The effect of lacosamide in peripheral neuropathic pain: A randomized, double-blind, placebo-controlled, phenotype-stratified trial.

BACKGROUND: Neuropathic pain is common and difficult to treat. The sodium channel blocker lacosamide is efficacious in animal models of pain, but its effect on neuropathic pain in humans is inconclusive. METHODS: In a multicentre, randomized, double-blinded placebo-controlled phenotype stratified trial, we examined if lacosamide produced better pain relief in patients with the irritable nociceptor phenotype compared to those without. The primary outcome was the change in daily average pain from baseline to last week of 12 weeks of treatment. Secondary and tertiary outcomes included pain relief, patient global impression of change and presence of 30% and 50% pain reduction. RESULTS: The study was prematurely closed with 93 patients included and 63 randomized to lacosamide or placebo in a 2:1 ratio, of which 49 fulfilled the per protocol criteria and was used for the primary objective. We did not find a better effect of lacosamide in patients with the irritable nociceptor phenotype, the 95% CI for the primary objective was 0.41 (-1.2 to 2.0). For all patients randomized, lacosamide had no effect on the primary outcome, but significantly more patients were responders to lacosamide than during placebo, with an NNT of 4.0 (95% CI 2.3-16.1) and 5.0 (95% CI 2.8-24.5) for 30% and 50% pain reduction respectively. We did not identify any predictors for response. Lacosamide was generally well tolerated. CONCLUSION: We could not confirm that lacosamide was more efficacious in patients with the irritable nociceptor type, but the study was prematurely closed, so we cannot exclude a small difference. SIGNIFICANCE: Treatment of neuropathic pain is often a trial and error process. Little is known about which patient benefit from which kind of medication. The sodium channel blocker lacosamide shows variable effect on neuropathic pain. Pain sensory phenotype, as defined by quantitative sensory testing, did not predict response to treatment with lacosamide.

Intake of marine n-3 polyunsaturated fatty acids and risk of hemorrhagic stroke and its subtypes: a Danish follow-up study.

BACKGROUND: A diet rich in marine n-3 polyunsaturated fatty acids (PUFAs) may lower the risk of coronary heart disease and ischemic stroke. However, the association between intake of marine n-3 PUFAs and risk of hemorrhagic stroke has only been sparsely explored. We aimed to investigate the associations between intake of the major marine n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their sum in relation to incident hemorrhagic stroke and its subtypes intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). METHODS: We analyzed data from the Danish Diet, Cancer and Health Cohort, which was established between 1993 and 1997. Information on dietary intake of marine n-3 PUFAs was obtained through a validated food frequency questionnaire. Potential hemorrhagic stroke cases were identified by linkage to the Danish National Patient Register and subsequently validated. Hazard ratios obtained by Cox proportional hazard regression were used as measures of association. RESULTS: A total of 394 subjects among 55,519 individuals developed hemorrhagic stroke during a median follow-up period of 13.5 years. In multivariable analyses including adjustment for established risk factors, we observed weak and statistically non-significant indications of inverse associations between intake of EPA, DHA, and EPA + DHA and the rate of incident hemorrhagic stroke. In analyses of hemorrhagic stroke subtypes, we found indications of lower rates of ICH among participants in the highest quartile of EPA, DHA, and EPA + DHA compared with those in the lowest quartile, and indications of lower rates of SAH in the highest quartile of EPA intake compared to the lowest quartile but the findings were statistically non-significant. CONCLUSIONS: Indications of inverse statistically non-significant associations were found between EPA, DHA, and EPA + DHA and hemorrhagic stroke.

Oral capsules of tetra-hydro-cannabinol (THC), cannabidiol (CBD) and their combination in peripheral neuropathic pain treatment.

