Secondary Hyperalgesia Research Articles

Evidence of Widespread Mechanical Hyperalgesia but Not Exercise-Induced Analgesia in Athletes With Mild Patellar Tendinopathy Compared With Pain-Free Matched Controls: A Blinded Exploratory Study.

The aim of the study was to assess centrally induced pain processing with pressure pain thresholds bilaterally and remotely in active volleyball and basketball athletes with mild patellar tendinopathy compared with asymptomatic control athletes. Secondary objective was to explore the role of exercise-induced analgesia during a training session in athletes with patellar tendinopathy. In this exploratory study, pressure pain thresholds of 21 patellar tendinopathy athletes and 16 age- and sex-matched asymptomatic team members were measured by a blinded assessor bilaterally on the patellar tendon and unilaterally on the elbow extensor tendon with a pressure algometer before, during, and after a regular training session. Patellar tendinopathy athletes had a significantly higher average body mass index compared with asymptomatic athletes (mean difference 1.75 kg/m2; 95% confidence interval = 0.35-3.15, P = 0.02). At baseline, athletes with patellar tendinopathy showed lowered pressure pain thresholds in the affected knee (P = 0.001), unaffected knee (P < 0.001), and elbow (P = 0.01) compared with controls. No clear patterns were identified to explain between-group differences in pressure pain thresholds before, during, and after exercise. This exploratory study found primary and secondary mechanical hyperalgesia in athletes with patellar tendinopathy compared with asymptomatic athletes. Further research is required on the effects of an acute exercise bout on pain thresholds in this population.

High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.

Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

Corrigendum to: Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

Corrigendum to: Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

The association between selected genetic variants and individual differences in experimental pain.

The underlying mechanisms for individual differences in experimental pain are not fully understood, but genetic susceptibility is hypothesized to explain some of these differences. In the present study we focus on three genetic variants important for modulating experimental pain related to serotonin (SLC6A4 5-HTTLPR/rs25531 A>G), catecholamine (COMT rs4680 Val158Met) and opioid (OPRM1 rs1799971 A118G) signaling. We aimed to investigate associations between each of the selected genetic variants and individual differences in experimental pain. In total 356 subjects (232 low back pain patients and 124 healthy volunteers) were genotyped and assessed with tests of heat pain threshold, pressure pain thresholds, heat pain tolerance, conditioned pain modulation (CPM), offset analgesia, temporal summation and secondary hyperalgesia. Low back pain patients and healthy volunteers did not differ in regards to experimental test results or allelic frequencies, and were therefore analyzed as one group. The associations were tested using analysis of variance and the Kruskal-Wallis test. No significant associations were observed between the genetic variants (SLC6A4 5-HTTLPR/rs25531 A>G, COMT rs4680 Val158Met and OPRM1 rs1799971 A118G) and individual differences in experimental pain (heat pain threshold, pressure pain threshold, heat pain tolerance, CPM, offset analgesia, temporal summation and secondary hyperalgesia). The selected pain-associated genetic variants were not associated with individual differences in experimental pain. Genetic variants well known for playing central roles in pain perception failed to explain individual differences in experimental pain in 356 subjects. The finding is an important contribution to the literature, which often consists of studies with lower sample size and one or few experimental pain assessments.

The Effect of Low-Level Light Therapy on Capsaicin-Induced Peripheral and Central Sensitization in Healthy Volunteers: A Double-Blinded, Randomized, Sham-Controlled Trial.

IntroductionSeveral clinical trials have demonstrated that low-level light therapy (LLLT), a method of photobiomodulation, is an effective analgetic treatment. However, the mechanism of action has not yet been finally clarified. In particular, unanswered questions include whether it only affects peripheral or whether it also affects the spinal or supraspinal level. This study aimed to evaluate the effect of low-level light therapy on primary and secondary hyperalgesia in a human pain model.MethodsThis study was planned as a randomized, sham-controlled, and double-blinded trial with repeated measures within subject design. Capsaicin was applied on both forearms of ten healthy volunteers to induce peripheral and central sensitization. One forearm was treated with low-level light therapy; the other served as sham control.ResultsLow-level light therapy significantly increased the mechanical pain threshold, heat pain threshold, and decreased pain intensity.ConclusionsOur data indicate that low-level light therapy is effective at reducing the heat and mechanical pain threshold in a human pain model, pointing to a significant modulating effect on peripheral and central sensitization. These effects—especially in the absence of reported side effects—make low-level light therapy a promising tool in pain management. The application of low-level light therapy to treat chronic pain should be considered for further clinical trials.

