Claus Madsen

Venlafaxine versus imipramine in painful polyneuropathy A randomized, controlled trial

Background: Tricyclic antidepressants (TCA) are often used in the treatment of painful polyneuropathy. Venlafaxine is a serotonin and weak noradrenaline reuptake inhibitor antidepressant with a different profile of other pharmacologic actions from those of TCA. Objective: To test if venlafaxine would relieve painful polyneuropathy and compare its possible efficacy with that of the TCA imipramine. Methods: The study design was randomized, double blind, and placebo controlled, with a three-way crossover. Forty patients were assigned to one of the treatment sequences, and 29 completed all three study periods. The daily doses were venlafaxine 225 mg and imipramine 150 mg. During the three treatment periods, each of 4 weeks’ duration, patients rated pain paroxysms, constant pain, and touch- and pressure-evoked pain by use of 0- to 10-point numeric rating scales. Results: The sum of the individual pain scores during treatment week 4 was lower on venlafaxine (80% of baseline score; p = 0.006) and imipramine (77%; p = 0.001) than on placebo (100%) and did not show any statistical difference between venlafaxine and imipramine (p = 0.44). The individual pain scores for pain paroxysms, constant pain, and pressure-evoked pain showed a similar pattern, whereas touch-evoked pain was uncommon and was not altered by any of the drugs. Numbers needed to treat to obtain one patient with moderate or better pain relief were 5.2 for venlafaxine and 2.7 for imipramine. Conclusion: Venlafaxine relieves pain in polyneuropathy and may be as effective as imipramine.

Tramadol relieves pain and allodynia in polyneuropathy: a randomised, double-blind, controlled trial.

It is generally believed that opioids relieve neuropathic pain less effectively than nociceptive pain and that they have no effect on some of the key characteristics of neuropathic pain such as touch-evoked pain (allodynia). Tramadol is an analgesic drug acting directly on opioid receptors and indirectly on monoaminergic receptor systems. The aim of this trial was to determine whether tramadol relieved painful polyneuropathy and reduced allodynia. The study design was randomised, double-blind, placebo-controlled and cross-over. After baseline observations, 45 patients were assigned to one of the two treatment sequences. The dose of tramadol slow-release tablets was titrated to at least 200 mg/day and at highest 400 mg/day. During the two treatment periods of 4 weeks duration, patients rated pain, paraesthesia and touch-evoked pain by use of 0-10 point numeric rating scales. Mechanical allodynia induced by stimulation with an electronic toothbrush was rated at the end of each treatment period with a similar scale. Thirty-four patients completed the study. Their ratings for pain (median 4 vs. 6, P=0.001), paraesthesia (4 vs. 6, P=0.001) and touch-evoked pain (3 vs. 5, P<0.001) were lower on tramadol than on placebo, as were their ratings of allodynia (0 vs. 4, P=0.012). The number needed to treat to obtain one patient with >/=50% pain relief was 4.3 (95% confidence interval 2.4-20). It is concluded that tramadol appears to relieve both ongoing pain symptoms and the key neuropathic pain feature allodynia in polyneuropathy.

Long-term effects of migraine on cognitive function A population-based study of Danish twins

Objective: To investigate the cognitive functioning of migraineurs vs nonmigraineurs in a large population-based sample of middle-aged twins where headache diagnoses were established by neurologists. Methods: Twins identified through the population-based Danish Twin Registry participated in face-to-face structured interviews, which included cognitive tests and two previously validated questions screening for migraine. Twins who screened positive for migraine and their co-twins were invited to participate in a telephone-based interview conducted by neurologists, who established headache diagnoses according to the International Headache Society criteria. Cognitive scores on fluency, digit span, delayed word recall, and symbol digit substitution test were compared between migraineurs and nonmigraineurs. Comparisons within monozygotic and dizygotic same sex twin pairs discordant for migraine were also performed. Results: Of the 1,789 twins who were eligible for inclusion in the present study, 1,393 (77.8%) were interviewed. A diagnosis of migraine was established in 536 twins (migraine without aura n = 347; migraine with aura n = 157). Average scores on cognitive tests in twins with migraine or one of the migraine subtypes did not differ from those of nonmigraineurs in any of the tests. Comparisons within twin pairs discordant for migraine produced highly comparable results. Adjustment for possible confounders and stratification by cumulated number of lifetime attacks did not influence the results. Conclusions: A lifetime diagnosis of migraine was not associated with cognitive deficits in middle-aged subjects.