BACKGROUND: Cannabinoids are often prescribed for neuropathic pain, but the evidence-based recommendation is 'weak against'. OBJECTIVES: The aim was to examine the effect of two cannabinoids and their combination in peripheral neuropathic pain. METHODS: This was a randomized, double-blind, trial with treatment arms for cannabidiol (CBD), tetra-hydro-cannabinol (THC), CBD and THC combination (CBD/THC), and placebo in a 1:1:1:1 ratio and flexible drug doses (CBD 5-50 mg, THC 2.5-25 mg, and CBD/THC 5 mg/2.5 mg-50 mg/25 mg). Treatment periods of 8-week duration were proceeded by 1 week for baseline observations. Patients with painful polyneuropathy, post-herpetic neuralgia and peripheral nerve injury (traumatic or surgical) failing at least one previous evidence-based pharmacological treatment were eligible for inclusion. The primary outcome was the change in weekly average of daily pain measured with a numeric rating scale (NRS). Trail Making Test (TMT) was used as one of the tests of mental functioning. RESULTS: In all, 145 patients were included in the study of which 118 were randomized and 115 included in the intention-to-treat analysis. None of the treatments reduced pain compared to placebo (p = 0.04-0.60). Effect sizes as estimated in week 8 (positive values worse and negative better than placebo) were CBD mean 1.14 NRS points (95% CI 0.11-2.19), THC 0.38 (CI -0.65 to 1.4) and CBD/THC -0.12 (-1.13 to 0.89). CONCLUSIONS: CBD, THC and their combination did not relieve peripheral neuropathic pain in patients failing at least one previous evidence-based treatment for neuropathic pain.

Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. METHODS: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. RESULTS: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). CONCLUSIONS: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Characterization and predictive mechanisms of experimentally induced tension-type headache.

OBJECTIVE: Studies have shown it is possible to elicit a tension-type headache episode in 15 to 30% of healthy individuals following a tooth-clenching or stress-inducing task. Despite this, no studies have attempted to understand why some healthy individuals develop a headache episode while others do not. METHODS: The present randomized, single-blind, controlled study recruited 60 healthy participants who participated in a 30-minute tooth-clenching task and 10 participants who participated in a control task. Before the tasks, participants had their pericranial tenderness and pain modulation profiles (wind-up ratio and conditioned pain modulation) assessed. Two hours later, pericranial tenderness and pressure pain thresholds were assessed as well as any developing temporomandibular disorders. Pain diaries were kept for 24 hours to register any developing pain or headache. RESULTS: Participants with a decrease in pericranial tenderness after the tooth-clenching task were less likely to develop headache when compared to participants without. Pain modulation profiles could not predict who developed headache and who did not. Finally, no difference was found between groups for developing temporomandibular disorders. No difference in frequency of participants who developed headache was found between the tooth-clenching and the control task. CONCLUSIONS: In conclusion, it was shown that increased pericranial tenderness was not required to trigger an episode of tension-type headache in healthy participants. Furthermore, pain modulation profiles could not predict who developed headache and who did not. Finally, activation of descending inhibitory pathways, as assessed by decreases in pericranial tenderness, was protective against the development of headache. These findings provide new insights into the pathophysiology of experimentally-induced tension-type headache.

Low-level exposure to arsenic in drinking water and incidence rate of stroke: A cohort study in Denmark.