Efficacy of Lidocaine and Ketamine Combination on Reduction of Pain Intensity, Improvement of Functional State and Central Desensitization of Chronic Low Back Pain

Abstract&#x0D; Background: Chronic low back pain (LBP) prevalence is approximately 20% of world population. Central and peripheral sensitization are considered as the main mechanism of pain chronification. This study hypothesize that lidocaine and ketamine combination reduces pain intensity, improves functional state and central desensitization of chronic low back pain. It is by modulating central sensitization in sub-anesthetic dose, prolonging inactivation of Na-channel, blocking NMDA-receptor and preventing secondary hyperalgesia.&#x0D; Aim of study: To evaluate the efficacy of lidocaine and ketamine combination on the intensity of pain, functional state and central desensitization of chronic low back pain.&#x0D; Methods:. This double blind randomized control trial study was carried out in Mohammad Hoesin General Hospital, Palembang, Indonesia from May 2018 to January 2019. A total of 20 patients with low back pain that last for more than 3 months, aged &gt;18 years old, of either sex who were willing to be enrolled in this study, were randomly allocated into one of the two groups of 10 each. The treatment group (n=10) received standardized therapy (analgesic and physiotherapy) + intravenous ketamine 0.5 mg/kg + lidocaine 2 mg/kg and the control group (n=10) received standardized therapy + 100 ml Nacl 0.9%. Pain intensity, functional state, and central desensitization were measured before the treatment, day 7 after treatment, and a month after treatment using Numeric Pain Rating Scale (NPRS), Functional Pain Scale (FPS), and Central Sensitization Inventory (CSI).&#x0D; Results: The administration of ketamine 0.5 mg/kg + lidocaine 2 mg/kg resulted in NPRS and CSI changes was effective since the 7th day post intervention (p-value=0.021 and p-value=0.001) while on FPS changes, it was effective since the 30th day post intervention (p-value=0.000)&#x0D; Conclusion: From the result, it could be concluded that the administration of ketamine and lidocaine is effective on decreasing pain intensity and central desensitization in chronic LBP.

Ketamine — a unique adjuvant drug in pain treatment

Ketamine is an anaesthetic with unique properties. Synthesised for the first time in the early 1960s, it causes dissociative anaesthesia, sedation, amnesia, and analgesia. Due to hallucinogenic effects, the use of the drug was significantly reduced in the 1980s. At present, ketamine is used to treat acute and chronic pain, especially pain resistant to other pain management methods. Ketamine can be effective in the treatment of chronic neuropathic pain syndromes, prevention of secondary hyperalgesia in burn injuries, treatment of muscle pain in patients with fibromyalgia, metastatic bone pain and treatment of pain caused by oral mucositis.

Pain-autonomic interaction: A surrogate marker of central sensitization.

Central sensitization represents a key pathophysiological mechanism underlying the development of neuropathic pain, often manifested clinically as mechanical allodynia and hyperalgesia. Adopting a mechanism-based treatment approach relies highly on the ability to assess the presence of central sensitization. The aim of the study was to investigate potential pain-autonomic readouts to operationalize experimentally induced central sensitization in the area of secondary hyperalgesia. Pinprick evoked potentials (PEPs) and sympathetic skin responses (SSRs) were recorded in 20 healthy individuals. Three blocks of PEP and SSR recordings were performed before and after heat-induced secondary hyperalgesia. All measurements were also performed before and after a control condition. Multivariate analyses were performed using linear mixed-effect regression models to examine the effect of experimentally induced central sensitization on PEP and SSR parameters (i.e. amplitudes, latencies and habituation) and on pinprick pain ratings. The noxious heat stimulation induced robust mechanical hyperalgesia with a significant increase in PEP and SSR amplitudes (p<0.001) in the area of secondary hyperalgesia. Furthermore, PEP and SSR habituation were reduced (p<0.001) after experimentally induced central sensitization. The findings demonstrate that combined recordings of PEPs and SSRs are sensitive to objectify experimentally induced central sensitization and may have a great potential to reveal its presence in clinical pain conditions. Corroborating current pain phenotyping with pain-autonomic markers has the potential to unravel central sensitization along the nociceptive neuraxis and might provide a framework for mechanistically founded therapies. Our findings provide evidence that combined recordings of sympathetic skin responses (SSRs) and pinprick evoked potentials (PEPs) might be able to unmask central sensitization induced through a well-established experimental pain model in healthy individuals. As such, these novel readouts of central sensitization might attain new insights towards complementing clinical pain phenotyping.

