Sleep, Experimental Pain and Clinical Pain in Patients with Chronic Musculoskeletal Pain and Healthy Controls.

PURPOSE: Everyday variations in night sleep in healthy pain-free subjects are at most weakly associated with pain, whereas strong alterations (eg, sleep deprivation, insomnia) lead to hyperalgesic pain changes. Since it remains unclear how substantial sleep alterations need to be in order to affect the pain system and lead to a coupling of both functions, the present study aimed at providing sufficient variance for co-variance analyses by examining a sample consisting of both healthy subjects and chronic pain patients. METHODS: A sample of 20 chronic musculoskeletal pain patients and 20 healthy controls was examined. This sample was assumed to show high inter-individual variability in sleep and pain, as pain patients frequently report sleep disturbances, whereas healthy subjects were required to be pain-free and normal sleepers. Sleep of two non-consecutive nights was measured using portable polysomnography and questionnaires. Experimental pain parameters (pressure pain thresholds (PPT), temporal summation of pain (TSP), conditioned pain modulation (CPM)) and situational pain catastrophizing (SCQ) were assessed in laboratory sessions before and after sleep. Pain patients' clinical pain was assessed via questionnaire. RESULTS: As expected, both groups differed in several sleep parameters (reduced total sleep time and sleep efficiency, more time awake after sleep onset, lower subjective sleep quality in the patients) and in a few pain parameters (lower PPTs in the patients). In contrast, no differences were found in TSP, CPM, and SCQ. Contrary to our expectations, regression analyses indicated no prediction of overnight pain changes by sleep parameters. CONCLUSION: Since sleep parameters were hardly apt to predict overnight pain changes, this leaves the association of both systems mainly unproven when using between-subject variance for verification.

Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease.

Chronic ischemic pain in peripheral arterial disease (PAD) is a leading cause of pain in the lower extremities. A neuropathic component of chronic ischemic pain has been shown independent of coexisting diabetes. We aimed to identify a morphological correlate potentially associated with pain and sensory deficits in PAD. Forty patients with symptomatic PAD (Fontaine stages II-IV), 20 with intermittent claudication (CI), and 20 with critical limb ischemia (CLI) were enrolled; 12 volunteers served as healthy controls. All patients were examined using pain scales and questionnaires. All study participants underwent quantitative sensory testing (QST) at the distal calf and skin punch biopsy at the distal leg for determination of intraepidermal nerve fiber density (IENFD). Additionally, S100 beta serum levels were measured as a potential marker for ischemic nerve damage. Neuropathic pain questionnaires revealed slightly higher scores and more pronounced pain-induced disability in CLI patients compared to CI patients. QST showed elevated thermal and mechanical detection pain thresholds as well as dynamic mechanical allodynia, particularly in patients with advanced disease. IENFD was reduced in PAD compared to controls (P<0.05), more pronounced in the CLI subgroup (CLI: 1.3 ± 0.5 fibers/mm, CI: 2.9 ± 0.5 fibers/mm, controls: 5.3 ± 0.6 fibers/mm). In particular, increased mechanical and heat pain thresholds negatively correlated with lower IENFD. Mean S100 beta levels were in the normal range but were higher in advanced disease. Patients with chronic ischemic pain had a reduced IENFD associated with impaired sensory functions. These findings support the concept of a neuropathic component in ischemic pain.

Activation of axonal Kv7 channels in human peripheral nerve by flupirtine but not placebo - therapeutic potential for peripheral neuropathies: results of a randomised controlled trial.

