Johannes Fleckenstein

Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na V 1.6-resurgent and persistent current

Infusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxaliplatin neuropathy, whereas a common symptom of chronic oxaliplatin neuropathy is pain. Here we examine the role of the sodium channel isoform NaV1.6 in mediating the symptoms of acute oxaliplatin neuropathy. Compound and single-action potential recordings from human and mouse peripheral axons showed that cooling in the presence of oxaliplatin (30–100 μM; 90 min) induced bursts of action potentials in myelinated A, but not unmyelinated C-fibers. Whole-cell patch-clamp recordings from dissociated dorsal root ganglion (DRG) neurons revealed enhanced tetrodotoxin-sensitive resurgent and persistent current amplitudes in large, but not small, diameter DRG neurons when cooled (22 °C) in the presence of oxaliplatin. In DRG neurons and peripheral myelinated axons from Scn8amed/med mice, which lack functional NaV1.6, no effect of oxaliplatin and cooling was observed. Oxaliplatin significantly slows the rate of fast inactivation at negative potentials in heterologously expressed mNaV1.6r in ND7 cells, an effect consistent with prolonged NaV open times and increased resurgent and persistent current in native DRG neurons. This finding suggests that NaV1.6 plays a central role in mediating acute cooling-exacerbated symptoms following oxaliplatin, and that enhanced resurgent and persistent sodium currents may provide a general mechanistic basis for cold-aggravated symptoms of neuropathy.

Discrepancy between prevalence and perceived effectiveness of treatment methods in myofascial pain syndrome: Results of a cross-sectional, nationwide survey

BackgroundMyofascial pain is a common dysfunction with a lifetime prevalence affecting up to 85% of the general population. Current guidelines for the management of myofascial pain are not available. In this study we investigated how physicians on the basis of prescription behaviour evaluate the effectiveness of treatment options in their management of myofascial pain.MethodsWe conducted a cross-sectional, nationwide survey with a standardized questionnaire among 332 physicians (79.8% male, 25.6% female, 47.5 ± 9.6 years) experienced in treating patients with myofascial pain. Recruitment of physicians took place at three German meetings of pain therapists, rheumatologists and orthopaedists, respectively. Physicians estimated the prevalence of myofascial pain amongst patients in their practices, stated what treatments they used routinely and then rated the perceived treatment effectiveness on a six-point scale (with 1 being excellent). Data are expressed as mean ± standard deviation.ResultsThe estimated overall prevalence of active myofascial trigger points is 46.1 ± 27.4%. Frequently prescribed treatments are analgesics, mainly metamizol/paracetamol (91.6%), non-steroidal anti-inflammatory drugs/coxibs (87.0%) or weak opioids (81.8%), and physical therapies, mainly manual therapy (81.1%), TENS (72.9%) or acupuncture (60.2%). Overall effectiveness ratings for analgesics (2.9 ± 0.7) and physical therapies were moderate (2.5 ± 0.8). Effectiveness ratings of the various treatment options between specialities were widely variant. 54.3% of all physicians characterized the available treatment options as insufficient.ConclusionsMyofascial pain was estimated a prevalent condition. Despite a variety of commonly prescribed treatments, the moderate effectiveness ratings and the frequent characterizations of the available treatments as insufficient suggest an urgent need for clinical research to establish evidence-based guidelines for the treatment of myofascial pain syndrome.

Retigabine reduces the excitability of unmyelinated peripheral human axons.

Enhancement of membrane K(+) conductance may reduce the abnormal excitability of primary afferent nociceptive neurons in neuropathic pain. It has been shown that retigabine, a novel anticonvulsant, activates Kv7 (KCNQ/M) channels in the axonal/nodal membrane of peripheral myelinated axons. In this study, we have tested the effects of retigabine on excitability parameters of C-type nerve fibers in isolated fascicles of human sural nerve. Application of retigabine (3-10 microM) produced an increase in membrane threshold. This effect was pronounced in depolarized axons and small in hyperpolarized axons. This finding indicates that retigabine produces a membrane hyperpolarization which is limited by the K(+) equilibrium potential. The retigabine-induced reduction in excitability was accompanied by modifications of the post-spike recovery cycle. Most notable is the development of a late subexcitability at 250-400 ms following a short burst of action potentials. All effects of retigabine were blocked in the presence of XE991 (10 microM). The data show that Kv7 channels are present on axons of unmyelinated, including nociceptive, peripheral human nerve fibers. It is likely that activation of these channels by retigabine may reduce the ectopic generation of action potentials in neuropathic pain.

