Area Of Allodynia Research Articles

Remifentanil-induced hyperalgesia in healthy volunteers: a systematic review and meta-analysis of randomized controlled trials.

Recent literature suggests that the withdrawal of remifentanil (RF) infusion can be associated with hyperalgesia in clinical and nonclinical settings. We performed a systematic review and a meta-analysis of randomized controlled trials with cross-over design, to assess the effect of discontinuing RF infusion on pain intensity and areas of hyperalgesia and allodynia in healthy volunteers. Nine studies were included. The intervention treatment consisted in RF infusion that was compared with placebo (saline solution). The primary outcome was pain intensity assessment at 30 ± 15 minutes after RF or placebo discontinuation, assessed by any pain scale and using any quantitative sensory testing. Moreover, postwithdrawal pain scores were compared with baseline scores in each treatment. Secondary outcomes included the areas (% of basal values) of hyperalgesia and allodynia. Subjects during RF treatment reported higher pain scores after discontinuation than during treatment with placebo [standardized mean difference (SMD): 0.50, 95% confidence interval (CI): 0.03-0.97; P = 0.04, I 2 = 71%]. A significant decrease in pain scores, compared with baseline values, was found in the placebo treatment (SMD: -0.87, 95% CI: -1.61 to -0.13; P = 0.02, I 2 = 87%), but not in the RF treatment (SMD: -0.28, 95% CI: -1.18 to 0.62; P = 0.54, I 2 = 91%). The area of hyperalgesia was larger after RF withdrawal (SMD: 0.55; 95% CI: 0.27-0.84; P = 0.001; I 2 = 0%). The area of allodynia did not vary between treatments. These findings suggest that the withdrawal of RF induces a mild but nonclinically relevant degree of hyperalgesia in HVs, likely linked to a reduced pain threshold.

Shrinking of Allodynia Area by Surrounding Acupuncture with Electroacupuncture in Two Cases of Postherpetic Neuralgia: A Case Report

Shrinking of Allodynia Area by Surrounding Acupuncture with Electroacupuncture in Two Cases of Postherpetic Neuralgia: A Case Report

Central Sensitization and Psychological State Distinguishing Complex Regional Pain Syndrome from Other Chronic Limb Pain Conditions: A Cluster Analysis Model.

Complex regional pain syndrome (CRPS) taxonomy has been updated with reported subtypes and is defined as primary pain alongside other chronic limb pain (CLP) conditions. We aimed at identifying CRPS clinical phenotypes that distinguish CRPS from other CLP conditions. Cluster analysis was carried out to classify 61 chronic CRPS and 31 CLP patients based on evoked pain (intensity of hyperalgesia and dynamic allodynia, allodynia area, and after-sensation) and psychological (depression, kinesiophobia, mental distress, and depersonalization) measures. Pro-inflammatory cytokine IL-6 and TNF-α serum levels were measured. Three cluster groups were created: ‘CRPS’ (78.7% CRPS; 6.5% CLP); ‘CLP’ (64.5% CLP; 4.9% CRPS), and ‘Mixed’ (16.4% CRPS; 29% CLP). The groups differed in all measures, predominantly in allodynia and hyperalgesia (p < 0.001, η² > 0.58). ‘CRPS’ demonstrated higher psychological and evoked pain measures vs. ‘CLP’. ‘Mixed’ exhibited similarities to ‘CRPS’ in psychological profile and to ‘CLP’ in evoked pain measures. The serum level of TNF-αwas higher in the ‘CRPS’ vs. ‘CLP’ (p < 0.001) groups. In conclusion, pain hypersensitivity reflecting nociplastic pain mechanisms and psychological state measures created different clinical phenotypes of CRPS and possible CRPS subtypes, which distinguishes them from other CLP conditions, with the pro-inflammatory TNF-α cytokine as an additional potential biomarker.