The effect of tramadol in painful polyneuropathy in relation to serum drug and metabolite levels

Tramadol is a racemic drug that may act through a monoaminergic effect of (+)‐ and (−)‐tramadol and through an opioid effect of its metabolite (+)‐M1. The objective of this study was to investigate the relationship between relief of pain and serum concentrations of tramadol and M1 in tramadol treatment of painful polyneuropathy.

St. John's wort has no effect on pain in polyneuropathy

&NA; Tricyclic antidepressants are the mainstay of treatment of painful polyneuropathy but cannot be used in a substantial number of patients. St. Johns wort is a herbal antidepressant, which may act via mechanisms similar to the tricyclics. The aim of this study was to test if St. Johns wort would relieve painful polyneuropathy. The study design was randomized, double‐blind, placebo‐controlled and cross‐over. Fifty‐four patients were assigned to one of the two treatment sequences. The daily dose of St. Johns wort was three tablets each containing 900 &mgr;g totalhypericin. During the two treatment periods of 5 weeks duration, patients rated constant pain, lancinating pain paroxysms, touch‐evoked pain and pain on pressure by use of 0–10 point numeric rating scales. Forty‐seven patients – 18 diabetics and 29 non‐diabetics – completed the study. There was a trend of lower total pain score (sum of the individual pain scores) on St. Johns wort than on placebo (median 14 vs. 15, P=0.05). None of the individual pain ratings were significantly changed by St. Johns wort as compared to placebo (P=0.09–0.33). Complete, good or moderate pain relief was experienced by nine patients with St. Johns wort and two with placebo (P=0.07). In conclusion, St. Johns wort has no significant effect on pain in polyneuropathy.

Evaluation of patients with symptoms suggestive of chronic polyneuropathy.

Objectives The aim of this study was to determine the diagnostic yield and to describe the spectrum of diagnosis encountered by evaluation of patients with symptoms suggestive of chronic polyneuropathy. Methods We prospectively evaluated 198 patients referred to a department of neurology with symptoms suggestive of polyneuropathy. The evaluation included nerve conduction studies with near-nerve technique, quantitative examination of temperature sensation, blood tests, chest x-rays, and skin biopsies as well as diagnostic tests for differential diagnoses. Results Polyneuropathy was found in 147 patients, alternative diagnoses in 25, and 26 remained undiagnosed. The etiology of polyneuropathy could not be identified in 25% of the patients with polyneuropathy. In the remaining 75%, the cause of neuropathy was diabetes and/or alcohol abuse (41%), monoclonal gammopathy of undetermined significance (5%), drugs (5%), connective tissue disease (3%), and a number of less frequent conditions. A previously undiagnosed condition was found in 30% of the patients with polyneuropathy. Conclusion Evaluation of patients with symptoms suggestive of polyneuropathy reveals a high fraction of patients with previously undiagnosed conditions both in patients ending up with a polyneuropathy diagnosis and those without this diagnosis.