BACKGROUND: Flupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels. Kv7 channels are expressed along myelinated and unmyelinated peripheral axons where their activation is expected to reduce axonal excitability and potentially contribute to flupirtine's clinical profile. TRIAL DESIGN: To investigate the electrical excitability of peripheral myelinated axons following orally administered flupirtine, in-vitro experiments on isolated peripheral nerve segments were combined with a randomised, double-blind, placebo-controlled, phase I clinical trial (RCT). METHODS: Threshold tracking was used to assess the electrical excitability of myelinated axons in isolated segments of human sural nerve in vitro and motoneurones to abductor pollicis brevis (APB) in situ in healthy subjects. In addition, the effect of flupirtine on ectopic action potential generation in myelinated axons was examined using ischemia of the lower arm. RESULTS: Flupirtine (3-30 µM) shortened the relative refractory period and increased post-conditioned superexcitability in human myelinated axons in vitro. Similarly, in healthy subjects the relative refractory period of motoneurones to APB was reduced 2 hours after oral flupirtine but not following placebo. Whether this effect was due to a direct action of flupirtine on peripheral axons or temperature could not be resolved. Flupirtine (200 mg p.o.) also reduced ectopic axonal activity induced by 10 minutes of lower arm ischemia. In particular, high frequency (ca. 200 Hz) components of EMG were reduced in the post-ischemic period. Finally, visual analogue scale ratings of sensations perceived during the post-ischemic period were reduced following flupirtine (200 mg p.o.). CONCLUSIONS: Clinical doses of flupirtine reduce the excitability of peripheral myelinated axons. TRIAL REGISTRATION: ClinicalTrials registration is NCT01450865.

Incidence and predictors of immediate complications following perioperative non-obstetric epidural punctures.

BACKGROUND: Epidural Anesthesia (EA) is a well-established procedure. The aim of the present study was to evaluate the incidence of immediate complications following epidural puncture, such as sanguineous puncture, accidental dural perforation, unsuccessful catheter placement or insufficient analgesia and to identify patient and maneuver related risk factors. METHODS: A total of 7958 non-obstetrical EA were analyzed. The risk of each complication was calculated according to the preconditions and the level of puncture. For probabilistic evaluation we used a logistic regression model with forward selection. RESULTS: The risk of sanguineous puncture (n = 247, 3.1%) increases with both the patient's age (P = 0.013) and the more caudal the approach (P < 0.01). Dural perforation (n = 123, 1.6%) was found to be influenced only by advanced age (P = 0.019). Unsuccessful catheter placement (n = 68, 0.94%) occurred more often in smaller individuals (P < 0.001) and at lower lumbar sites (P < 0.01). Amongst all cases with successful catheter placement a (partial) insufficient analgesia was found in 692 cases (8.8%). This risk of insufficient analgesia decreased with patient's age (P <0 .01), being least likely for punctures of the lower thoracic spine (P < 0.001). CONCLUSIONS: Compared to more cranial levels, EA of the lower spine is associated with an increased risk of sanguineous and unsuccessful puncture. Insufficient analgesia more often accompanies high thoracic and low lumbar approaches. The risk of a sanguineous puncture increases in elderly patients. Gender, weight and body mass index seem to have no influence on the investigated complications.

Impact of surgical intervention and postoperative pain on electrical skin resistance at acupuncture points: an exploratory study.

OBJECTIVES: One theory about acupuncture suggests that pathological processes can cause measurable changes in electrical skin resistance (ESR) at acupuncture points (APs). Although the theory has yet to be proven, ESR measurements (ESRMs) form a frequently used part of contemporary acupuncture. The aim of this study was to test the so-called 'electrical responsiveness' of APs in the setting of a defined operative trauma. METHODS: ESRMs (n=424) were performed at the APs and surrounding skin of GB34 and ST38 in 163 participants using an impedance meter array developed for the purpose of ESRMs. For each group the percentage of measurements with a significantly different ESR between the APs and the surrounding skin was calculated and compared with each other. Measurements of four groups were compared: healthy control subjects (n=30) and patients after ophthalmic (n=29), hip (n=42) and shoulder (n=30) surgery. The influence of postoperative pain intensity was also assessed. RESULTS: Group comparison showed no significant differences for ST38. The ESRMs at GB34 had a significantly higher percentage of measurements with an increased ESR after ophthalmic (23.2%) and hip (22.2%) surgery, but not after shoulder surgery (7.5%). Subgroup analysis showed that an increase in pain intensity tended to lead to a decrease in the number of APs with ESR changes. CONCLUSION: These results suggest that reactive changes in ESR at APs might exist. Pain and alertness seem to have an impact on ESR at APs. However, the current data do not allow for conclusions to be drawn concerning the clinical use of ESRMs.

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.

Etoricoxib--preemptive and postoperative analgesia (EPPA) in patients with laparotomy or thoracotomy--design and protocols.