Evaluation of analgetic properties of etoricoxib and lornoxicam and their effect on central sensitization in chronic low back pain

Introduction. Chronic low back pain is a serious health problem in the world. The phenomena of peripheral and central sensitization play an important role in the transition of acute pain to chronic, as well as in the maintenance of chronic pain. One of the descending inhibitory mechanisms that modulates the perception of pain is conditioned pain modulation. Activation of this mechanism reduces neuronal activity at the level of the dorsal horn of the spinal cord, which leads to a decrease in pain and inhibition of hyperalgesia. For pathogenetic therapy of chronic low back pain drugs from the groups of antidepressants and anticonvulsants are indicated, but in practice, drugs from the group of nonsteroidal anti-inflammatory drugs are more often used. The purpose of the study: to evaluate the analgesic activity of etoricoxib and lornoxicam and their effect on central sensitization in chronic low back pain. Materials and methods. The study included 60men and women with chronic low back pain. Patients were randomly divided into 2 even groups: 1st group — patients who took etoricoxib at a dose of 90 mg orally once a day for 21 days; 2nd group— patients who took lornoxicam at a dose of 8 mg orally twice a day for 21 days. All patients were examined neurologically, painDETECT questionnaire and central sensitization inventory were used, quantitative sensory testing along with conditioned pain modulation test was performed to determine pain thresholds. Results. Etoricoxib and lornoxicam have shown a significant pain reduction on the visual analog scale (VAS), but its dynamics in the etoricoxib group was higher: 7.47 points on the first day and 3.73 points on the 21st day, while in the lornoxicam group dynamics corresponded to 6.80 and 5.10 points, respectively. The number of patients with allodynia compared with the 1st day decreased on the 21st day of treatment from 18 to 4 patients in the etoricoxib group, and from 18 to 15 patients in the lornoxicam group. Dynamics of allodynia area: in the etoricoxib group on 21st day the allodynia area decreased compared to the 1st day from 15.11 to 6 cm2 and in the lornoxicam group— from 17.5 to 9.4 cm2. Dynamics of central sensitization inventory scores on day 21: in the etoricoxib group changes were more significant (decrease from 54.13 to 33.67 points) and corresponded to a mild degree of central sensitization, while in the lornoxicam group it decreased to a moderate level — from 54.80 to 46.00 points. The neuropathic signs in the painDETECT questionnaire were statistically significantly reduced throughout the treatment period in the etoricoxib group, reaching almost a 2-fold decrease on day 21st (from 12.40 on the first day to 6.67), while in the lornoxicam group a significant improvement was observed on day 7th of treatment, and later, on days 14th and 21st, the results almost returned to previous level. On the 14th day of therapy with etoricoxib the pain threshold of the nail area significantly improved after the conditioned pain modulation test, the same was also observed on the 21st day both in the nail and back area. Both improvements were not observed in the lornoxicam group. Conclusions. Etoricoxib and lornoxicam have shown different impact on pain reduction and central sensitization. Etoricoxib has shown better level of pain reduction by VAS, better allodynia and central sensitization questionnaire score reduction after 21 days of treatment compared to baseline. In addition, the use of etoricoxib was accompanied by a decrease in neuropathic signs by the painDETECT questionnaire, as well as an increase in pain thresholds before and after the conditioned pain modulation test.

Pain response to cannabidiol in opioid-induced hyperalgesia, acute nociceptive pain, and allodynia using a model mimicking acute pain in healthy adults in a randomized trial (CANAB II).

Opioids in general and remifentanil in particular can induce hyperalgesia. Preclinical data suggest that cannabidiol might have the capacity to reduce opioid-induced hyperalgesia (OIH). Thus, we investigated the effect of oral cannabidiol on OIH in healthy volunteers using an established pain model. Twenty-four healthy participants were included in this randomized, double-blinded, crossover study and received either a 1600-mg single-dose oral cannabidiol or placebo. Hyperalgesia, allodynia, and pain were induced by intracutaneous electrical stimulation. To provoke OIH, participants recieved an infusion of 0.1 µg/kg/min remifentanil over a time frame of 30 minutes, starting 100 minutes after oral cannabidiol ingestion. The primary outcome was the area of hyperalgesia (in square centimetres) up to 60 minutes after remifentanil administration. The area of allodynia (in square centimetres) and pain (numeric rating scale) were also assessed.Cannabidiol had no significant effect on hyperalgesia, allodynia, or pain at any time point of measurement compared with placebo. The area of hyperalgesia after remifentanil administration significantly increased compared with baseline (17.0 cm 2 [8.1-28.7] vs 25.3 cm 2 [15.1-39.6]; P = 0.013). Mean cannabidiol blood levels were 4.1 ± 3.0 µg/L (mean ± SD) at 130 minutes after ingestion and were 8.2 μg/L ± 6.9 µg/L (mean ± SD) at 200 minutes. Cannabidiol was well tolerated. We conclude that a high single-oral dose of 1600-mg cannabidiol is not effective in reducing OIH. Before excluding an effect of cannabidiol on OIH, research should focus on drug formulations enabling higher cannabidiol concentrations.