Does central sensitization affect hyperalgesia after staged bilateral total knee arthroplasty? A randomized controlled trial.

ObjectiveOsteoarthritis (OA) patients who undergo staged bilateral total knee arthroplasty (TKA) feel postoperative hyperalgesia in the second operated knee compared with the first knee. Ketamine is an important drug for central temporal summation and inhibition of secondary mechanical hyperalgesia. This study investigated whether central sensitization has a significant effect on hyperalgesia after consecutive operations.MethodsSeventy-one of 80 OA patients were randomly allocated to the ketamine or saline group. A bolus of ketamine (group K) or saline (group C) (0.5 mg/kg) was injected before induction and at an infusion rate of 3 µg/kg/minute during surgery. A visual analog scale (VAS) was used to assess resting and moving pain and opioid consumption on postoperative days 1, 2, and 3.ResultsThe difference in the VAS score between stages 1 and 2 (DV2-V1) was higher in the ketamine compared with the saline group. DV2-V1 for movement between the two groups was not inferior for all periods. Ketamine did not show a large analgesic effect on second-operated knee hyperalgesia in staged bilateral TKAs.ConclusionsWe could not confirm that hyperalgesia was only related to central sensitization with low-dose ketamine. Other factors might be also associated with the hyperexcitability of nociceptive stimuli.Clinical Research Information Service (CRIS) trial registry no: KCT0001481

Assessment of the anti-hyperalgesic efficacy of J-2156, relative to clinically available analgesic/adjuvant agents in a rat model of mild to moderate chronic mechanical low back pain (LBP).

Chronic mechanical low back pain (cLBP) is a leading cause of disability and a major socio-economic burden internationally. The lifetime prevalence of non-specific LBP is approximately 84%, with the prevalence of cLBP at about 23%. Clinically available analgesic/adjuvant medications often provide inadequate pain relief in patients experiencing cLBP. Hence, the urgency for discovery of effective and better tolerated medications. Fourteen days after the induction of five shallow annular punctures (5X) in the lumbar intervertebral discs at L4/L5 and L5/L6 in male Sprague-Dawley rats, mechanical hyperalgesia was fully developed in the lumbar axial deep tissues at L4/L5 (primary) and L1 (secondary). Importantly, mechanical allodynia in the hindpaws was absent. From day 28, we assessed the face validity of our mild to moderate LBP-5X rat model using four clinically available analgesic/adjuvant drugs, namely gabapentin, morphine, meloxicam and amitriptyline relative to vehicle. Additionally, the anti-hyperalgesic effects of J-2156, a highly selective small molecule somatostatin type 4 receptor agonist was assessed. Single i.p. bolus doses of gabapentin and meloxicam at the highest doses tested (100 and 30mg/kg, respectively) alleviated secondary hyperalgesia (L1) but not primary hyperalgesia (L4/5). Morphine at 1mg/kg alleviated both primary and secondary hyperalgesia in these tissues, whereas amitriptyline at the doses tested, lacked efficacy. These findings attest to the face validity of our model. J-2156 at 10 and 30mg/kg alleviated secondary hyperalgesia in the lumbar axial deep tissues at L1 with a non-significant trend for relief of primary hyperalgesia in the corresponding tissues at L4/L5 in these animals.

The Effect of Preoperative Pentoxifylline on Postoperative Pain and Development of Secondary Hyperalgesia in Patients Undergoing Laparoscopic Appendectomy: A Randomized, Double-Blind, Placebo-Controlled Trial Study.