BACKGROUND AND OBJECTIVE: Our objective was to report on the design and essentials of the Etoricoxib protocol- Preemptive and Postoperative Analgesia (EPPA) Trial, investigating whether preemptive analgesia with cox-2 inhibitors is more efficacious than placebo in patients who receive either laparotomy or thoracotomy. DESIGN AND METHODS: The study is a 2 x 2 factorial armed, double blinded, bicentric, randomised placebo-controlled trial comparing (a) etoricoxib and (b) placebo in a pre- and postoperative setting. The total observation period is 6 months. According to a power analysis, 120 patients scheduled for abdominal or thoracic surgery will randomly be allocated to either the preemptive or the postoperative treatment group. These two groups are each divided into two arms. Preemptive group patients receive etoricoxib prior to surgery and either etoricoxib again or placebo postoperatively. Postoperative group patients receive placebo prior to surgery and either placebo again or etoricoxib after surgery (2 x 2 factorial study design). The Main Outcome Measure is the cumulative use of morphine within the first 48 hours after surgery (measured by patient controlled analgesia PCA). Secondary outcome parameters include a broad range of tests including sensoric perception and genetic polymorphisms. DISCUSSION: The results of this study will provide information on the analgesic effectiveness of etoricoxib in preemptive analgesia and will give hints on possible preventive effects of persistent pain. TRIAL REGISTRATION: NCT00716833.

Bilateral acupuncture analgesia observed by quantitative sensory testing in healthy volunteers.

BACKGROUND: There is evidence that acupuncture activates different spinal and supraspinal antinociceptive systems, but the specific modulatory effects on the sensory system have not been systematically investigated. In this study, we evaluated the immediate effects of different types of acupuncture on thermal, mechanical, and vibratory sensory thresholds. METHODS: Twenty-four healthy volunteers (12 men and 12 women, mean age 33.1 years) received 3 different forms of acupuncture in a single-blinded crossover design; these included manual acupuncture, acupuncture with low-frequency electrical stimulation, and acupuncture with high-frequency electrical stimulation. The time between the interventions was 1 week. All forms of acupuncture were applied unilaterally in the leg at standard acupuncture points: spleen 6, spleen 9, stomach 36, and gallbladder 39. The effects of acupuncture were evaluated by systematic quantitative sensory testing (QST) immediately after each intervention. QST was performed on bilateral lower extremities, including thermal and mechanical perception and pain and vibratory thresholds. RESULTS: The heat pain threshold was increased after manual acupuncture on the treated and untreated side compared with baseline. Low- and high-frequency electrostimulation led to a higher mechanical pain threshold on the treated side compared with baseline and manual acupuncture. The pressure pain threshold was increased by all forms of acupuncture on both sides, with individual changes from baseline ranging from 25% to 52%. CONCLUSIONS: There were congruent changes on QST after 3 common acupuncture stimulation methods, with possible unilateral as well as bilateral effects.

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

BACKGROUND: Myofascial 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: Myofascial 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.

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

BACKGROUND: Acute herpes zoster is a prevalent condition. One of its major symptoms is pain, which can highly influence patient's 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/DESIGN: Three-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. DISCUSSION: This 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 REGISTRATION: NCT00885586.

Characteristics of electrical skin resistance at acupuncture points in healthy humans.

OBJECTIVES: The aim of this study was to evaluate the phenomenon of electrical skin resistance (ESR) changes at different acupuncture points (APs). SETTING: This single-blinded study was performed at the hospital of the University of Munich. DESIGN: Six common APs were measured (TE5, PC6, LU6, ST36, SP6, GB39) in 53 subjects. Subgroups were formed with varying time intervals for follow-ups (1 minute, 1 hour, 1 week) and a varying grade of reduction of the stratum corneum. METHODS: Electrical skin resistance measurements (ESRMs) were taken from a skin area of 6 x 6 cm using an array consisting of 64 (8 x 8) electrodes. The electrodes corresponding to the AP were located and the ESRM results were compared to those of the surrounding electrodes. The methodological setting made it possible to minimize major influence factors on electrical skin impedance measurements. RESULTS: A total of 631 ESRMs was evaluated: In 62.8% of the measured APs, no significant ESR difference was found. In 234 (37.2%) of the ESRMs, the ESR at the AP was significantly different from the surrounding skin area, with 163 (25.9%) points showing a lower and 71 (11.3%) points showing a higher ESR. Reproducibility was extremely high after 1 minute but was low after 1 hour and 1 week. CONCLUSIONS: This study shows that electrical skin resistance at APs can either be lower or higher compared to the surrounding area. The phenomenon is characterized by high short-term and low long-term reproducibility. Therefore, we conclude that APs might possess specific transient electrical properties. However, as the majority of the measured APs did not show a changed ESR, it cannot be concluded from our data that electrical skin resistance measurements can be used for acupuncture point localization or diagnostic/therapeutic purposes.

