and clinical data provide further evidence for functional connectivity between cervical and trigeminal nerves in humans. The trigeminocervical complex does not seem to be primarily facilitated in cluster headache, suggesting a more centrally located pathology of the disease. However, the significant changes of trigeminal function as a consequence of inhibition of the greater occipital nerve were not mirrored by a significant clinical effect, suggesting that the clinical improvement of occipital nerve blockades is not due to a direct inhibitory effect on trigeminal transmission.

Impaired trigeminal nociceptive processing in patients with trigeminal neuralgia.

BACKGROUND: Trigeminal neuralgia (TN) usually leads to paroxysms of short lasting but very severe pain. Between the attacks the patient is usually asymptomatic, but a constant dull background pain may persist in some cases. The mechanisms associated with the development of this chronic pain are not well understood. OBJECTIVE: To determine trigeminal nociceptive fiber impairment in patients with TN comparing symptomatic and nonsymptomatic sides using the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP) and to identify possible central mechanisms of pain chronicity. METHODS: We investigated 24 patients with TN without and 18 patients with TN with concomitant chronic facial pain. PREP and nBR were investigated following nociception specific electrical stimulation on both sides of the face and in each division of the trigeminal nerve (V1, V2, and V3). RESULTS: We found prolonged PREP and nBR latencies and reduced amplitudes comparing symptomatic and nonsymptomatic sides in all patients with TN. In patients with chronic facial pain, however, PREP amplitudes were larger and latencies shorter compared to patients with TN without facial pain, while nBR results were similar across groups. CONCLUSION: The data suggest an impairment of the trigeminal nociceptive system due to demyelination and/or axonal dysfunction on the symptomatic side and locate this defect close to the root entry zone in the brainstem. Moreover, central facilitation of trigeminal nociceptive processing was observed in patients with trigeminal neuralgia with concomitant chronic facial pain indicating overactivation of central sensory transmission. This may represent a possible adaptive mechanism for the development of chronic pain.

Sumatriptan and corneal reflexes in headache-free migraine patients: a randomized and placebo-controlled crossover study.

A temporary sensitization of central trigeminal neurones in migraine patients during acute attacks has been described in previous studies using the electrically evoked nociceptive blink reflex. The cornea is innervated by small myelinated A-delta and unmyelinated C-fibres only. Stimulation with air puffs activates peripheral nociceptors and allows the investigation of peripheral trigeminal nerve structures. Our objective was to investigate whether corneal reflex examinations with air puff stimulation detect abnormalities in migraineurs during their pain-free interval and if the corneal reflex may be modulated by the administration of an oral triptan. After validation of the nociceptive air puff technique by investigating the corneal reflexes before and after a local anaesthesia of the cornea, we recorded corneal reflexes in 25 migraineurs during their pain-free period and 25 healthy controls before and after the oral administration of 100 mg sumatriptan in a randomized, placebo-controlled, crossover study. Baseline response areas under the curve (AUCs) and latencies of the R2 components of the corneal reflexes did not show any significant differences between patients and controls. Patients did not show any significant differences regarding their headache and non-headache side. The use of an oral triptan had no significant influence on latencies or AUCs in both patients and controls. Our data suggest that there is no facilitation of the trigeminal system in the headache-free interval among patients with migraine. The stable corneal reflexes after the oral administration of 100 mg sumatriptan suggest that there was no inhibition of the trigeminal system, both in patients during their headache-free period and in healthy controls.

Increased urinary excretion of nitric oxide metabolites in longitudinally monitored migraine patients.

This study evaluated a relationship between nitric oxide (NO) and migraine attacks in order to gain insight into migraine pathomechanism. The study groups consisted of 12 migraineurs and eight controls. All subjects collected morning urine samples for 40 consecutive days. Urinary NO metabolites, nitrite/nitrate (NO(x)) levels were measured with the vanadium-based assay, whilst creatinine (Cr) and neopterin were determined with high-performance liquid chromatography. The mean urinary NO(x)/Cr ratio and number of NO(x) peaks was significantly greater in the migraine group compared with controls (P = 0.01 and P = 0.007, respectively). In the second approach, high NO(x) values were re-assessed in relation to raised neopterin, a marker of systemic infection or inflammation, and were excluded. The excretion of NO(x) persisted being pulsatile, and migraineurs had more peaks compared with controls (P = 0.01). In seven patients, NO(x) peaks coincided with headache days. This was more frequent than expected by random association in four patients (Monte-Carlo simulation; odds ratios: 2.16-7.77; no overlap of 95% CI). In four patients, NO(x) peaks preceded or followed headache days. Although there is a difference in the pattern of urinary NO(x) excretion between control and migraine populations, the variable temporal association of NO(x) peaks and headaches suggests a complex role of NO in this condition.

Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures.