After surgery and loss of anesthetic effect, postoperative pain can annoy the patient and affect patient satisfaction with treatment. This study was aimed at evaluating the effect of preoperative pentoxifylline (PTX) on postoperative pain and development of secondary hyperalgesia in patients undergoing laparoscopic appendectomy (LA). This randomized, double-blind, placebo-controlled clinical trial study was conducted on 91 eligible subjects with acute appendicitis referred to Shahid Beheshti hospital of Sabzevar, Iran, in 2018. The intervention and control groups were administered with a single oral dose of PTX (10mg/kg) and placebo an hour before surgery, respectively. Postoperative pain was measured within 24hours after surgery using a VAS, and the area of secondary hyperalgesia was measured 24hours after surgery using the Stubhaug et al. method. The mean age of the subjects was 26.74±9.99 years, and 57.14% were female. Pain intensity during rest was significantly greater in the control group as compared to the PTX group 24 hours after surgery (VAS scores 2.19±0.49 and 3.13±0.66, respectively; P<0.001). Moreover, pain intensity during cough was substantially lower in the PTX group compared with the control group 24 hours after surgery (VAS scores 2.65±1.90 and 4.10±2.60, respectively; P=0.003 in turn). The dynamic hyperalgesia was significantly greater in the control group as compared with the PTX group (3.80±1.82 and 7.43±2.38, respectively; P<0.001). Findings suggest that oral administration of PTX 1 hour before surgery in patients undergoing LA can reduce postoperative pain in patients and prevent secondary hyperalgesia at a surgical site.

Within- and between-session reliability of secondary hyperalgesia induced by electrical high-frequency stimulation.

An increasing number of studies are focusing on secondary hyperalgesia to better understand central sensitization, as this phenomenon may play an important role in persistent pain. Recent studies have shown that, compared to the classical high-frequency stimulation protocol (HFS) at 100Hz, a protocol using 42Hz stimulation induces a more intense and a larger area of secondary hyperalgesia (SH). The aim of this study was to investigate the within- and between-session reliability of SH induced by this optimized HFS protocol. Thirty-two healthy subjects received HFS to their volar forearm in two sessions, separated by at least 2weeks. SH was assessed by measuring the area size of increased sensitivity to pinprick stimuli after applying HFS, the sensitivity to pinprick stimuli after applying HFS and the change in pinprick sensitivity after versus before HFS. Assessments were made before HFS, and 30, 35 and 40min after HFS. Relative and absolute reliability were analysed using intraclass correlation coefficients (ICCs), coefficients of variation (CVs), standard error of means (SEMs) and the minimum detectable changes (MDCs). The area of SH showed good to excellent within-session and between-session relative reliability (ICCs>0.80), except for the change in pinprick sensitivity, which showed close to poor between-session relative reliability (ICC=0.53). Furthermore, measures of absolute reliability generally demonstrated large between-subject variability and significant fluctuations across repeated measurements. HFS-induced hyperalgesia is suitable to discriminate or compare individuals but it may not be sensitive to changes due to an intervention. It is crucial to evaluate central sensitization adequately in humans. This study formally establishes the reliability of secondary hyperalgesia induced by electrical high-frequency stimulation. The results of this study will improve future studies investigating secondary hyperalgesia in humans.

Tyrosine Kinase Inhibitors Reduce NMDA NR1 Subunit Expression, Nuclear Translocation, and Behavioral Pain Measures in Experimental Arthritis.

In the lumbar spinal cord dorsal horn, release of afferent nerve glutamate activates the neurons that relay information about injury pain. Here, we examined the effects of protein tyrosine kinase (PTK) inhibition on NMDA receptor NR1 subunit protein expression and subcellular localization in an acute experimental arthritis model. PTK inhibitors genistein and lavendustin A reduced cellular histological translocation of NMDA NR1 in the spinal cord occurring after the inflammatory insult and the nociceptive behavioral responses to heat. The PTK inhibitors were administered into lumbar spinal cord by microdialysis, and secondary heat hyperalgesia was determined using the Hargreaves test. NMDA NR1 cellular protein expression and nuclear translocation were determined by immunocytochemical localization with light and electron microscopy, as well as with Western blot analysis utilizing both C- and N-terminal antibodies. Genistein and lavendustin A (but not inactive lavendustin B or diadzein) effectively reduced (i) pain related behavior, (ii) NMDA NR1 subunit expression increases in spinal cord, and (iii) the shift of NR1 from a cell membrane to a nuclear localization. Genistein pre-treatment reduced these events that occur in vivo within 4 h after inflammatory insult to the knee joint with kaolin and carrageenan (k/c). Cycloheximide reduced glutamate activated upregulation of NR1 content confirming synthesis of new protein in response to the inflammatory insult. In addition to this in vivo data, genistein or staurosporin inhibited upregulation of NMDA NR1 protein and nuclear translocation in vitro after treatment of human neuroblastoma clonal cell cultures (SH-SY5Y) with glutamate or NMDA (4 h). These studies provide evidence that inflammatory activation of peripheral nerves initiates increase in NMDA NR1 in the spinal cord coincident with development of pain related behaviors through glutamate non-receptor, PTK dependent cascades.