Impact of endovascular intervention on pain and sensory thresholds in nondiabetic patients with intermittent claudication: a pilot study.

UNLABELLED: Pain and sensory neuropathy are common in patients with peripheral arterial disease. So far it is unknown to what extent pain and sensory parameters can be ameliorated by endovascular intervention used to resolve the arterial obstruction. Seventeen nondiabetic patients with intermittent claudication were investigated in the present study. The patients had to undergo percutaneous transluminal angioplasty (PTA) to improve blood flow in the affected leg. To acquire detailed information of their sensory state quantitative sensory testing (QST) was performed before and 24 hours and 3 months after PTA. QST is a standardized clinical testing procedure for the detection of sensory changes that consists of multiple tests for thermal and mechanical detection and pain thresholds as well as vibratory thresholds and stimulus response functions. An age-matched control group was investigated with an interval of 3 months. Pain during exercise decreased by 60% (examined by numerical rating scale) after endovascular intervention, whereas the ankle/brachial-index-representing the peripheral hemodynamic situation-increased by 29%. Sensory function determined by QST did not change significantly following PTA over a 3-month period. Successfully performed PTA is highly effective in reducing exercise induced pain in patients with intermittent claudication. PERSPECTIVE: The study demonstrates that successfully performed PTA is a highly effective tool in reducing exercise induced pain in patients with intermittent claudication. However, the pain reduction observed cannot be verified by evaluating sensory functions using standardized quantitative sensory testing.

Characteristics of chronic ischemic pain in patients with peripheral arterial disease.

Chronic ischemic pain is a leading cause of pain in the lower extremities. A neuropathic component in ischemic pain has been shown. Neuropathic pain questionnaires are established as a common tool in pain research. The aim of this study was to analyze the clinical nature and the character of chronic ischemic pain in peripheral arterial disease (PAD). One hundred and two patients suffering from symptomatic PAD (Fontaine stages II-IV) were surveyed using validated pain questionnaires (VAS, NPSI, S-LANSS, PDI, SF-MPQ). Pain related disability was 22.7+/-1.7 (mean+/-SEM) in patients with intermittent claudication (CI) and 34.0+/-2.3 in patients with critical limb ischemia (CLI). Neuropathic pain questionnaires revealed distinctly higher scores for CLI than for CI: The S-LANSS indicated pain of predominantly neuropathic origin in patients with CLI (17.2+/-0.8) compared to CI (6.7+/-0.8; p<0.001). Global NPSI scores were 34.1+/-3.1 for CLI and 6.6+/-1.1 for CI (p<0.001). S-LANSS and NPSI correlated well (Spearman's rho=0.779; p<0.001). The SF-MPQ revealed that patients with CLI scored significantly higher for pain descriptors stabbing, hot-burning, tender and cruel-punishing compared to those with CI. The results suggest that the character of ischemic pain changes from nociceptive pain in patients with CI to predominantly neuropathic pain in patients with CLI. A neuropathic pain component seems to be a serious aspect in CLI, while it is not in CI. Questionnaires might be a helpful tool to investigate and diagnose ischemic pain.

Differential contribution of sodium channel subtypes to action potential generation in unmyelinated human C-type nerve fibers.