INTRODUCTION: High arsenic concentration in drinking water is associated with a higher incidence rate of stroke, but only few studies have investigated an association with arsenic in drinking water at low concentration (<50 µg/L). OBJECTIVE: To examine if arsenic in drinking water at low concentration was associated with higher incidence rate of stroke in Denmark. METHODS: A total of 57,053 individuals from the Danish Diet, Cancer, and Health cohort was included in the study (enrolment in 1993-1997, age 50-64 years), of which 2195 individuals had incident stroke between enrolment and November 2009. Individuals were enrolled in two major cities (Copenhagen and Aarhus). Residential addresses in the period 1973-2009 were geocoded and arsenic concentration in drinking water at each address was estimated by linking addresses with water supply areas. Associations between arsenic concentration and incidence rate of stroke were analysed using a generalized linear model with a Poisson distribution. Incidence rate ratios (IRR) were adjusted for differences in age, sex, calendar-year, lifestyle factors, and educational level. RESULTS: Median arsenic concentration in drinking water was 0.7 µg/L at enrolment addresses (range: 0.03 to 25 µg/L), with highest concentrations in the Aarhus area. The adjusted IRRs were 1.17 (95% CI: 1.04-1.32) for the highest arsenic quartile (1.93-25.3 µg/L) when compared with the lowest quartile (0.049-0.57 µg/L), but the highest IRR was seen in the second quartile (0.57-0.76 µg/L) (IRR = 1.21; 95% CI: 1.07-1.36). The highest IRR in the upper quartile was seen in the Aarhus area (IRR = 1.79; 95% CI: 1.41-2.26). Having ever been exposed to10 µg/L or more arsenic in drinking water resulted in an IRR at 1.44 (95% CI: 1.00-2.08) for all strokes and 1.63 (95% CI: 1.11-2.39) for ischemic strokes. CONCLUSION: The results indicate that arsenic in drinking water even at low concentration is associated with higher incidence rate of stroke.

Linoleic Acid in Adipose Tissue and Development of Ischemic Stroke: A Danish Case-Cohort Study.

BACKGROUND: We investigated the association between the content of linoleic acid in adipose tissue, a biomarker of long-term intake of linoleic acid, and the risk of ischemic stroke and its subtypes. METHODS AND RESULTS: The Danish cohort study Diet, Cancer and Health included 57 053 patients aged 50 to 65 years at enrollment. All participants had an adipose tissue biopsy performed at enrollment, while information on ischemic stroke during follow-up was obtained from the Danish National Patient Register. Stroke diagnoses were all validated and classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. Cases and a randomly drawn subcohort of 3500 patients had their fatty acid composition in adipose tissue determined by gas chromatography. Hazard ratios with 95% confidence intervals were calculated using weighted Cox proportional hazard regression. During 13.5 years of follow-up, 1879 ischemic stroke cases were identified, for which 1755 adipose biopsies were available, while adipose biopsies were available for 3203 participants in the subcohort. When comparing the highest and the lowest quartiles of adipose tissue content of linoleic acid there was a negative association with the rate of total ischemic stroke (hazard ratio, 0.78; 95% confidence interval, 0.65-0.93) and large artery atherosclerosis (hazard ratio, 0.61; 95% confidence interval, 0.43-0.88), while there was an indication of a negative association with small-vessel occlusion (hazard ratio, 0.87; 95% confidence interval, 0.69-1.11). There was no clear association with the rate of cardioembolism. CONCLUSIONS: The content of linoleic acid in adipose tissue was inversely associated with the risk of total ischemic stroke and stroke caused by large artery atherosclerosis.

Theophylline as an add-on to thrombolytic therapy in acute ischaemic stroke (TEA-Stroke): A randomized, double-blinded, placebo-controlled, two-centre phase II study.

INTRODUCTION: Early reperfusion of brain tissue at risk of injury (penumbra salvage) is crucial in treating acute ischaemic stroke. Neuroprotective agents may extend the time window for the reperfusion. The vasoactive agent theophylline redistributes the perfusion to ischaemic brain tissue and thus reduces brain damage, brain tissue oedema and mortality in animal stroke models. Furthermore, treatment with theophylline has been shown to result in considerable and rapid clinical improvement, albeit only temporary, in some stroke patients.We hypothesize that treatment with theophylline will improve the collateral supply in acute ischaemic brain tissue and thus facilitate reperfusion despite proximal vessel occlusion. The primary study objective is to evaluate whether theophylline is safe and efficient in acute ischaemic stroke patients as an add-on to thrombolytic therapy. METHODS: The TEA-Stroke Trial is a two-centre, proof of concept phase II clinical study with a randomized, double-blinded, placebo-controlled design. One hundred and twenty patients with acute ischaemic stroke and significant perfusion-diffusion mismatch, as determined by magnetic resonance imaging, are randomized 1:1 to either theophylline or placebo as an add-on to standard thrombolytic therapy. STUDY OUTCOME: The dual primary outcome measures include penumbra salvage (penumbral tissue not developing into infarcted tissue) and clinical improvement at the 24-h follow-up. DISCUSSION: Results from studies of theophylline in stroke animal models, clinical case series and randomized clinical trials are controversial. A Cochrane analysis from 2004 concluded that there was not enough evidence to assess whether theophylline is safe and improves outcomes in patients with acute ischaemic stroke. The TEA-Stroke Trial will clarify whether theophylline as an add-on to standard thrombolytic therapy improves penumbra salvage with a reduced risk of reperfusion damage, reduced final infarct size, and improved clinical outcome.