Surgical Neuropelveology: Lateral Femoral Cutaneous Nerve Endometriosis. Laparoscopic Resection and Nerve Transplantation

To demonstrate the application of surgical neuroanatomic principles for the diagnosis and treatment of deep infiltrating endometriosis involving the lateral femoral cutaneous nerve. Video demonstration of laparoscopic lateral femoral cutaneous endometriosis resection with nerve transplant. Endometriosis infiltrating somatic nerves is a poorly known condition, which can cause severe neuropathic symptoms [1] and is often unrecognized with a subsequent treatment delay [1]. Intimate knowledge of pelvic neuroanatomy and expertise in minimally invasive surgery are essential to manage this challenging surgical scenario [2-4]. Thirty-six years old patient with primary infertility and chronic pelvic pain associated with dysmenorrhea, dyspareunia, dysuria, and dyschezia. Preoperative magnetic resonance imaging detected a 3-cm parauterine and a 2-cm retrocervical endometriosis nodule. Magnetic resonance imaging did not demonstrate pelvic nerve involvement. Preoperative neuropelveologic assessment demonstrated a significant hypoesthesia of the corresponding lateral femoral cutaneous nerve dermatome, representing the primary complaint. A swab test showed spotting areas of allodynia. These findings prompted us to investigate for a right lateral femoral cutaneous entrapment. Laparoscopy showed an endometriosis nodule infiltrating the right lateral femoral cutaneous nerve. A resection of the nerve was necessary, and a subsequent reconstruction with a collagen bovine neuro-guide was carried out. The operative time was 300 minutes, and the estimated blood loss was 150 mL. Hospital stay was 3 days. After 3 months, the patient showed a clinical improvement in the pain and hypoesthesia on the reconstructed nerve dermatome. Neuropelvic anatomic assessment should be considered during the preoperative evaluation for patients with endometriosis who have pelvic pain and neuropathy as part of the diagnostic process [5]. This unique case demonstrates that nerve resection and transplantation can be used in specific situations for neuropathy related to deep infiltrative endometriosis of pelvic nerves.

The Analgesic and Emotional Response to Intravenous Lidocaine Infusion in the Treatment of Postherpetic Neuralgia: A Randomized, Double-Blinded, Placebo-controlled Study.

This study evaluated the analgesic efficacy and emotional response to intravenous lidocaine infusion compared with placebo in patients with postherpetic neuralgia (PHN). In this randomized, double-blinded study, patients with PHN received 5 mg/kg intravenous lidocaine infusion or placebo. The primary outcome was pain measured by Visual Analogue Scale, Von Frey, and area of allodynia. Moreover, emotional status of anxiety and depression were evaluated by Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS). Quality of life was assessed by Short Form Health Survey 36. In total, 197 patients were enrolled and eligible data were collected from 183 of those patients. The Visual Analogue Scale scores were reduced to a minimum at 2 weeks (2.74, 2.99) after infusion, but no significant difference was found between the lidocaine and placebo groups. Similar changes were also found in mechanical pain threshold and area of allodynia. However, the lidocaine group was associated with a statistically significant reduction in consumption of analgesics with a relative risk of 6.2 (95% confidence interval [CI], 2.24-17.16). Lidocaine infusion also significantly improved the anxiety and depression status; the values of mean change in anxiety and depression were 3.89 (95% CI, 1.43-6.35) and 4.3 (95% CI, 0.63-7.98), respectively, at 2 weeks. Moreover, improvement was exhibited in Short Form Health Survey 36 health status, with the mean change of 49.81 (95% CI, 28.17-71.46) at 1 week, in particular scores on vitality, physical and emotional role functioning, and mental health. The analgesic response of 5 mg/kg lidocaine intravenous infusion is comparable to placebo in patients with PHN, but intravenous lidocaine infusion significantly reduced total analgesic consumption, and improved the overall emotional and health status.

The analgesic effect of intravenous methylprednisolone on acute neuropathic pain with allodynia due to central cord syndrome: a retrospective study.

