Ralf Baron

EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision

Background and objectives:u2002 This second European Federation of Neurological Societies Task Force aimed at updating the existing evidence about the pharmacological treatment of neuropathic pain since 2005.

Efficacy of lidocaine patch 5% in the treatment of focal peripheral neuropathic pain syndromes: a randomized, double-blind, placebo-controlled study

&NA; Peripheral neuropathic pain syndromes (PNPS) are difficult to treat because commonly used analgesics are often ineffective when, for example, touch‐evoked allodynia, hyperalgesia, and pain paroxysms are present. To investigate whether lidocaine patch 5% treatment is also effective in postherpetic neuropathy (PHN) and in other PNPS, 40 patients with various forms and localizations of PNPS completed a prospective, randomized, placebo‐controlled, two‐way, cross‐over study in three medical hospitals. Patients suffering from pain in a localized skin area with intensity above 40 mm visual analog scale (VAS) and a stable consumption of pain medication were included in this study. The study was divided into four phases: 3‐day run‐in phase, treatment phase 1, wash‐out period, and treatment phase 2, each lasting 1 week. At the discretion of the patients, up to four patches (covering a maximum of 560 cm2) were applied onto the maximally painful area for 12 consecutive hours daily, always either by day or at night. Throughout the four phases, ongoing pain, allodynia, quality of neuropathic symptoms, quality of sleep, and adverse events were assessed. When, after the wash‐out period, the pain intensity scores did not return to the pre‐treatment values (±20%), these patients were excluded from the study. The present study revealed that, as an add‐on therapy, the lidocaine patch 5% was clearly effective in reducing ongoing pain (P=0.017) and allodynia (P=0.023) during the first 8 h after application and that the patches also worked well over a period of 7 days (P=0.018) in diverse focal PNPS. Calculation of the numbers needed to treat (NNT) to obtain one patient with more than 50% relief of ongoing pain revealed that the NNT of 4.4 in the present study compared reasonably well with other studies of PHN, such as topically applied capsaicin (NNT: 5.3–∞) or systemic treatment with gabapentin (NNT: 3.2–5.0).

Causalgia and reflex sympathetic dystrophy: Does the sympathetic nervous system contribute to the generation of pain?

The striking response of causalgia and reflex sympathetic dystrophy (RSD) to sympatholytic procedures together with signs of autonomic nervous system abnormalities suggest that the sympathetic efferent system can generate or enhance pain (sympathetically maintained pain, SMP). This concept is supported by human and animal experiments indicating that sympathetic activity and catecholamines can activate primary afferent nociceptors. Some clinical evidence, however, calls the SMP concept into question and alternative explanations have been advanced. In this review, we describe the clinical features of causalgia and RSD and the evidence for sympatholytic efficacy. The major barrier to proving the SMP concept is that all available sympatholytic procedures are problematic. We conclude that, although the weight of current evidence supports the SMP concept and its relevance to causalgia and RSD, it remains unproven by scientific criteria. More careful adherence to diagnostic criteria and well‐controlled trials of sympatholysis are needed to finally settle the issue.

Interventional management of neuropathic pain: NeuPSIG recommendations

&NA; Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high‐quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long‐term studies, and head‐to‐head comparisons among different interventional and noninterventional treatments.

5% lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study

ABSTRACT Objective: To compare efficacy and safety of 5% lidocaine medicated plaster with pregabalin in patients with post-herpetic neuralgia (PHN) or painful diabetic polyneuropathy (DPN). Study design and methods: This was a two-stage adaptive, randomized, open-label, multicentre, non-inferiority study. Data are reported from the initial 4-week comparative phase, in which adults with PHN or painful DPN received either topical 5% lidocaine medicated plaster applied to the most painful skin area or twice-daily pregabalin capsules titrated to effect according to the Summary of Product Characteristics. The primary endpoint was response rate at 4 weeks, defined as reduction averaged over the last three days from baseline of ≥2 points or an absolute value of ≤4 points on the 11-point Numerical Rating Scale (NRS-3). Secondary endpoints included 30% and 50% reductions in NRS-3 scores; change in allodynia severity rating; quality of life (QoL) parameters EQ-5D, CGIC, and PGIC; patient satisfaction with treatment; and evaluation of safety (laboratory parameters, vital signs, physical examinations, adverse events [AEs], drug-related AEs [DRAEs], and withdrawal due to AEs). Results: Ninety-six patients with PHN and 204 with painful DPN were analysed (full analysis set, FAS). Overall, 66.4% of patients treated with the 5% lidocaine medicated plaster and 61.5% receiving pregabalin were considered responders (corresponding numbers for the per protocol set, PPS: 65.3% vs. 62.0%). In PHN more patients responded to 5% lidocaine medicated plaster treatment than to pregabalin (PPS: 62.2% vs. 46.5%), while response was comparable for patients with painful DPN (PPS: 66.7% vs 69.1%). 30% and 50% reductions in NRS-3 scores were greater with 5% lidocaine medicated plaster than with pregabalin. Both treatments reduced allodynia severity. 5% lidocaine medicated plaster showed greater improvements in QoL based on EQ-5D in both PHN and DPN. PGIC and CGIC scores indicated greater improvement for 5% lidocaine medicated plaster treated patients with PHN. Improvements were comparable between treatments in painful DPN. Fewer patients administering 5% lidocaine medicated plaster experienced AEs (safety set, SAF: 18.7% vs. 46.4%), DRAEs (5.8% vs. 41.2%) and related discontinuations compared to patients taking pregabalin. Conclusion: 5% lidocaine medicated plaster showed better efficacy compared with pregabalin in patients with PHN. Within DPN, efficacy was comparable for both treatments. 5% lidocaine medicated plaster showed a favourable efficacy/safety profile with greater improvements in patient satisfaction and QoL compared with pregabalin for both indications, supporting its first line position in the treatment of localized neuropathic pain.

