[Clinical use of botulinum toxin type A in pain medicine]. / Klinische Anwendung von Botulinumtoxin Typ A in der Schmerzmedizin.

Botulinum toxin has been used for decades in the treatment of a variety of painful diseases. Botulinum toxin not only blocks neuromuscular transmission, but also the secretion of neuropeptides, such as substance P, glutamate and calcitonin gene-related peptide (CGRP) and thus inhibits neurogenic inflammation. In addition, it has a modulatory pain-relieving effect via retrograde transport into the central nervous system. In addition to approval for the treatment of dystonia or spasticity, onabotulinum toxin A is also approved for the prophylaxis of chronic migraine if the oral prophylactic migraine medication has had an insufficient effect or has not been tolerated. In addition, botulinum toxin is also recommended in guidelines as a third-line treatment for neuropathic pain, but in Germany this is an off-label application. This article provides an overview of the current clinically relevant areas of application of botulinum toxin in the field of pain medicine.

Distraction by a cognitive task has a higher impact on electrophysiological measures compared with conditioned pain modulation.

BACKGROUND: Conditioned pain modulation (CPM) evaluates the effect of a painful conditioning stimulus (CS) on a painful test stimulus (TS). Using painful cutaneous electrical stimulation (PCES) as TS and painful cold water as CS, the pain relief was paralleled by a decrease in evoked potentials (PCES-EPs). We now aimed to compare the effect of CPM with cognitive distraction on PCES-induced pain and PCES-EP amplitudes. METHODS: PCES was performed using surface electrodes inducing a painful sensation of 60 (NRS 0-100) on one hand. In a crossover design healthy subjects (included: n = 38, analyzed: n = 23) immersed the contralateral hand into 10 °C cold water (CS) for CPM evaluation and performed the 1-back task for cognitive distraction. Before and during the CS and 1-back task, respectively, subjects rated the pain intensity of PCES and simultaneously cortical evoked potentials were recorded. RESULTS: Both CPM and cognitive distraction significantly reduced PCES-EP amplitudes (CPM: 27.6 ± 12.0 µV to 20.2 ± 9.5 µV, cognitive distraction: 30.3 ± 14.2 µV to 13.6 ± 5.2 µV, p < 0.001) and PCES-induced pain (on a 0-100 numerical rating scale: CPM: 58 ± 4 to 41.1 ± 12.3, cognitive distraction: 58.3 ± 4.4 to 38.0 ± 13.0, p < 0.001), though the changes in pain intensity and PCES-amplitude did not correlate. The changes of the PCES-EP amplitudes during cognitive distraction were more pronounced than during CPM (p = 0.001). CONCLUSIONS: CPM and cognitive distraction reduced the PCES-induced pain to a similar extent. The more pronounced decrease of PCES-EP amplitudes after distraction by a cognitive task implies that both conditions might not represent the general pain modulatory capacity of individuals, but may underlie different neuronal mechanisms with the final common pathway of perceived pain reduction.

Conditioned pain modulation using painful cutaneous electrical stimulation or simply habituation?

BACKGROUND AND AIMS: Cold pressor test was recently reported to significantly reduce painful cutaneous electrical stimulation (PCES)-induced pain and corresponding evoked potentials (PCES-EPs), but whether this reduction is an effect of conditioned pain modulation (CPM) remains unknown. To what extent these findings are confounded by habituation is also unknown. We thus compared the effect of CPM and habituation on PCES-induced pain and PCES-EPs and analysed whether increased attention by a random change of electric stimulation would intensify this possible habituation effect. METHODS: Three custom-built concentric surface electrodes were used to induce a pain intensity of 60 on a 0-100 numerical rating scale (NRS) among 29 healthy subjects (age 20-35y, 16 females). PCES-EPs (including P0N1 and N1P1 amplitudes, N1 latencies) were assessed over Cz. Group A received 14 min of electrical stimulation with constant intensity followed by 14 min of electrical stimulation with variable intensities, group B vice versa. Afterwards, subjects perceived cold-water pain (10 °C) contralaterally as conditioning stimulus to assess CPM. Statistical analysis was conducted with ANOVA and t-test. RESULTS: In both groups, N1 latencies remain unchanged, but the intensity of PCES-induced pain (12 ± 17%; p < 0.01) and N1P1 amplitudes of PCES-EPs (10 ± 16%; p < 0.05) decreased significantly during the 14-min PCES with constant current intensity. CPM also significantly reduced pain ratings (36 ± 19%; p < 0.001) and amplitudes (37.2 ± 15.8%), p < 0.001). A significant decline of P0N1 amplitudes occurred only during CPM (18 ± 61%; p < 0.001). CONCLUSION: We found a significant effect of habituation on PCES-induced pain and PCES-EPs, although the effect of CPM was significantly larger and could not be explained by habituation alone. SIGNIFICANCE: Painful cutaneous electrical stimulation leads to moderate habituation of pain and evoked potential amplitudes, but the conditioned pain modulation effect using this method is significantly larger, which might indicate a different mechanism in central processing.

[Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies]. / Wirksamkeit, Verträglichkeit und Sicherheit von Cannabinoiden bei neuropathischen Schmerzsyndromen : Eine systematische Übersichtsarbeit von randomisierten, kontrollierten Studien.

BACKGROUND: Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain. MATERIAL AND METHODS: A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool. RESULTS: We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2 with nabilone and 1 with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12). CONCLUSION: Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.

Presence of hyperalgesia predicts analgesic efficacy of topically applied capsaicin 8% in patients with peripheral neuropathic pain.

BACKGROUND: Topical high-dose capsaicin acting on TRPV1 receptors and inducing an intraepidermal decrease in the small nerve fibre count is effective in treating neuropathic pain (NP). Sensory changes after capsaicin application, their correlation with pain relief and their role as possible predictors of response have been insufficiently analysed. We hypothesized a positive correlation between pain relief and increase in the warmth detection threshold (WDT), indicating loss of C-fibre function, and higher response rates in patients with preserved C-fibre function or heat hyperalgesia before application. METHODS: Quantitative Sensory Testing (DFNS protocol) was conducted in 20 unilaterally treated patients with peripheral NP (peripheral nerve injury: n = 14, polyneuropathy: n = 4, postherpetic neuralgia: n = 2) before and 2, 4, 6 and 8 weeks after application of capsaicin (8%) in this open-label study. Response was defined as ≥30% or ≥2 (Numeric Rating Scale: 0-10) decrease of current pain at any follow-up compared to baseline. RESULTS: In all patients, WDT significantly increased 8 weeks after capsaicin application, but did not correlate with pain relief in responders (n = 10, r = 0.179, p = 0.141). Before treatment, responders showed significantly higher z-values for the cold (CPT, +0.7 ± 1.1 vs. -0.4 ± 0.9) and mechanical pain threshold (MPT; 0.7 ± 2.5 vs. -1.2 ± 1.3), but did not differ from non-responders regarding WDT or heat pain threshold. A sum of the z-values for CPT and MPT >0.8 before treatment identified responders with 100% specificity and 70% sensitivity. CONCLUSIONS: Efficacy of capsaicin does not correlate with the induced loss of function of small fibres, measured by QST. Presence of cold and pinprick hyperalgesia seems to be predictive of response to capsaicin (8%).