BackgroundCentral cord syndrome (CCS) may be associated with severe neuropathic pain that often resists to conventional pain therapy regimens and affects the patients’ quality of life (QoL) seriously. Current treatments for CCS-associated neuropathic pain have limited evidence of efficacy. This retrospective study was performed to present the effects of early treatment with methylprednisolone (MP) on acute neuropathic pain relief and the QoL in CCS patients.Patients and methodsData were collected from the medical records of CCS patients who suffered from acute neuropathic pain with allodynia. All the patients received intravenous MP treatment for up to 1 week. Patients were evaluated with standard measures of efficacy: neuropathic pain intensity, the area of allodynia, and the QoL at baseline, daily treatment, and at 1 and 3 months after the end of MP treatment.ResultsThirty-four eligible patients were enrolled in our study. By the end of MP treatment, the proportion of patients who gained total or major (visual analog scale [VAS] score decreased by 50% or more) allodynia relief from the treatment was 91.18%, and a decrease in spontaneous pain was also observed. Moreover, this study showed MP could significantly improve the QoL of patients based on McGill Pain Questionnaire Short Form and EuroQol Five Dimensions Questionnaire. Four patients (11.76%) during MP treatment experienced mild or moderate side effects. None of the patients manifested CCS-associated neuropathic pain recurrence and MP-associated side effects at follow-up.ConclusionThe current results suggested that MP offered an effective therapeutic alternative for relieving CCS-associated acute neuropathic pain with allodynia. Given the encouraging results of this study, it would be worthwhile to confirm these results in randomized placebo-controlled clinical trials.

Somatosensory rehabilitation for allodynia in complex regional pain syndrome of the upper limb: A retrospective cohort study

Study DesignRetrospective cohort study. IntroductionSomatosensory rehabilitation is a standardized method of evaluation and conservative treatment of painful disorders of vibrotactile sensation, including the mechanical allodynia and burning pain of complex regional pain syndrome (CRPS). Purpose of the StudyThe purpose of this study was to examine the effectiveness of somatosensory rehabilitation for reducing allodynia in persons with CRPS of 1 upper limb in a retrospective consecutive cohort of patients. MethodsAn independent chart review of all client records (May 2004-August 2015) in the Somatosensory Rehabilitation Centre (Fribourg, Switzerland) identified 48 persons meeting the Budapest criteria for CRPS of 1 limb who had undergone assessment and treatment. Outcomes of interest were the French version of the McGill Pain Questionnaire (Questionnaire de la Douleur St-Antoine [QDSA]), total area of allodynia as recorded by mapping the area of skin where a 15-g monofilament was perceived as painful, and the allodynia threshold (minimum pressure required to elicit pain within the allodynic territory). ResultsThis cohort was primarily women (70%), with a mean age of 45 years (range: 18-74). Mean duration of burning pain was 31 months (range: 1 week-27.5 years), and baseline QDSA core was 48. The average primary area of allodynia was 66 cm2 (range: 2.6-320), and the most common allodynia threshold was 4.0 g. The average duration of treatment was 81 days. At cessation of treatment, the average QDSA score was 20 (effect size Cohen's d = 1.64). Allodynia completely resolved in 27 persons (56% of the total sample where only 58% completed treatment). DiscussionThis uncontrolled retrospective study suggests that somatosensory rehabilitation may be an effective treatment with a large effect size for reducing the allodynia and painful sensations associated with CRPS of the upper limb. More work is in progress to provide estimates of reliability and validity for the measurement tools for allodynia employed by this method. Level of Evidence2c.

Histaminergic and non-histaminergic elicited itch is attenuated in capsaicin-evoked areas of allodynia and hyperalgesia: A healthy volunteer study.

Chronic pain patients with sensitization may exhibit decreased sensitivity to normally pruritogenic sensory stimuli and moreover occasionally perceive these as painful. This study explored the relationship between itch and pain, by evaluating histaminergic and non-histaminergic itch evoked in capsaicin-induced allodynic and hyperalgesic areas. In 28 healthy volunteers, capsaicin (100μg/0.1mL) was injected intradermally in the volar forearm to establish secondary dysesthesias. After the capsaicin-induced pain subsided, the areas of allodynia and hyperalgesia were mapped and itch was provoked inside these areas by histamine (10mg/mL) and cowhage (25-40 spicules). The evoked itch and pain were recorded on a visual analogue scale (VAS 0-10cm). Contralateral injection of 0.1mL isotonic saline served as a control. Histaminergic and non-histaminergic evoked itch were significantly decreased when provoked in allodynic skin (p<0.05). The area-under-the-curve of the evoked itch was reduced -43% from 18.0±2.6cm10min in normal skin to 10.3±1.8cm10min in allodynic skin (p<0.01) for cowhage and -56% from 20.0±3.5cm10min in normal skin to 8.8±2.3cm10min allodynic skin (p<0.001) for histamine. The pain responses to the pruritogens were not significantly altered between the areas of allodynia and normal skin (p>0.1). An additional experiment showed that pinprick hyperalgesia in the absence of allodynia was sufficient to evoke the observed reduced sensitivity to itch stimuli. Cutaneous sensitization (secondary allodynia and hyperalgesia) reduced itch responses regardless of the type of itch model applied and without attenuation of the associated pruritogen-induced pain responses. This could explain the decreased sensitivity to itch provocations previously observed in patients with chronic pain. This study shows that the neuronal sensitization processes underlying the development secondary hyperalgesia involve significant gating of histaminergic as well as non-histaminergic pruriceptive transmission. Because these itch provocations normally target specific subpopulations of C-nociceptors they could be of relevance for exploratory purposes in pain patients.