TRAUMATIC NEURALGIAS: Complex Regional Pain Syndromes (Reflex Sympathetic Dystrophy and Causalgia): Clinical Characteristics, Pathophysiologic Mechanisms and Therapy

Complex regional pain syndromes (CPRS) may develop as a disproportionate consequence of a trauma affecting the limbs without (CRPS I, reflex sympathetic dystrophy) or with (CRPS II, causalgia) obvious nerve lesions. The clinical picture of CRPS consists of asymmetrical distal extremity pain, swelling, and autonomic (sympathetic) and motor symptoms. Changes in the peripheral and central somatosensory, autonomic and motor processing, and a pathologic interaction of sympathetic and afferent systems are discussed as underlying pathophysiologic mechanisms. Therapeutic strategies include pharmacologic pain relief, sympatholytic interventions, and rehabilitation.

Dynamic mechanical allodynia in humans is not mediated by a central presynaptic interaction of Aβ-mechanoreceptive and nociceptive C-afferents

Recently, Cervero and Laird (NeuroReport, 7 (1996) 526-528; Pain, 68 (1996) 13-23) proposed a new pathophysiological mechanism of dynamic mechanical allodynia in skin. Using the capsaicin pain model in humans, they showed that light mechanical stimulation within an area of secondary mechanical allodynia induces vasodilatation measured by laser-Doppler flowmetry. They suggested that the low-threshold A beta-mechanoreceptive fibres depolarize the central terminals of nociceptive primary afferent neurons via interneurons. Consequently, the vasodilatation is produced by impulses conducted antidromically in nociceptive C-axons. The allodynia was proposed to result from depolarization of central terminals of primary afferent neurons with C-fibres with activation of nociceptive dorsal horn neurons. In order to extend these findings, we used the same experimental approach but additionally stimulated the A beta-fibres electrically to evoke secondary allodynia during simultaneous monitoring skin blood flow. Twenty microlitres of a 0.5% capsaicin solution was injected intradermally into the dorsal forearm. Skin sites that demonstrated dynamic mechanical allodynia but were not located within the area of primary hyperalgesia and flare were investigated. Ten mm away from a laser-Doppler probe, dynamic mechanical allodynia was induced for 1 min (1) by moving a cotton swab and (2) by electrically stimulating the afferent nerve endings transdermally. Increasing stimulus intensities were applied (0.3-4 mA, 40 Hz, pulse duration 0.2 ms). After intracutaneous injection of capsaicin, light mechanical stimulation elicited a burning painful sensation (numeric analogue scale (NAS) 1.5-3) and concomitant movement artefacts at the laser signal. Antidromic vasodilatation was never observed. In this area of dynamic allodynia, electrical stimulation at stimulus intensities that were not painful before capsaicin injection (A beta-stimulation) was now able to elicit a burning painful sensation (NAS 1.5-3). No change in blood flow was detected. When the stimulus intensities were increased reaching levels that were also painful before capsaicin treatment (C-fibre stimulation), an increase in blood flow could be induced showing the time course of an axon reflex vasodilatation. In conclusion, electrical stimulation of A beta-fibres in allodynic skin does not induce antidromic vasodilatation. Consequently, interaction of A beta-mechanoreceptive fibres and nociceptive C-fibres at a presynaptic level is unlikely to produce antidromically conducted impulses and therefore cannot explain the pathophysiology of mechanical allodynia. Alternatively, it is much more likely that under pathophysiological conditions, activity in A beta-fibres may activate nociceptive second-order neurons, i.e. in the spinal cord.