Mechanism of aspirin-induced inhibition on the secondary hyperalgesia in osteoarthritis model rats

AimsThe daily activity of osteoarthritis (OA) patients is limited by chronic pain and central sensitization. Although non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are the first-line drugs for the treatment of OA-related pain, their efficacy on central sensitization remains unclear. In the present study, we evaluated the effect of acetylsalicylic acid (ASA, Aspirin) using an OA model induced by monosodium iodoacetate (MIA), which has a similar disease progression to human OA. Main methodsSecondary hyperalgesia was assessed at the plantar surface of the hind paw by Von Frey test. We evaluated the expression of acid-sensing ion channel 3 (ASIC3) in dorsal root ganglia and that of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the spinal cord, which may cause secondary hyperalgesia in OA, by immunohistochemical analysis and real-time qPCR. Key findingsThe administration of ASA attenuated secondary hyperalgesia at 1–3 weeks after MIA, while celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, failed to attenuate secondary hyperalgesia at week 2 after MIA injection, suggesting that ASA exerts its analgesic effect through a COX-2-independent pathway. Immunohistochemical analysis of the dorsal root ganglia indicated that ASA reduced the expression of ASIC3 during OA progression. Expression of TNF-α mRNA, but not IL-1β mRNA, in the spinal cord following MIA injection was suppressed by ASA administration. SignificanceThese findings suggest that ASA may have the ability to attenuate secondary hyperalgesia through suppression of ASIC3 and/or TNF-α expression. ASA is therefore a clinically useful analgesic drug for treatment of secondary hyperalgesia in OA.

Ablation of TRPV1+ Afferent Terminals by Capsaicin Mediates Long-Lasting Analgesia for Trigeminal Neuropathic Pain.

Trigeminal neuropathic pain (TNP) is often resistant to current pharmacotherapy, and there is a pressing need to develop more efficacious treatments. Capsaicin is a pungent ingredient of chili peppers and specifically activates transient receptor potential vanilloid subtype 1 (TRPV1), a Ca2+-permeable ion channel. Topical capsaicin invariably induces burning pain. Paradoxically, the transient pain is often followed by prolonged attenuation of the preexisting pathologic pain from the same region. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Although the reports of the involvement of TRPV1 and TRPV1+ afferents in neuropathic pain are controversial, we recently demonstrated that TRPV1 and TRPV1+ afferents are involved in mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). Consistently, chemogenetic inhibition of TRPV1-lineage (TRPV1-LN) afferents attenuated mechanical hyperalgesia and ongoing pain. In mice with ION-CCI, we found that a single focal injection of capsaicin into facial skin led to attenuation of mechanical hyperalgesia over two weeks. Capsaicin treatment also attenuated secondary hyperalgesia in extraterritorial mandibular skin. Furthermore, capsaicin treatment decreased ongoing pain. Longitudinal in vivo two-photon imaging of cutaneous nerve fibers showed that such capsaicin-induced analgesia is correlated with cutaneous nerve terminal density. Furthermore, preventing capsaicin-induced ablation of afferent terminals by co-administration of capsaicin with MDL28170, an inhibitor of calpain, abolished capsaicin-induced analgesia. These results suggest that a single focal injection of capsaicin induces long-lasting analgesia for neuropathic pain via selective ablation of TRPV1+ afferent terminals and that TRPV1+ afferents contribute to the maintenance of TNP.

Capsaicin-Induced Changes in Electrical Pain Perception Threshold Can Be Used to Assess the Magnitude of Secondary Hyperalgesia in Humans.