Transcutaneous electrical nerve stimulation using an LTP-like repetitive stimulation protocol for patients with upper limb complex regional pain syndrome: A feasibility study

Introduction This feasibility study aimed to (i) develop a clinical protocol using a long-term potentiation-like repetitive stimulation protocol for transcutaneous electrical nerve stimulation in patients with upper limb complex regional pain syndrome and (ii) develop a research protocol for a single-blind randomised controlled trial investigating the efficacy of transcutaneous electrical nerve stimulation for complex regional pain syndrome. Methods This small-scale single-blind feasibility randomised-controlled trial planned to randomise 30 patients with upper limb complex regional pain syndrome to either a variant of transcutaneous electrical nerve stimulation or placebo transcutaneous electrical nerve stimulation for three weeks. Stimulation comprised 20 pulses over 1 s with a non-stimulation interval of 5 s, a so-called repetitive electrical stimulation protocol following the timing of long-term potentiation. Pain, function and body image were measured at baseline, post-treatment and at three months follow-up. At three months, participants were invited to one-to-one interviews, which were analysed thematically. Results A transcutaneous electrical nerve stimulation protocol with electrodes applied proximal to the area of allodynia in the region of the upper arm was developed. Participant concordance with the protocol was high. Recruitment was below target (transcutaneous electrical nerve stimulation (n = 6), placebo (n = 2)). Mean (SD) pain intensity for the transcutaneous electrical nerve stimulation group on a 0 to 10 scale was 7.2 (2.4), 6.6 (2.8) and 7.8 (1.9), at baseline, post-treatment and at three-month follow-up, respectively. Qualitative data suggested that some patients found transcutaneous electrical nerve stimulation beneficial, easy to use and were still using it at three months. Conclusion Patients tolerated transcutaneous electrical nerve stimulation well, and important methodological information to facilitate the design of a large-scale trial was obtained (ISRCTN48768534).

Abstract PR327

Background & Objectives: Worldwide there is extensive morbidity due to musculoskeletal pain. This is problematic in developing countries due to the high cost and access to therapy. Agnikarma is an ancient surgical treatment for pain (1). It involves thermal cauterization (first or second degree burn) delivered precisely to the trigger point in the area of allodynia. Advances in herbal cream for burns has facilitated a revival and re evaluation of this technique. Our objective was to document that the technique can improve pain management for patients. In addition we set out to establish a clinical evidence base that was appropriate to time and place. This environment is not suitable for a randomised trial but holds the potential to make a significant statement on efficacy nonetheless. We set up the global Agnikarma centre - www.globalagnikarma.com to offer the treatment. Materials & Methods: The international consultants (authors) experts in pain medicine and holistic medicine agreed a protocol whereby the same clinical information was collected on every patient at each visit setting up an extensive clinical database. Furthermore an extensive video library of pre and post treatment records was generated. Having learned the technique the presenting author offered the treatment to a specific group of patients in Ireland. These patients all had a diagnosis of chronic pain and had failed all conventional pain management.They all had graduated from a cognitive behavioural pain management programme. 100 patients were invited to visit the web site and self select for treatment. Results: We treated 14173 patients with 39658 procedures as of 21-2-2016 over a two year period. The case mix was 50% knee, 25% lumbar spine, 15% shoulder & neck and 10 % miscellaneous. The average number of treatment sessions is three (range 1-6) to achieve benefit. In Ireland the one year audit data for resistant chronic pain - 51 patients self selected, 25 were deemed suitable and completed 4 sessions. 76% had greater than 50 % pain relief, 80% had improved function, 30 % had improved sleep, 60 % stated that the benefit was still present at the end of the year, 80 % would have the procedure again. Conclusion: We have introduced a novel interventional pain therapy which offers hope to patients suffering from pain as it is simple efficacious and sustained. We have set up a transparent clinical data base complemented by a clinical video library which can be audited by interested parties. We have piloted a sample audit in resistant chronic pain patients where no efficacy would be anticipated in a totally different environment and documented benefit. There is now sufficient proof of concept for a more detailed investigation.