Blockade of glutamate release by botulinum neurotoxin type A in humans: a dermal microdialysis study.

BACKGROUND: The analgesic action of botulinum neurotoxin type A (BoNTA) has been linked to the blockade of peripheral release of neuropeptides and neurotransmitters in animal models; however, there is no direct evidence of this in humans. OBJECTIVES: To investigate the effect of BoNTA on glutamate release in humans, using an experimental model of pain and sensitization provoked by capsaicin plus mild heat. METHODS: Twelve healthy volunteers (six men, six women) were pretreated with BoNTA (10 U) on the volar forearm and with a saline control on the contralateral side. Dermal microdialysis was applied one week later to collect interstitial samples before and after the application of a capsaicin patch (8%) plus mild heat (40°C/60 min) to provoke glutamate release, pain and vasodilation. Samples were collected every hour for 3 h using linear microdialysis probes (10 mm, 100 kD). Dialysate was analyzed for glutamate concentration. Pain intensity and skin vasomotor reactions (temperature and blood flow changes) were also recorded. RESULTS: BoNTA significantly reduced glutamate release compared with saline (P<0.05). The provoked pain intensity was lower in the BoNTA-pretreated arm (P<0.01). The reduction in pain scores was not correlated with glutamate level. Cutaneous blood flow (P<0.05), but not cutaneous temperature (P≥0.05), was significantly reduced by BoNTA. There was a correlation between glutamate level and skin blood flow (r=0.58/P<0.05) but not skin temperature (P≥0.05). No differences according to sex were observed in any response. CONCLUSIONS: The present study provided the first direct evidence supporting the inhibitory effect of BoNTA on glutamate release in human skin, which is potentially responsible for some of the analgesic action of BoNTA.

MRI of the central nervous system in MS patients with and without pain.

BACKGROUND: Central pain (CP) is a common symptom in MS. Multiple theories are present about the mechanism of CP. Previous studies suggested that lesion of the spinothalamic tract is a necessary condition for development of CP. No previous study has in detail evaluated the association between the specific site of demyelinations and the presence of CP in MS. OBJECTIVE: The study aimed to evaluate the location of plaques in MS patients with CP including a group of MS patients without pain as a reference group. METHODS: All patients underwent a bedside sensory examination and MRI of the brain and spinal cord. MR imaging was acquired on an 1.5 Tesla MR equipment. A trained neuroradiologist, blinded to pain status, evaluated the MRI. RESULTS: Thirteen MS patients with CP and 10 MS patients without pain were included. Allodynia and/or dysesthesia were more frequent in pain patients (11/13 vs. 1/10, P<0.01). No difference was found in the number of patients with plaques in spinothalamic tract, dorsal column-medial lemniscus, dorsolateral funiculus, grey substance, thalamus or capsula interna. A non-significantly lower number of pain patients had lesions in thalamo-cortical pathways (8/13 vs. 10/10, P=0.027). CONCLUSIONS: No association between CP and site of demyelinations was found, although a trend toward a higher prevalence of intact thalamo-cortical pathways was seen in pain patients. CP was associated with allodynia, suggesting central hyperexcitability.