BACKGROUND: Multiple voltage-dependent sodium channels (Na(v)) contribute to action potentials and excitability of primary nociceptive neurons. The aim of the current study was to characterize subtypes of Na(v) that contribute to action potential generation in peripheral unmyelinated human C-type nerve fibers. METHODS: Registration of C-fiber compound action potentials and determination of membrane threshold was performed by a computerized threshold tracking program. Nerve fibers were stimulated with a 1-ms current pulse either alone or after a small ramp current lasting 300 ms. RESULTS: Compound C-fiber action potentials elicited by supramaximal 1-ms current pulses were rather resistant to application of tetrodotoxin (30-90 nM). However, the same concentrations of tetrodotoxin strongly reduced the peak height and elevated membrane threshold of action potentials evoked at the end of a 300-ms current ramp. A similar effect was observed during application of lidocaine and mexiletine (50 microM each). CONCLUSIONS: These data indicate that more than one type of Na(v) contributes to the generation of action potentials in unmyelinated human C-type nerve fibers. The peak height of an action potential produced by a short electrical impulse is dependent on the activation of tetrodotoxin-resistant ion channels. In contrast, membrane threshold and action potential peak height at the end of a slow membrane depolarization are regulated by a subtype of Na(v) with high sensitivity to low concentrations of tetrodotoxin, lidocaine, and mexiletine. The electrophysiologic and pharmacologic characteristics may indicate the functional activity of the Na(v) 1.7 subtype of voltage-dependent sodium channels.

Chemosensitivity of unmyelinated axons in isolated human gastric vagus nerve.

Vagal afferent neurons from the stomach may be activated not only by chemical stimuli in the mucosa but also by circulating factors. In the present study, we have used electrophysiological techniques to characterize functional activity of several receptors for chemical mediators on unmyelinated axons in isolated fascicles of human gastric vagus nerve. Application of agonists at the nicotinic acetylcholine receptor (nAChR), 5-HT(3) subtype of serotonin receptor, and the transient receptor potential vanilloid receptor-1 (TRPV1) resulted in a change in the height and/or threshold of the C-fiber compound action potential. These effects were blocked by specific antagonists of nAChR (mecamylamine), 5-HT(3) (Y-25130), and TRPV1 (capsazepine). We conclude that the chemosensitivity of unmyelinated vagal axons can be studied using isolated segments of human gastric vagus nerve. The presence of receptors indicates that circulating factors may modify vagal afferent neurons also by effects on the axonal membrane.

Post-spike excitability indicates changes in membrane potential of isolated C-fibers.

Recording of action potentials from single unmyelinated nerve fibers by microneurography is an important tool to investigate peripheral neural functions in human neuropathies. However, the interpretation of microneurography recordings can be difficult because axonal membrane potential is not revealed by this method. We tested the hypothesis that the recovery cycle of excitability after a single action potential is correlated with changes in the axonal membrane potential. To this end, we used the threshold tracking technique to study how different chemical mediators, with known effects on the membrane potential, influence the post-spike superexcitability of C-fiber compound action potentials in isolated rat sural and vagus nerves. We found that: (1) some chemical mediators (e.g., adenosine 5'-triphosphate) produce a reduction or loss of superexcitability together with increased axonal excitability, indicating membrane depolarization; (2) blockade of axonal hyperpolarization-activated (Ih) currents produces an enhancement of superexcitability together with a decreased excitability, indicating membrane hyperpolarization; and (3) application of calcium produces an increase in membrane threshold without an alteration in superexcitability, indicating a non-specific increase in surface charge and a change in the voltage-dependent activation of sodium channels. In addition, we demonstrated that membrane depolarization and hyperpolarization induce opposite post-spike latency shifts (changes in supernormality) in rat and human nerve segments. Thus, recordings of post-spike excitability and shifts in latency are sensitive techniques for detection of various types of neuromodulation, which are correlated with changes in membrane potential of unmyelinated peripheral axons and may help to understand observations obtained by microneurography in peripheral human neuropathies.

[Adenosine for treatment of ischemic pain in thromboangiitis obliterans. A case report]. / Adenosin zur Behandlung von Ischämieschmerzen bei Thrombangiitis obliterans. Ein Fallbericht.

Treating ischemic pain is often unsatisfactory. Current findings demonstrate that patients with chronic ischemia may develop sensory neuropathy and signs of central sensitization. This issue makes is reasonable treating with conventional analgesics and drugs against neuropathic pain. Adenosine has also a pain reducing effect in neuropathic pain which makes it a possible therapeutic option in ischemic pain.We report of a patient with thromboangiitis obliterans. We treated his pain with a broad analgesic therapy and administered adenosine intravenously, which resulted in a reduction of pain for several hours. Afterwards the patient received buflomedil to increase adenosine plasma levels. A long term pain reduction could be achieved. Modulation of adenosine demonstrates an experimental approach in the therapy of ischemic pain in thromboangiitis obliterans.