Areas of secondary hyperalgesia can be assessed using quantitative sensory testing (QST). Delivering noxious electrocutaneous stimulation could provide added benefit by allowing multiple measurements of the magnitude of hyperalgesia. We aimed to characterize the use of electrical pain perception (EPP) thresholds alongside QST as a means by which to measure changes in pain thresholds within an area of secondary mechanical hyperalgesia. EPP and heat pain thresholds (HPTs) were measured at five distinct points at baseline and following 1% capsaicin cream application, one within a central zone and four within a secondary zone. Areas of secondary mechanical hyperalgesia were mapped using QST. In a further 14 participants, capsaicin-induced reduction in EPP thresholds was mapped using a radial lines approach across 24 points. There was a reduction in EPP threshold measured at the four points within the secondary zone, which was within the mapped area of mechanical secondary hyperalgesia. The magnitude of secondary hyperalgesia could be split into a mild (∼4% reduction) and severe (∼21% reduction) area within an individual subject. There was no reduction in HPT within the secondary zone, but there was a reduction in both HPT and EPP threshold within the primary zone. EPP mapping revealed differences in the magnitude and spread of hyperalgesia across all subjects. Measuring capsaicin-induced reduction in EPP thresholds can be used to map hyperalgesic areas in humans. This semi-automated approach allows rapid assessment of the magnitude of hyperalgesia, both within an individual subject and across a study population.

Anodal transcranial direct current stimulation over the primary motor cortex attenuates capsaicin-induced dynamic mechanical allodynia and mechanical pain sensitivity in humans.

Anodal transcranial direct current stimulation over the primary cortex has been shown to activate regions of the brain involved in the descending modulation of pain sensitivity. However, more research is required to dissect the spinal cord analgesic mechanisms associated with the development of central sensitization. In this randomized, double blind, crossover study 12 healthy participants had baseline mechanical stimulus response (S/R) functions measured before and after the development of capsaicin-induced ongoing pain sensitivity. The effects of 20min of either real or sham transcranial direct current stimulation (tDCS, 2mA) over the primary motor cortex on dynamic mechanical allodynia (DMA) and mechanical pain sensitivity (MPS) were then investigated. Topical application of capsaicin resulted in an increase in area under the pain ratings curve for both DMA (p<.01) and MPS (p<.01). The effects of tDCS on the area under the curve ratio (i.e. post-/pre-treatment) revealed significant analgesic effects over DMA (p<.05) and MPS (p<.05) when compared with sham. This study demonstrates that anodal tDCS over the primary motor cortex can reduce both dynamic and static forms of mechanical pain sensitivity associated with the development of DMA and MPS, respectively. The use of tDCS may provide a novel mechanism-driven therapy in chronic pain patients with altered mechanical S/R functions. This research shows new evidence that anodal tDCS over the primary motor cortex can reduce dynamic and static forms of mechanical pain sensitivity in the capsaicin model of ongoing pain. By using this approach, it may be possible to provide mechanism-driven analgesia in chronic pain patients who have dynamic mechanical allodynia and/or secondary mechanical hyperalgesia.

GABAergic modulation of secondary hyperalgesia: A randomized controlled 4-way crossover trial with the α2-subunit preferring GABA positive allosteric modulator, N-desmethyl-clobazam in healthy volunteers.

The antihyperalgesic and sedative effects of the α2-subunit preferring GABAA positive allosteric modulator (GAM), N-desmethyl-clobazam (NDMC), 20 and 60mg, were assessed in a randomized, placebo and active-controlled (clonazepam 1,5mg), 4-way crossover study, in healthy volunteers, using the ultraviolet B-induced experimental pain model. Single (20, 40, 60mg) and repeated doses (20mg over 15days) of NDMC pharmacokinetics were evaluated. Thirty-two subjects participated in the study. Primary outcome parameter was maximal change in the area of cutaneous UVB irradiation-induced secondary hyperalgesia (ASH). ASH decreased under all treatments. Mean (SD) relative change was 79 (22)%, 83 (24)%, 77 (30)% and 92 (16)% for placebo, NDMC20, NDMC60 and clonazepam, respectively. Neither absolute change nor relative change in ASH was significantly different between NDMC60 and placebo (mean difference=2.3cm2 [95% CI 4.0-8.5], p=.462 and 0.4% [-11.9 to 12.6], p=.952, respectively). An overall treatment effect was found on level of sedation. Compared to placebo, sedation was higher under clonazepam (mean difference=39mm [30-49] on a visual analogue scale, p<.001) while NDMC was free of sedative effect. NDMC pharmacokinetics after single doses showed poor absorption, but was linear. Steady-state plasma concentrations of NDMC20 were attained within 14days, with low between-subjects variability. Mean steady-state concentration (CS-S , SD) reached 209 (22) ng/ml. NDMC absence of sedative effect and its overall well-characterized safety coming from years of utilization as a metabolite from clobazam, raise the prospect of dose escalating trials in patients to quantify its clinical utility. SIGNIFICANCE: This article, presenting the Phase I data of the new antihyperalgesic compound, α2-subunit GABAA positive allosteric modulator, N-desmethyl-clobazam (NDMC) is exploring the modulation of a new target in the treatment of neuropathic pain. Based on these results and on its preclinical properties NDMC would qualify as a good tool compound to seek confirmation of the clinical utility of selective GABA allosteric modulators in neuropathic pain patients.