[Definition, classification and epidemiology of whiplash]. / Definition, klassifikation og epidemiologi ved whiplash.

A whiplash trauma is caused by an acceleration-deceleration force transferring its energy to the cervical spine. Whiplash-associated disorder (WAD) refers to the symptoms that develop after a whiplash injury. The prognosis is favorable with recovery in over 90% of the injured subjects. In a fraction of patients, long-term symptoms with pain and cognitive and emotional symptoms may occur, causing long-term disability. The pathophysiology is unclear. Most research groups favor a multifactorial pathophysiology similar to that observed for other chronic pain conditions without a clear nociceptive or neuropathic component.

[Treatment of whiplash-associated disorders]. / Behandling af gener efter whiplash.

Treatment of whiplash-associated disorders starts with a thorough clinical examination, which may be repeated after 1-3 weeks. For optimal results it is essential that the patient receives clear information about the condition and that any pain is treated effectively with analgesics. Risk factors for persistent symptoms can often be identified early and should be addressed adequately. If symptoms persist and conservative treatments are chosen, these should be active and they should focus on sustaining or regaining usual activities.

Experimental forearm immobilization in humans reduces capsaicin-induced pain and flare.

In a recent study we found that 4 weeks of human experimental forearm immobilization induced hypersensitivity to mechanical and cold stimuli and a higher skin temperature on the immobilized hand. Identical findings are reported in immobilization studies in rats where increased substance P signaling is suggested to play a central role. Capsaicin releases substance P from axon collaterals in the periphery initiating vasodilatation and plasma extravasation. The effect of immobilization on capsaicin-induced responses is, however, not known. Therefore, the present study examined the effect of experimental forearm immobilization on capsaicin-induced pain and flare responses in healthy subjects. Twenty-seven human volunteers were exposed to 4 weeks of scaphoid cast immobilization of the left forearm. Before and after immobilization, skin temperature and blood flow were measured at the thumbs of both hands during 5 min of rest. Subjects then received topical capsaicin (5%) randomly on the dorsum of the right and left hands. Time to sensory detection of capsaicin and pain onset was significantly increased on the immobilized left hand. Immobilization significantly reduced capsaicin-evoked pain, neurogenic flare area, and skin blood flow (perfusion units), and the reduced capsaicin-evoked pain was significantly correlated to an increase in peripheral skin temperature but not to skin blood flow. The correlation between reduced capsaicin-evoked pain and increased skin temperature suggests an increased substance P release while the delayed onset and diminished magnitude of capsaicin-induced pain may be due to reduced penetration of capsaicin into the epidermis.

Education of patients after whiplash injury: is oral advice any better than a pamphlet?

STUDY DESIGN: Randomized parallel-group trial with 1-year follow-up. OBJECTIVE: To evaluate whether education of patients communicated orally by a specially trained nurse is superior to giving patients a pamphlet after a whiplash injury. SUMMARY OF BACKGROUND DATA: Long-lasting pain and physical disability after whiplash injuries are related to both serious personal suffering and huge socio-economic costs. Pure educational interventions after such injuries seem generally as effective as more costly interventions, but it is unknown if the way advice is communicated is of any importance. METHODS: Participants with relatively mild complaints after car collisions were recruited from emergency departments and GPs. A total of 182 participants were randomized to either: (1) a 1 hour-educational session with a specially trained nurse, or (2) an educational pamphlet. Outcome parameters were neck pain, headache, disability, and return to work. Recovery was defined as scoring pain 0 or 1 (0-10 point scale) and not being off sick at the time of the follow-ups. RESULTS: After 3, 6, and 12 months 60%, 58%, and 66%, respectively of the participants had recovered. Group differences were nonsignificant on all outcome parameters, even though the outcome tended to be better for the group receiving personal advice. CONCLUSION: Prognosis did not differ between patients who received personal education and those who got a pamphlet. However, a systematic tendency toward better outcome with personal communicated information was observed and the question how patients should be educated to reduce the risk of chronicity after whiplash is worth further investigation, since no treatment have been proven to prevent long-lasting symptoms, and all forms of advice or educational therapy are so cheap that even a modest effect justifies its use.