Exploration of the conditioning electrical stimulation frequencies for induction of long-term potentiation-like pain amplification in humans.

Spinal nociceptive long-term potentiation (LTP) can be induced by high- or low-frequency conditioning electrical stimulation (CES) in rodent preparations in vitro. However, there is still sparse information on the effect of different conditioning frequencies inducing LTP-like pain amplification in humans. In this study, we tested two other paradigms aiming to explore the CES frequency effect inducing pain amplification in healthy humans. Cutaneous LTP-like pain amplification induced by three different paradigms (10, 100, and 200Hz CES) was assessed in fifteen volunteers in a crossover design. Perceptual intensity ratings to single electrical stimulation at the conditioned site and to mechanical stimuli (pinprick and light stroking) in the immediate vicinity were recorded; superficial blood flow was also measured. The short form of the McGill Pain Questionnaire (SF-MPQ) was used for characterizing the perception induced by CES. Compared with the control session, pain perception to pinprick stimuli and area of allodynia significantly increased after all three CES paradigms. In the 10 and 200Hz sessions, the superficial blood flow 10min after CES was significantly higher than in the control session reaching a plateau after 20 and 10min, respectively; for the 100Hz paradigm, a stable level was found without significant differences compared with CES and control sessions. 10Hz CES caused a lower SF-MPQ score than 100Hz. High-frequency (200Hz) and low-frequency (10Hz) paradigms can induce heterotopic pain amplification similar to the traditional 100Hz paradigm. The 10Hz paradigm can be an appealing alternative paradigm in future studies due to its specific association with low-level discharging of C-fibers during inflammation.

A randomized, double-blind, crossover study to evaluate the depth response relationship of intradermal capsaicin-induced pain and hyperalgesia in healthy adult volunteers.

The purpose of this study was to evaluate pain and hyperalgesia in response to different depths of intradermal (ID) capsaicin injections in healthy volunteers. Double-blind, cross-over study. Clinical Research Laboratory. Fifteen healthy male subjects received ID capsaicin injections into the volar aspect of each forearm at depths of 1 mm, 3 mm, 5 mm, and 7 mm. After injection, spontaneous pain, elicited pain, flare response, heat thresholds, and area of hyperalgesia were measured at various time points. Spontaneous pain, elicited pain (pinprick, stroking, and hot pain), hyperalgesia area, and allodynia area. No significant difference was found between any depths in spontaneous pain, elicited pain (pinprick, stroking, hot pain), hyperalgesia area, or allodynia area. A significant difference was found in the change in heat threshold between 5 mm and 1 mm, 7 mm and 1 mm, 5 mm and 3 mm, 7 mm and 3 mm depths. A significant difference was found in flare area between 5 mm and 3 mm depths. A significant difference was found in systolic blood pressure area under the curve (AUC) between 7 mm and 1 mm depths, and for both systolic and diastolic pressures for 5 mm and 1 mm depths, and 5 mm and 3 mm depths. A significant difference was found in pulse AUC between 5 mm and 1 mm depths and 5 mm and 3 mm depths. Injection of capsaicin at different depths in the skin had different effects on heart rate and blood pressure but no effect on pain. These results may have implications on the pharmacology and analgesic predictive value of the model of ID capsaicin.

Intradermal Injection with Nerve Growth Factor: A Reproducible Model to Induce Experimental Allodynia and Hyperalgesia.