A randomized, placebo-controlled trial of levetiracetam in central pain in multiple sclerosis

Levetiracetam is an anticonvulsant which is assumed to act by modulating neurotransmitter release via binding to the vesicle protein SV2A. This could have an impact on signalling in the pain pathway. The aim of this study was to test the analgesic effect of levetiracetam in central pain in multiple sclerosis. This was a randomized, double‐blind, placebo‐controlled, cross‐over trial with levetiracetam 3000 mg/day versus placebo (6‐week treatment periods). Patients with multiple sclerosis, symptoms and signs complying with central neuropathic pain and pain symptoms for more than 6 months, as well as pain intensity of more than 4 on a 0 to 10‐point numeric rating scale were included in the study. The primary outcome measure was pain relief at the end of each treatment period as measured on a 6‐point verbal scale. Eighty‐nine patients were screened for participation and 30 patients entered the study. Twenty‐seven patients were included in the data analysis. There were no differences in the ratings of pain relief (levetiracetam 2.4 vs. placebo 2.1, p = 0.169), total pain intensity (levetiracetam 5.3 vs. placebo 5.7, p = 0.147) or any of the other outcome measures (p = 0.086–0.715) in the total sample of patients. However, there was significant reduction of pain, increased pain relief and/or more favourable pain relief with levetiracetam than with placebo in patients with lancinating or without touch‐evoked pain (p = 0.025–0.046). This study found no effect of the anticonvulsant levetiracetam in non‐selected patients with central pain in multiple sclerosis, but an effect in subgroups with specific pain symptoms was indicated.

Diagnostic yield by testing small fiber function in patients examined for polyneuropathy.

Abstract  We assessed the diagnostic yield of adding quantitative sensory testing to the standard work‐up for polyneuropathy in unselected patients. All patients aged 18 to 70 years referred to our department for electrodiagnosis with a tentative diagnosis of polyneuropathy and symptoms complying with predefined criteria were included in the study. We performed near nerve conduction studies in 4 nerves and determined heat and cold detection thresholds on hand and foot with a Thermotest (Somedic AB, Sweden). In order to uncover CNS diseases, somatosensory‐evoked potentials were recorded in patients with abnormal quantitative sensory testing and normal nerve conduction studies. A total of 198 patients completed the study and 149 were considered to have polyneuropathy. Twenty‐five patients remained undiagnosed and in 24 patients, other diseases were responsible for the symptoms. Of the patients with either polyneuropathy or no other diagnosis, 76% (n = 174) had abnormal nerve conduction. Abnormal cold sensation, heat sensation or abnormality in at least 1 of these and normal nerve conduction were found in 14, 12 and 17 patients. Of the 174 patients, 86% (95% CI 80–90%) had an abnormality in at least 1 of the tests (i.e. abnormal nerve conduction and/or abnormal quantitative testing of temperature sensation). In conclusion, quantitative testing of temperature sensation improves the diagnostic yield in patients examined for chronic polyneuropathy.

Stereological estimation of nuclear mean volume in invasive meningiomas

A stereological estimation of nuclear mean volume in bone and brain invasive meningiomas was made. For comparison the nuclear mean volume of benign meningiomas was estimated. The aim was to investigate whether this method could discriminate between these groups. We found that the nuclear mean volume in the bone and brain invasive meningiomas was larger than in the benign tumors. The difference was significant and moreover it was seen that there was no overlap between the two groups. In the bone invasive meningiomas the nuclear mean volume appeared to be larger inside than outside the bone. No significant difference in nuclear mean volume was found between brain and bone invasive meningiomas. The results demonstrate that invasive meningiomas differ from benign meningiomas by an objective stereological estimation of nuclear mean volume (p< 0.00005).

The innovative development in interferon beta treatments of relapsing-remitting multiple sclerosis

The introduction of interferon beta therapies more than 20 years ago marked a milestone in the treatment of relapsing‐remitting multiple sclerosis (RRMS) with a significant impact on the approach to modern multiple sclerosis (MS) care. Key learnings and perspectives from the early days of disease modifying therapies in MS have improved the knowledge base of MS, need for treatment, and patient care. The continuous development of interferons over the past two decades outlines a journey with increased understanding of the pharmacodynamics and pharmacokinetic mechanisms of interferons, leading to innovative formulations with an improved benefit/risk profile.