Experimenter- and Infrared Thermography-Derived Measures of Capsaicin-Induced Neurogenic Flare Among Non-Hispanic White and Black Adults.

Capsaicin is a widely utilized experimental pain stimulus; however, few studies have reported on ethnic differences in pain responses to capsaicin. The present study used infrared thermography to 1) measure differences in capsaicin-induced neurogenic flare between non-Hispanic black (NHB) and non-Hispanic white (NHW) adults and 2) determine the association between neurogenic flare and secondary hyperalgesia. Fifty-four participants (NHB N = 28) underwent heat/capsaicin sensitization model procedures. Neurogenic flare was examined using experimenter (i.e., subjective) and thermography (i.e., objective) measurements. A typically nonpainful mechanical punctate probe was used to measure secondary hyperalgesia. Ethnic groups did not significantly differ in age, sex, marital status, or personal income. Although experimenters rated a significantly wider area of capsaicin-related neurogenic flare among NHW compared with NHB participants (F1, 52 = 8.33, P = 0.006), thermography results showed no differences between groups in neurogenic flares (F1, 52 = 0.01, P = 0.93). Further, although NHB individuals reported greater average pain during the capsaicin procedures compared with NHW individuals (NHB = 58.57 [3.67], NHW = 46.46 [3.81]; F2, 51 = 5.19, P = 0.03), the groups did not differ in secondary hyperalgesia (F2, 51 = 0.03, P = 0.86), and ethnicity did not moderate the association between neurogenic flare and secondary hyperalgesia (F3, 50 = 0.24, P = 0.87). Findings cautiously support the use of infrared thermography over subjective experimenter report when measuring neurogenic inflammation in diverse samples. However, infrared thermography should not be used as a diagnostic tool for pain, given the lack of association between these factors. Future research is warranted to replicate these findings in a larger and more diverse sample to determine accurate neurogenic inflammation measures across other ethnic minority populations.

Effects of Intramuscular Heating-needle Stimulation in Controlling Adjuvant-induced Muscle Nociception in Rats: Differential Roles of Thalamic Purinergic P2X3 Receptors

Here we investigated effects of intramuscular (i.m.) heating-needle stimulation on persistent muscle nociception evoked by i.m. injection of different doses (50–200 µl) of complete Freund’s adjuvant (CFA) in rats. Paw withdrawal reflexes evoked by noxious mechanical and heat stimulation as well as hind limb swelling were determined prior to and two weeks after the CFA injection. The unilateral injection of CFA induced a dose-related and long-lasting (5–14 d), bilateral secondary mechanical hyperalgesia and heat hypoalgesia associated with long-term limb swelling. A period of 30–45 min 43 °C heating-needle stimulation significantly enhanced the i.m. CFA-induced bilateral heat hypoalgesia and alleviated hind limb swelling. In contrast, 30–45 min 46 °C heating-needle stimulation markedly enhanced both mechanical hyperalgesia and heat hypoalgesia, but failed to influence the CFA-induced hind limb swelling. Microinjection of P2X3 receptor antagonist A-317491 (0.5–4.5 nmol/0.5 µl) into the thalamic ventromedial (VM) nucleus dose-dependently inhibited the 43 °C and 46 °C heating-needle stimulation-induced heat hypoalgesia, whereas the 46 °C heating-needle stimulation-induced mechanical hyperalgesia was significantly prevented by microinjection of A-317491 into the thalamic mediodorsal (MD) nucleus. In contrast, the hind limb swelling was not affected by the microinjection of A-317491 into the thalamic VM or MD nucleus. The present study indicates that in the CFA-induced persistent muscle nociception condition, 43 °C heating-needle stimulation selectively increases descending inhibition, which effect is modulated by the thalamic VM nucleus. In addition to the antinociceptive role of P2X3 receptors in the thalamic VM nucleus, P2X3 receptors within the thalamic MD nucleus participate in the descending facilitation evoked by i.m. 46 °C heating-needle stimulation.