Neck collar, "act-as-usual" or active mobilization for whiplash injury? A randomized parallel-group trial.

STUDY DESIGN: Randomized, parallel-group trial. OBJECTIVE: To compare the effect of 3 early intervention strategies following whiplash injury. SUMMARY OF BACKGROUND DATA: Long-lasting pain and disability, known as chronic whiplash-associated disorder (WAD), may develop after a forced flexion-extension trauma to the cervical spine. It is unclear whether this, in some cases disabling, condition can be prevented by early intervention. Active interventions have been recommended but have not been compared with information only. METHODS: Participants were recruited from emergency units and general practitioners within 10 days after a whiplash injury and randomized to: 1) immobilization of the cervical spine in a rigid collar followed by active mobilization, 2) advice to "act-as-usual," or 3) an active mobilization program (Mechanical Diagnosis and Therapy). Follow-up was carried out after 3, 6, and 12 months postinjury. Treatment effect was measured in terms of headache and neck pain intensity (0-10), disability, and work capability. RESULTS: A total of 458 participants were included. At the 1-year follow-up, 48% of participants reported considerable neck pain, 53% disability, and 14% were still sick listed at 1 year follow-up. No significant differences were observed between the 3 interventions group. CONCLUSION: Immobilization, "act-as-usual," and mobilization had similar effects regarding prevention of pain, disability, and work capability 1 year after a whiplash injury.

[Pain and depression]. / Smerter og depression.

Pain and depression are often associated. The frequency of pain complaints in depressed patients is 13-100%. In general, depressed patients have a higher pain threshold than do controls, but lower and unchanged thresholds have also been observed. The frequency of depression in chronic pain patients is 1.5-100%. Pain etiology, short education, marital status, gender, psychiatric family history and unemployment are risk factors for depression. Possible mechanisms underlying the pathophysiology of depression and pain could be involvement of the monoamines (5-HT and NA) and the HPA axis.

Reduced cold pressor pain tolerance in non-recovered whiplash patients: a 1-year prospective study.

UNLABELLED: Whiplash injury and chronic whiplash syndrome represent major health problems in certain western communities, pain being the main symptom. Sensitization of the nociceptive system may play a role for non-recovery after whiplash injury. AIMS: This study examined if tolerance to endure pain stimuli may predict outcome in whiplash injury. In a prospective fashion, 141 acute whiplash patients exposed to rear-end car collision (WAD grade 1-3) and 40 ankle-injured controls were followed and exposed to a cold pressor test, respectively, 1 week, 1, 3, 6 and 12 months after the injury. VAS score of pain and discomfort was obtained before, during and after immersion of the dominant hand into cold water for 2 min. The McGill Pain Questionnaire showed that ankle-injured controls had higher initial pain scores than the corresponding whiplash group, while whiplash-injured subjects had higher scores at 6 months; pain scores being similar at other time points. No difference was found in cold pressor pain between recovered whiplash patients and ankle-injured subjects. Non-recovery was only encountered in whiplash injury. Eleven non-recovered whiplash patients (defined as: handicap after 1 year) showed reduced time to peak pain from 1 week to 3 months (P<0.001), 6 months (P<0.01), but not 12 months after the injury. A larger pain area was seen in non-recovered vs. recovered whiplash-injured subjects during the entire observation period (P<0.001). Non-recovery after whiplash was associated with initially reduced cold pressor pain endurance and increased peak pain, suggesting that dysfunction of central pain modulating control systems plays a role in chronic pain after acute whiplash injury.

Sensory function and quality of life in patients with multiple sclerosis and pain.