Activation of the somatosensory cortex during Aβ-fiber mediated hyperalgesia : a MSI study

Objective: To investigate the neural activation in the primary somatosensory cortex (SI) that is induced by capsaicin-evoked secondary Aβ-fiber-mediated hyperalgesia with magnetic source imaging (MSI) in healthy humans. Background: Dynamic mechanical hyperalgesia, i.e. pain to innocuous light touching, is a symptom of painful neuropathies. Animal experiments suggest that alterations in central pain processing occur so that tactile stimuli conveyed in Aβ low threshold mechanoreceptive afferents become capable of activating central pain signalling neurons. A similar state of central sensitization can be experimentally produced with capsaicin. Methods: In six individuals the somatosensory evoked magnetic fields (SEFs) induced by non-painful electrical stimulation of Aβ-afferents at the forearm skin were recorded. Capsaicin was injected adjacent to the stimulation site to induce secondary dynamic Aβ-hyperalgesia. Thereafter, the SEFs induced by the identical electrical stimulus applied within the secondary hyperalgesic skin were analyzed. The electrical stimulus was subsequently perceived as painful without changing the stimulus intensity and location. Latencies, anatomical source location and amplitudes of SEFs during both conditions were compared. Results: Non-painful electrical stimulation of Aβ-afferents induced SEFs in SI at latencies between 20 and 150 ms. Stimulation of Aβ-afferents within the capsaicin-induced secondary hyperalgesic skin induced SEFs at identical latencies and locations as compared with the stimulation of Aβ-afferents within normal skin. The amplitudes, i.e., the magnetic dipole strengths of the SEFs were higher during Aβ-hyperalgesia. Conclusions: Acute application of capsaicin produces an increase in the excitability of central neurons, e.g., in SI. This might be due to sensitization of central neurons so that normally innocuous stimuli activate pain signalling neurons or cortical neurons might increase their receptive fields.

Quantitative sensorische Testung

ZusammenfassungDie quantitative sensorische Testung (QST) ist eine standardisierte und formalisierte klinische Sensibilitätsprüfung. Bei dem subjektiven (psychophysischen) Verfahren kommt es auf die Mitarbeit der zu untersuchenden Person an. Mit kalibrierten Reizen werden Wahrnehmungs- und Schmerzschwellen erfasst, die Auskunft über das Vorhandensein sensibler Plus- oder Minuszeichen geben. Die vorgestellte QST-Batterie imitiert natürliche thermische oder mechanische Reize. Ziel ist die Erfassung von Symptommustern eines sensiblen Funktionsdefizits sowie einer Funktionszunahme bei gleichzeitiger Erfassung der Oberflächen- sowie Tiefensensibilität. Die meisten getesteten QST-Parameter sind erst nach Logarithmierung normalverteilt (sekundäre Normalverteilung). Ein vollständiges QST-Profil kann innerhalb einer Stunde gemessen werden. Die QST eignet sich für klinische Studien, aber auch in der Praxis als diagnostisches Verfahren zur Charakterisierung der Funktion des somatosensorischen Systems.AbstractQuantitative sensory testing (QST) is a standardized and formalized set of clinical sensitivity tests based on subjective (psychophysical) methods, which depends on the cooperation of the subject being investigated. Calibrated stimuli are used to measure the perception and pain thresholds, which provide information on the presence of sensory plus or minus signs. The QST equipment presented mimics natural thermal or mechanical stimuli. The rationale is to test for patterns of functional sensory loss or gain by simultaneous assessment of both cutaneous and deep pain sensitivity. The majority of QST parameters are normally distributed only after logarithmic transformation (i.e. secondary normalization). With QST a complete somatosensory profile can be obtained within 1xa0h. The QST is a suitable method for characterizing the function of the somatosensory system in clinical trials and also in clinical practice as a diagnostic procedure.

Examination of the role of the cerebral cortex in the perception of pain using functional magnetic resonance imaging

In the following review we outline several of the unique difficulties associated with designing and interpreting functional imaging studies of pain perception. Unlike other sensory modalities, the cortical processing of pain is unique, as is the pain experience itself. Unlike other sensory systems, pain processing does not take place in one dedicated region of the cortex. Rather, nociceptive cells are sparsely distributed through the somatosensory cortex. Further, pain is singular in that it has both sensorydiscriminative and affective-motivational components, which are probably subserved by different neuroanatomic substrates. Finally, abnormal pain sensation, such as neuropathic pain syndromes, may have different or additional mechanisms that require special consideration. We have illustrated these points with examples from our own work on acute pain and secondary mechanical hyperalgesia, and work from other laboratories.