Nerve growth factor (NGF) plays a pivotal role in survival, growth, and differentiation of the nervous system. Increased levels of NGF have been reported in human pain disorders. Experimental injection of NGF in humans is known to evoke long-lasting mechanical sensitization and subsequent allodynia and hyperalgesia. Reproducibility of intradermal injection of NGF was investigated. Twenty healthy male volunteers were included (mean age 24 years, range 19 to 31). The experiment consisted of 3 identical treatment periods with period 1 stimulating the right arm, period 2 the left arm, and period 3 stimulating the right arm again (period one and three were separated by at least 21 days). Pain intensity was assessed in response to several phasic stimuli in 3 adjacent sites of the volar forearm: pressure; pinprick; brush; and heat before and after NGF injection. Additionally, areas of allodynia and secondary hyperalgesia were assessed. Rekindling with pressure was performed 1 hour and 24 hours after injection. Reproducibility was assessed with intraclass correlation coefficient (ICC 3,1). ICC values > 0.6 for all phasic stimuli and for the area of hyperalgesia. After NGF injection, pressure pain (P < 0.001) and heat pain (P < 0.01) sensitivity increased significantly. After rekindling, the area of hyperalgesia (von Frey 26 g) was significantly increased (P = 0.03) and sensitivity to pinprick was increased (P < 0.02). Intradermal NGF injection is capable of inducing reproducible allodynia and hyperalgesia, and the model is recommended for future experimental and pharmacological pain studies.

The effect of a combination of gabapentin and donepezil in an experimental pain model in healthy volunteers: Results of a randomized controlled trial

This double-blind, placebo-controlled, 3-period cross-over, 4-treatment option, incomplete block study (ClinicalTrials.gov number NCT01485185), with an adaptive design for sample size re-estimation, was designed to evaluate gabapentin plus donepezil in an established experimental model of electrical hyperalgesia. Thirty healthy male subjects aged 18–55years were randomized to receive gabapentin 900mg or gabapentin 900mg+donepezil 5mg for 2 of the 3 treatment periods, with 50% of subjects randomized to receive placebo (negative control) and 50% to gabapentin 1800mg (positive control) for the remaining period. Each treatment period was 14days. Gabapentin or corresponding placebo was administered on Day 13 and the morning of Day 14. Donepezil or corresponding placebo was administered nocturnally from Day 1–13 and the morning of Day 14. Co-primary endpoints were the area of pinprick hyperalgesia (260mN von Frey filament) and allodynia (stroking by cotton bud) evoked by electrical hyperalgesia on Day 14. Gabapentin 1800mg (n=14) significantly reduced the area of allodynia vs placebo (n=14; −12.83cm2; 95% confidence interval [CI] −23.14 to −2.53; P=0.015) with supportive results for hyperalgesia (−14.04cm2; 95% CI −28.49–0.41; P=0.057), validating the electrical hyperalgesia model. Gabapentin+donepezil (n=30) significantly reduced the area of hyperalgesia vs gabapentin 900mg (n=30; −11.73cm2; 95% CI −21.04 to −2.42; P=0.014), with supportive results for allodynia (−6.62cm2; 95% CI −13.29–0.04; P=0.052). The adverse event profile for gabapentin+donepezil was similar to the same dose of gabapentin. Data are supportive of further clinical investigation of a gabapentin-and-donepezil combination in patients with an inadequate response to gabapentin.

Systemic ropivacaine diminishes pain sensitization processes: a randomized, double-blinded, placebo-controlled, crossover study in healthy volunteers.

IntroductionRopivacaine is a local anesthetic widely used for regional anesthesia. One of its advantages is low toxicity at plasma concentrations reached systemically during continuous peripheral or central nervous block. The objective of this study was to test the effect of systemic ropivacaine on pain, hyperalgesia, dynamic allodynia, and flare response.MethodsThis randomized, double-blinded, placebo-controlled, crossover study was carried out in at the Clinical Trials Centre, University of Zurich, Switzerland. Twenty healthy male volunteers were included in the study. Exclusion criteria were contraindications or hypersensitivity to local anesthetics, vulnerable subjects (intellectually or mental impaired), drug, alcohol or nicotine abuse, known peripheral neuropathies, diabetes mellitus and/or congestive heart disease. Ropivacaine and saline were infused intravenously during a subcutaneous electrical stimulation. The stimulation software adjusted the stimulus strength according to the rating on a numeric rating scale (NRS; 0–10) maintaining a NRS of 5. Areas of punctate hyperalgesia, dynamic allodynia, and flare response were measured before and after the infusion.ResultsThe area of hyperalgesia increased significantly with saline (303 ± 380%, P < 0.05) and ropivacaine (186 ± 137%, P < 0.05). The area of allodynia (253 ± 299%, P < 0.05) and flare response (112 ± 24%, P < 0.05) increased only during the placebo infusion.ConclusionThe results of this study imply that systemic ropivacaine may diminish pain sensitization processes.Electronic supplementary materialThe online version of this article (doi:10.1007/s40122-013-0021-z) contains supplementary material, which is available to authorized users.