Activity-dependent modulation of axonal excitability in unmyelinated peripheral rat nerve fibers by the 5-HT(3) serotonin receptor.

Activity-dependent fluctuations in axonal excitability and changes in interspike intervals modify the conduction of trains of action potentials in unmyelinated peripheral nerve fibers. During inflammation of a nerve trunk, long stretches of axons are exposed to inflammatory mediators such as 5-hydroxytryptamine [5-HT]. In the present study, we have tested the effects of m-chlorophenylbiguanide (mCPBG), an agonist at the 5-HT(3) serotonin receptor, on activity- and potential-dependent variations in membrane threshold and conduction velocity of unmyelinated C-fiber axons of isolated rat sural nerve segments. The increase in axonal excitability during application of mCPBG was much stronger at higher frequencies of action potentials and/or during axonal membrane hyperpolarization. The effects on the postspike recovery cycle also depended on the rate of stimulation. At an action potential frequency of 1 Hz or in hyperpolarized axons, mCPBG produced a loss of superexcitability. In contrast, at 0.33 Hz, a small increase in the postspike subexcitability was observed. Similar effects on excitability changes were found when latency instead of threshold was recorded, but only at higher action potential frequencies: at 1.8 Hz, mCPBG increased conduction velocity and reduced postspike supernormality. The latter effect would increase the interspike interval if pairs of action potentials were conducted along several cm in an inflamed nerve trunk. These data indicate that activation of axonal 5-HT(3) receptors not only enhances membrane excitability but also modulates action potential trains in unmyelinated, including nociceptive, nerve fibers at high impulse rates.

Sensory neuropathy and signs of central sensitization in patients with peripheral arterial disease.

Patients with peripheral arterial disease (PAD) may develop a broad range of peripheral nerve dysfunctions including pain and sensory deficiencies due to chronic ischemia mostly involving the lower limbs. To investigate the degree of sensory abnormalities in such patients quantitative sensory testing (QST) might be a useful tool. Forty-five patients and 20 controls were enrolled in the present study and underwent QST according to the protocol of the German Research Network on Neuropathic Pain. PAD was graded according to the Rutherford classification. PAD patients were divided into two groups: 16 patients with critical limb ischemia (severe PAD) and 29 patients with intermittent claudication (moderate PAD). QST revealed impaired cold and warm detection, increased mechanical and vibration detection thresholds, and increased perceptual wind-up on the affected leg (all p<0.001). Paradoxical heat sensation (p<0.05) and dynamic mechanical allodynia (p<0.01) were also observed. Subgroup analysis of patients without diabetes (control n=20, moderate PAD n=21, severe PAD n=8) confirmed most of these findings. In patients with severe PAD, sensory deficits were more pronounced than in patients with moderate PAD and were detected even in the face. These data indicate that QST can detect sensory abnormalities in PAD patients. While the pattern of decreased perception suggests deafferentation for Abeta-, Adelta-, and C-fiber inputs, the presence of allodynia suggests that central sensitization also plays a role in the pain state of PAD patients. Subgroup analysis points towards a PAD-associated peripheral neuropathy independent of diabetes.

A conus peptide blocks nicotinic receptors of unmyelinated axons in human nerves.

The novel alpha-conotoxin Vc1.1 is a potential analgesic for the treatment of painful neuropathic conditions. In the present study, the effects of Vc1.1 were tested on the nicotine-induced increase in excitability of unmyelinated C-fiber axons in isolated segments of peripheral human nerves. Vc1.1 in concentrations above 0.1 microM antagonized the increase in axonal excitability produced by nicotine; the maximal inhibition was observed with 10 microM. We also demonstrate immunoreactivity for alpha 3 and alpha 5 subunits of neuronal nicotinic receptors on unmyelinated peripheral human axons. Blockade of nicotinic receptors on unmyelinated peripheral nerve fibers may be helpful in painful neuropathies affecting unmyelinated sympathetic and/or sensory axons.