Central neuropathic pain is well known in multiple sclerosis (MS), but the underlying mechanisms are unclear. In the present study we studied sensory function in MS patients with pain, MS patients without pain and healthy subjects in order to clarify the role of sensory abnormalities in pain. Fifty MS patients with pain were randomly recruited from a previous epidemiological MS study in Aarhus County, Denmark. Age and gender stratified MS patients without pain (N=50) and healthy subjects (N=50) served as controls. Patients with pain underwent a structured pain interview. Sensory function was examined by bedside and quantitative sensory testing. Quality of life was assessed using the health-related quality of life questionnaire, SF-36. Patients with pain had lower pressure pain threshold than pain-free patients (260 kPa vs. 322 (median), P=0.02) otherwise quantitative sensory testing was similar. Pain patients more frequently had cold allodynia (9/50 vs. 0/50, P=0.003) and abnormal temporal summation (10/48 vs. 3/49, P=0.03). Fifty-eight percent had central pain. Central pain patients did not differ from musculoskeletal pain patients in quantitative sensory testing, but allodynia was more common in MS patients with central pain. Pain patients scored lower in all dimensions of SF-36 compared with pain-free patients and healthy subjects. The results suggest that pain in MS is central in more than half of the patients and is associated with mechanical or thermal hyperalgesia.

Symptoms and signs in patients with suspected neuropathic pain.

The study sought to determine if symptoms and signs cluster differentially in groups of patients with increasing evidence of neuropathic pain (NP). We prospectively looked at symptoms and signs in 214 patients with suspected chronic NP of moderate to severe intensity. According to a set of clinical criteria the patients were a priori classified as having the so-called 'Definite NP' (n = 91), 'Possible NP' (n = 71), or 'Unlikely NP' (n = 52). A recording of symptoms including pain descriptors, intensity of five categories of pain, Short Form McGill Pain Questionnaire, and Major Depression Inventory were done. Sensory tests including repetitive pinprick stimulation, examination for cold-evoked pain by an acetone drop and brush-evoked pain were carried out in the maximal pain area and in a control area. High intensity of superficial ongoing pain, and touch or cold provoked pain was associated with chronic pain classified as definite or possible neuropathic. Intensity of deep ongoing pain, and 'paroxysms' was similar in the three groups. Brush-evoked pain was more frequent in definite NP. The McGill Pain Questionnaire and the used pain descriptors could not distinguish between the three clinical categories. Although certain symptoms (touch or cold provoked pain) and signs (brush-evoked allodynia) are more prominent in patients with definite or possible NP, we found considerable overlap with the clinical presentation of patients with unlikely NP.

Differential effects of peripheral ketamine and lidocaine on skin flux and hyperalgesia induced by intradermal capsaicin in humans.

The capsaicin-induced flux in the primary and secondary hyperalgesic area after pretreating the capsaicin injection site with local ketamine, lidocaine or saline 10 min prior to injection was examined in this study. Twelve healthy volunteers participated in two randomized, double-blinded, placebo-controlled, cross-over experiments. In the first experiment, the skin on the volar forearm was pretreated with s.c. ketamine or saline, 10 min prior to capsaicin injection. Flux was recorded before and continuously after the injection of capsaicin in the primary and secondary hyperalgesic area. Spontaneous pain, evoked pain and areas of hyperalgesia were measured. In the second experiment, a similar capsaicin test was carried out 10 min after pretreating the skin with s.c. lidocaine or saline. Ketamine reduced flux significantly both in the primary and secondary hyperalgesic area. Lidocaine reduced flux significantly in the primary hyperalgesic area. No effect was observed on flux in the secondary hyperalgesic area. Only lidocaine reduced spontaneous pain, evoked pain and areas of hyperalgesia, whereas ketamine had no effect. Our results suggest that there is no simple and close relation between vascular and sensory reactions to pharmacological manipulation following intradermal capsaicin injection. We propose distinct mechanisms for local lidocaine and ketamine based on the differential effects of local lidocaine and ketamine on flux and pain.