Evaluation of the effects of a metabotropic glutamate receptor 5‐antagonist on electrically induced pain and central sensitization in healthy human volunteers

This study aimed to investigate the effect of a single dose of the mGluR5-antagonist AZD9272 on electrically induced pain, central sensitization and axon reflex flare. This was a randomized, double-blind, placebo-controlled crossover study. Twenty-five healthy male volunteers received a single oral dose of AZD9272 or placebo on two occasions separated by 10-20 days. Electrical stimulation with a constant current for 100 min delivered through intracutaneous electrodes inserted on the forearm was used to induce a stable level of pain (6 of 10 on a 0-10 numerical rating scale; NRS). Pain intensity was assessed every 10 min during stimulation. The area of punctate hyperalgesia, area of dynamic mechanical allodynia, and area and intensity of flare reaction were measured every 20 min during stimulation. The stimulation procedure, current intensity and measurements were identical at both treatment visits. The AUC0-100 min (area under curve, 100 min stimulation) was calculated for each variable. The AUC0-100 min for pain NRS and hyperalgesia area were defined as primary variables. Linear mixed effects models were used for the statistical analysis. Twenty-one subjects completed the study per protocol. No significant differences were found between AZD9272 and placebo regarding any of the AUC0-100 min variables for pain NRS, hyperalgesia area, allodynia area, flare area or flare intensity. The plasma levels of AZD9272 were maximal during the pain measurements and corresponded to >50% brain mGluR5 receptor occupancy. Single doses of the centrally acting mGluR5-antagonist AZD9272 did not reduce C-fibre evoked pain, central sensitization or flare reaction.

Allodynic skin in post‐herpetic neuralgia: Histological correlates

Most post-herpetic neuralgia (PHN) patients suffer from tactile allodynia (pain evoked by lightly touching the skin) and it is frequently the dominant clinical manifestation. The pathophysiology of tactile allodynia in PHN patients is poorly understood and this is one of the major limits to the development of appropriate therapies. Epidermal nerve fibres (ENFs) are free nerve endings of small-diameter A-delta and C primary afferents, which can easily be assessed by neurodiagnostic skin biopsy (NSB). The aim of this study was to establish the correlation between the residual epidermal innervation of the allodynic skin and the intensity of tactile allodynia in that area. Twenty-five patients (13 males and 12 females) with PHN were enrolled. Eighteen patients had PHN in the thoracic dermatome, four in the cervical, two in the trigeminal and one in the lumbar. The severity of allodynia evoked by a paintbrush was graded according to an eleven-point numerical scale. A skin biopsy was obtained from the maximal allodynia area and from the contralateral skin. Nerve fibres were labelled with indirect immunofluorescence. Results showed that epidermal innervation was lower in the allodynic skin than in the contralateral skin, although there was great variability among patients. There was no correlation between severity of allodynia and epidermal innervation of the PHN skin. In conclusion, the present study further indicates peripheral nervous system involvement in PHN but does not support a direct correlation between epidermal innervation changes and tactile allodynia.

Fluoroscopic Stellate Ganglion Block for Postmastectomy Pain

Stellate ganglion block is usually performed with the classic anterior paratracheal approach. The anatomy of the stellate ganglion being in close proximity to various critical structures renders a number of complications, which are potentially associated with its blockade. The aim of this study was to assess the analgesic efficacy and safety of a new approach of the stellate ganglion block using an oblique fluoroscopic view. Fifty patients with postmastectomy pain syndrome were randomly allocated into 1 of 2 groups: the anterior paratracheal stellate block group and the oblique fluoroscopic stellate block group. Four blocks were performed for each patient using the same approach each time. The results were evaluated in terms of pain intensity as assessed by the visual analog scale score, morphine consumption, and allodynia surface area (in cm). Patient satisfaction score (PSS), skin temperature, side effects, and complications were recorded and compared between the 2 studied groups after each block had been performed. The mean visual analog scale score, daily morphine consumption, and areas of allodynia were significantly decreased and the PSS was significantly increased after each block and for up to 3 months after the last block in both the groups. However, there were no statistically significant differences between the 2 groups at the same study period apart from PSS, which was statistically more significant in group oblique at certain times. The incidences of side effects were significantly more in group classic than in group oblique. The oblique fluoroscopic approach of the stellate ganglion block is as effective as the anterior paratracheal approach but is safer and more satisfactory to the patients.