Trigeminal and somatic nociceptive systems were studied in controls (n=15), episodic migraine (n=16), analgesics (n=14) and triptan-induced medication overuse headache (MOH) (n=15) before and after withdrawal. Patients with MOH and comorbid depressive symptoms and depression without headache were studied to investigate the influence of depression. Trigeminal nociception was studied by simultaneous registration of pain-related cortical potentials (PREP) and nociceptive blink reflex (nBR) following nociceptive-specific electrical stimulation of the forehead. Somatic nociception was evaluated using PREP of upper limbs. We found facilitation of both trigeminal and somatic PREP but not of nBR in MOH, which normalized after withdrawal. No differences were found comparing analgesics vs. triptan MOH. No differences were observed between controls and patients with episodic migraine and depression without headache. A transient facilitation was found of trigeminal and somatic nociceptive systems in MOH, which was more pronounced on a supraspinal level.

Functional connectivity between trigeminal and occipital nerves revealed by occipital nerve blockade and nociceptive blink reflexes.

Headache syndromes often suggest occipital and neck involvement, although it is still unknown to what extent branches of segment C1-C3 contribute actively to primary headache. Pain within the occipital area may be referred to the trigeminal territory. However, a modulation of trigeminal transmission by affecting cervical input in humans has not been elucidated so far. A convergence of cervical and trigeminal input at the level of the caudal part of the trigeminal nucleus in the brainstem has been suggested due to anatomical and neurophysiological studies in animals. We examined the R2 components of the nociceptive blink reflex responses in 15 healthy subjects before and after unilateral nerve blockade of the greater occipital nerve with 5 ml prilocain (1%). R2 response areas (AUC) decreased and the R2 latencies increased significantly after the nerve blockade only on the side of injection. AUC and latencies on the non-injection side remained stable. Thresholds for sensory or pain perception did not differ significantly between the repeated measurements on both sides. Our findings extend previous results related to anatomical and functional convergence of trigeminal and cervical afferent pathways in animals and suggest that the modulation of this pathway is of potential benefit in primary headache disorders.

Occipital activation in glyceryl trinitrate induced migraine with visual aura.

A case of migraine is presented with visual aura triggered on two separate occasions by glyceryl trinitrate (GTN). Positron emission tomography was carried out during the second triggering session. Activation in the primary visual area of the occipital cortex was demonstrated during the aura. This is the first published case of migraine aura triggered reproducibly by GTN.

A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate.

Migraine is a common disabling condition likely to be associated with dysfunction of brain pathways involved in pain and other sensory modalities. A cardinal, indeed signature, feature of the disorder that led to its name is that the pain may be lateralized. H(2)15O-labelled PET was used to study 24 migraineurs and eight healthy controls. The migraineurs were divided into three groups according to the site of their headache: right, left or bilateral. In each group, a migraine was induced using a glyceryl trinitrate (GTN) infusion. The subjects were scanned at predefined points: pre-infusion, during GTN, during migraine and post-migraine. SPM99 software was used to analyse the data. Significant brainstem activation was seen in the dorsal lateral pons (P < 0.05 after small volume correction) during the migraine state versus the pain-free state when comparing migraineurs with controls. When each group was analysed separately, to investigate laterality, it was found that the dorsal pontine activation was ipsilateral in the right-sided and left-sided groups and bilateral in the bilateral headache group with a left-sided preponderance. Consistent with previous work, the activation persisted after pain was controlled by sumatriptan. These results suggest that lateralization of pain in migraine is due to lateralized brain dysfunction.

Glyceryl trinitrate triggers premonitory symptoms in migraineurs.

Studying attacks of migraine is considerably hampered by its fundamentally episodic nature. Developing approaches to triggering migraine reliably is important for advancing understanding of the disorder by facilitating its study. Based on the work of the Copenhagen Group we administered an intravenous infusion of 0.5 microg/kg/min glyceryl trinitrate (GTN) to 44 migraineurs, 23 migraine without aura, 21 migraine with aura, and to 12 healthy controls. We sought to characterise the GTN-induced migraine in terms of the clinical features of the attacks and reproducibility of triggering, and included a non-migraine control group for the purpose of comparing any effects to exclude an ordering effect. Of the 44 patients administered GTN, 33 had a migraine attack fulfilling International Headache Society criteria. Thirty-two attacks were of migraine without aura and one of migraine with aura. Twelve patients described typical premonitory symptoms, which have not been previously documented with GTN-induced migraine. A repeat attack was triggered in all subjects but one. In one case a visual aura was also triggered both times. Our study shows that GTN-induced triggering is common in our patients, and remarkably reproducible. The data will facilitate the use of the GTN model in studies requiring extensive planning, such as brain imaging, or where preventive questions are at issue. We also report the first patient with a reproducible GTN-triggered migraine with aura.