Is Sham Laser a Valid Control for Acupuncture Trials

Methodological problems of acupuncture trials focus on adequate placebo controls. In this trial we evaluated the use of sham laser acupuncture as a control procedure. Thirty-four healthy volunteers received verum laser (invisible infrared laser emission and red light, 45 s and 1 J per point) and sham laser (red light) treatment at three acupuncture points (LI4, LU7 and LR3) in a randomized, double-blinded, cross-over design. The main outcome measure was the ratio of correct to incorrect ratings of treatment immediately after each session. The secondary outcome measure was the occurrence of deqi-like sensations at the acupuncture points and their intensity on a 10-fold visual analog scale (VAS; 10 being the strongest sensible sensation). We pooled the results of three former trials to evaluate the credibility of sham laser acupuncture when compared to needle acupuncture. Fifteen out of 34 (44%) healthy volunteers (age: 28 ± 10.7 years) identified the used laser device after the first session and 14 (41%) after the second session. Hence, both treatments were undistinguishable (P = .26). Deqi-like sensations occurred in 46% of active laser (2.34 VAS) and in 49.0% of sham laser beams (2.49 VAS). The credibility of sham laser was not different from needle acupuncture. Sham laser acupuncture can serve as a valid placebo control in laser acupuncture studies. Due to similar credibility and the lack of sensory input on the peripheral nervous system, sham laser acupuncture can also serve as a sham control for acupuncture trials, in order to evaluate needling effects per se.

Test order of quantitative sensory testing facilitates mechanical hyperalgesia in healthy volunteers

UNLABELLED Quantitative sensory testing (QST) has become a widely used method to evaluate different submodalities of the somatic sensory system (predominantly) in patients with neuropathic pain. QST consists of 7 tests measuring 13 parameters in order to assess and quantify the perception of temperature, touch, pain, pressure, and vibration. The German Research Network on Neuropathic Pain implemented a standardized QST protocol including a defined testing order of the measurements. Accordingly, subjects tested with QST undergo thermal before mechanical testing. In the present study, we investigated the effect of testing order on the results of QST. Twenty healthy subjects were tested twice, 1 week apart with 2 different QST testing orders: the standardized testing order according to the German Research Network on Neuropathic Pain and a modified testing order in which mechanical stimuli were applied before thermal stimuli. For the test protocol that began with thermal testing, subjects exhibited signs of an increased mechanical perception: The mechanical pain sensitivity was significantly increased (P = .001, Wilcoxon test) for each pinprick stimulator and the mechanical pain threshold was lowered by a factor of 2 when compared with the modified testing order in which mechanical parameters were tested at the beginning of the session without prior thermal stimulation. Thermal parameters were the same for both test-order paradigms. These data indicate that preceding mild thermal stimulation might lead to a sensitization to mechanical stimuli and thus to mechanical hyperalgesia. Alternative habituation mechanisms in the modified testing order resulting from repeated pinprick stimulation at the beginning should also be debated. QST is a helpful diagnostic tool but interpretation should be done with consideration of interaction between test parameters. Reference data are only valid in the testing order from which they are obtained. PERSPECTIVE Present data showed that mechanical hyperalgesia followed thermal testing. This article demonstrates that the test order of quantitative sensory testing is relevant in interpreting the results obtained. Reference values are suitable in the test order from which they are obtained.

Trigger Points and Classical Acupuncture Points: Part 1: Qualitative and Quantitative Anatomic Correspondences

BackgroundData from a recently published study suggest that substantial anatomic, clinical, and physiologic overlap of myofascial trigger points (mTrPs) and acupoints exists in the treatment of pain disorders.ObjectiveTo evaluate the anatomic relationships between classical acupoint locations and those of mTrPs both qualitatively and quantitatively.MethodsGraphics software was used to demonstrate the different muscle layers of a virtual, digitized human cadaver. The locations of 255 “common” mTrPs described in the Trigger Point Manual were superimposed as a separate layer to these graphics as were the locations of the 361 classical acupoints and the meridians they exist on. The relationships of the anatomic locations of acupoints and meridians to those of muscles and common mTrPs could then be directly visualized. Classical acupoints and mTrPs that entered the same muscle regions and were physically closest to each other, as confirmed by acupuncture and human anatomy references, were termed “anatomically corresponding” point pairs. A quantitative analysis of these anatomically corresponding mTrP-acupoint pairs was also performed.ResultsOf 255 common mTrPs, 238 (93.3 %) had anatomically corresponding classical acupoints. Quantitatively, 89 (37 %) of these 238 corresponding mTrP-acupoint pairs were estimated to be within 1 cm of each other, 107 point pairs (45 %) within 1–2 cm of each other, and another 32 point pairs (13 %) within 2–3 cm of each other. Trigger-acupuncture point correspondences would rise to 95.7 % if six other common mTrPs are considered anatomically corresponding.ConclusionsAnalysis of the relationships of the anatomic locations of mTrPs and acupoints while adhering to the modern conceptualization of myofascial pain as a regional muscle disorder demonstrates ≥ 93.3 % anatomic correspondence of common mTrPs to classical acupoints.ZusammenfassungHintergrundEine mögliche Überschneidung myofaszialer Triggerpunkte (mTrPs) mit Akupunkturpunkten in Bezug auf deren anatomische, klinische und physiologische Eigenschaften in der Behandlung von Schmerzsyndromen ist Gegenstand neuester Publikationen.ZielsetzungDie anatomischen Beziehungen zwischen klassischen Akupunkturpunkten und mTrPs sollten qualitativ und quantitativ analysiert werden.MethodikEs wurde ein spezielles Bildprogramm eines virtualisierten, digitalisierten menschlichen Leichnams zur Darstellung der verschiedenen Muskelschichten verwendet. Die Lokalisation der 255 im Trigger Punkt Manual beschriebenen und häufig gebräuchlichen mTrPs wurden ebenso wie die 361 klassischen Akupunkturpunkte mit ihren dazugehörigen Meridianen als zusätzliche Bildebenen in dieses Programm aufgenommen. Somit konnten die anatomischen Lagebeziehungen von klassischen Akupunkturpunkten und Meridianen zu Muskeln und mTrPs bildhaft gemacht werden. Klassische Akupunkturpunkte und mTrPs, die, wie auch durch Literaturquellen gesichert, in derselben Muskelgruppe lagen und die engste räumliche Zuordnung hatten, wurden als anatomisch entsprechende Punkte definiert. Zusätzlich wurde eine quantitative Analyse dieser anatomisch korrespondierenden mTrP Akupunkturpunktpaare durchgeführt.Ergebnis238 der 255 gebräuchlichen mTrPs (93,3 %) entsprachen anatomisch klassischen Akupunkturpunkten. 89 dieser 238 entsprechenden mTrP-Akupunkturpunktpaare (37 %) lagen näher als 1 cm, 107 Punktpaare (45 %) zwischen 1 und 2 cm, und weitere 32 Punktpaare (13 %) zwischen 2 und 3 cm voneinander.SchlussfolgerungDas gegenwärtige Konzept myofaszialer Schmerzen hält an der Vorstellung einer pathophysiologischen Störung des regionalen Muskels fest. Die Analyse der anatomischen Lagebeziehungen zwischen mTrPs und Akupunkturpunkten zeigt eine anatomische Beziehung von über 93,3 % der gebräuchlichen mTrPs zu klassischen Akupunkturpunkten.

Enhancement of axonal potassium conductance reduces nerve hyperexcitability in an in vitro model of oxaliplatin-induced acute neuropathy

Oxaliplatin is used in the chemotherapeutic treatment of malignant tumours. A common side effect of oxaliplatin is an acute peripheral neuropathy characterized by axonal hyperexcitability, which can be painful and is aggravated by exposure to cold. Electrophysiological studies on isolated segments of peripheral rodent nerve have been able to replicate oxaliplatins effect on axonal hyperexcitability in vitro. In the present study we have used this in vitro model to examine whether flupirtine, a clinically available analgesic, which activates slow axonal potassium (Kv7) channels, can suppress axonal hyperexcitability resulting from exposure of peripheral nerve to oxaliplatin. In the presence of oxaliplatin (30μM), the A-fibre compound action potential response of isolated rat nerve segments to a brief electrical stimulus (0.1ms) changed considerably with the emergence of after-activity that persisted for a period of tens of milliseconds after the electrical stimulus. Lowering the bath temperature by 4°C enhanced the magnitude and prolonged the time course of this axonal after-activity. Application of flupirtine (10μM) reduced both the magnitude and duration of oxaliplatin-induced axonal after-activity in myelinated axons. These findings were also confirmed in isolated human sural nerve segments. The data indicate that activation of slow potassium channels in the A-fibres of peripheral nerve may attenuate the acute neuropathy associated with oxaliplatin in humans.

Acupuncture in acute herpes zoster pain therapy (ACUZoster) - design and protocol of a randomised controlled trial.

BackgroundAcute herpes zoster is a prevalent condition. One of its major symptoms is pain, which can highly influence patients quality of life. Pain therapy is limited. Acupuncture is supposed to soften neuropathic pain conditions and might therefore act as a therapeutic alternative. Objective of the present study is to investigate whether a 4 week semi-standardised acupuncture is non-inferior to sham laser acupuncture and the anticonvulsive drug gabapentine in the treatment of pain associated with herpes zoster.Methods/DesignThree-armed, randomised, placebo-controlled trial with a total follow-up time of 6 months. Up to estimated 336 patients (interim analyses) with acute herpes zoster pain (VAS > 30 mm) will be randomised to one of three groups (a) semi-standardised acupuncture (168 patients); (b) gabapentine with individualised dosage between 900–3600 mg/d (84 patients); (c) sham laser acupuncture. Intervention takes place over 4 weeks, all patients will receive analgesic therapy (non-opioid analgesics: metamizol or paracetamol and opioids: tramadol or morphine). Therapy phase includes 4 weeks in which group (a) and (c) consist of 12 sessions per patient, (b) visits depend on patients needs. Main outcome measure is to assess the alteration of pain intensity before and 1 week after treatment sessions (visual analogue scale VAS 0–100 mm). Secondary outcome measure are: alteration of pain intensity and frequency of pain attacks; alteration of different aspects of pain evaluated by standardised pain questionnaires (NPI, PDI, SES); effects on quality of life (SF 36); analgesic demand; alteration of sensoric perception by systematic quantitative sensory testing (QST); incidence of postherpetic neuralgia; side effects and cost effectiveness. Credibility of treatments will be assessed.DiscussionThis study is the first large-scale randomised placebo controlled trial to evaluate the efficacy of acupuncture compared to gabapentine and sham treatment and will provide valuable new information about the clinical and physiological effects of acupuncture and gabapentine in the treatment of acute herpes zoster pain. The study has been pragmatically designed to ensure that the study findings can be implemented into clinical practice if acupuncture can be shown to be an effective treatment strategy in acute herpes zoster pain.Trial registrationNCT00885586

GABA increases electrical excitability in a subset of human unmyelinated peripheral axons.

Background A proportion of small diameter primary sensory neurones innervating human skin are chemosensitive. They respond in a receptor dependent manner to chemical mediators of inflammation as well as naturally occurring algogens, thermogens and pruritogens. The neurotransmitter GABA is interesting in this respect because in animal models of neuropathic pain GABA pre-synaptically regulates nociceptive input to the spinal cord. However, the effect of GABA on human peripheral unmyelinated axons has not been established. Methodology/Principal Findings Electrical stimulation was used to assess the effect of GABA on the electrical excitability of unmyelinated axons in isolated fascicles of human sural nerve. GABA (0.1–100 µM) increased electrical excitability in a subset (ca. 40%) of C-fibres in human sural nerve fascicles suggesting that axonal GABA sensitivity is selectively restricted to a sub-population of human unmyelinated axons. The effects of GABA were mediated by GABAA receptors, being mimicked by bath application of the GABAA agonist muscimol (0.1–30 µM) while the GABAB agonist baclofen (10–30 µM) was without effect. Increases in excitability produced by GABA (10–30 µM) were blocked by the GABAA antagonists gabazine (10–20 µM), bicuculline (10–20 µM) and picrotoxin (10–20 µM). Conclusions/Significance Functional GABAA receptors are present on a subset of unmyelinated primary afferents in humans and their activation depolarizes these axons, an effect likely due to an elevated intra-axonal chloride concentration. GABAA receptor modulation may therefore regulate segmental and peripheral components of nociception.

Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve

Background and purpose:  Amitriptyline is often prescribed as a first‐line treatment for neuropathic pain but its precise mode of analgesic action remains uncertain. Amitriptyline is known to inhibit voltage‐dependent ion channels and also to act as an antagonist at ligand‐gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). In the present study, we tested the effect of amitriptyline on nicotinic responses of unmyelinated axons in isolated segments of human peripheral nerve. In particular, a comparison was made between the concentrations of amitriptyline necessary for inhibition of nAChRs and those required for inhibition of the compound C‐fibre action potential.