Number Of Chronic Pain Conditions Research Articles

Trends in spinal cord stimulation utilization: change, growth and implications for the future

Chronic pain impacts more than 100 million Americans and has a significant impact on the economy and quality of life. Spinal cord stimulation (SCS) has demonstrated efficacy in managing a...

Relationship Between Opioid Prescriptions and Number of Chronic Pain Conditions in Women With Interstitial Cystitis

(Abstracted from Urogynecology 2022;28:547–553) Up to 8 million women in the United States are affected by interstitial cystitis (IC), which is a chronic condition characterized by coexisting urinary and pelvic pain conditi0ons. Managing the condition frequently proves challenging due to its chronic nature and a lack of effective IC treatments, but several medical organizations (such as the American Urological Association, Canadian Urological Association, the European Association of Urology, and the Royal College of Obstetricians and Gynecologists) have issued guidelines for management.

Relationship Between Opioid Prescriptions and Number of Chronic Pain Conditions in Women With Interstitial Cystitis.

The aim of this study was to determine the relationship between opioid prescriptions and number of chronic pain conditions in women with interstitial cystitis (IC). This was a cross-sectional study. Women diagnosed with IC based on International Classification of Diseases, Ninth Revision/Tenth Revision codes over an 11-year period (2010-2020) were identified from electronic medical records. Data on comorbidities and ambulatory opioid prescriptions were also extracted. Univariable and multivariable logistic regressions were used to assess the relationship between opioid prescriptions and the number and type of coexisting chronic pain conditions. Of the 1,219 women with IC, 207 (17%) had received at least 1 opioid prescription. The proportions of women with opioid prescriptions for no, 1, 2, and 3 or more coexisting chronic pain conditions were 13%, 20%, 28%, and 32%, respectively. On univariable analysis, factors significantly associated with opioid use were higher body mass index ( P < 0.001), depression ( P < 0.001), sleep disorder ( P < 0.001), endometriosis ( P < 0.05), chronic pelvic pain ( P < 0.001), fibromyalgia ( P < 0.05), joint pain ( P < 0.001), and number of coexisting chronic pain diagnoses ( P < 0.001). On multivariable analysis, opioid prescriptions remained significantly associated with the number of coexisting chronic pain diagnoses: 1 diagnosis (adjusted odds ratio [aOR], 1.8; 95% confidence interval [CI], 1.3-2.7), 2 diagnoses (aOR, 2.6; 95% CI, 1.6-4.3), 3 or more diagnoses (aOR, 2.5; 95% CI, 1.1-5.5), diagnosis of chronic pelvic pain (aOR, 2.1; 95% CI, 1.3-3.5), endometriosis (aOR, 2.4; 95% CI, 1.4-4.3), chronic joint pain (aOR, 1.8; 95% CI, 1.1-2.9), and sleep disorders (aOR, 2.4; 95% CI, 1.6-3.6). The likelihood of opioid prescriptions in women with IC increases with the number and type of coexisting chronic pain conditions and sleep disorders.

A Ketogenic Diet Prevents Methylglyoxal-Evoked Nociception by Scavenging Methylglyoxal

Methylglyoxal is a reactive dicarbonyl byproduct of glycolysis that has been implicated in a growing number of chronic pain conditions, including diabetic peripheral neuropathy (DPN). We previously demonstrated the efficacy of a ketogenic diet in reversing sensory symptoms in a rodent model of DPN. The purpose of this study was to determine whether a ketogenic diet modified methylglyoxal-evoked nociception as a potential mechanism of improving sensory symptoms of DPN. We delivered methylglyoxal to C57Bl/6 mice by intraperitoneal or intraplantar injections. Sensory behaviors were quantified for mechanical thresholds as assessed by von Frey filament testing and spontaneous nonreflexive nociceptive behaviors (shaking, biting, lifting, etc. of the injected paw). Intraperitoneal methylglyoxal injection induced lasting mechanical allodynia in standard chow-fed mice, while ketogenic diet-fed mice were protected. Importantly, ketogenic diet-fed mice exhibited significantly decreased methylglyoxylated-protein concentrations following injection relative to standard, chow-fed mice, and methylglyoxylated-protein concentration correlated negatively with blood ketones. A reaction between the ketone body acetoacetate and methylglyoxal was recently demonstrated in vivo as a potential mechanism of methylglyoxal detoxification, consistent with this observation. To assess whether ketone bodies modified methylglyoxal-evoked nociception by direct methylglyoxal detoxification, we incubated methylglyoxal with either β-hydroxybutyrate or acetoacetate overnight prior to intraplantar injection. Mice receiving an injection of methylglyoxal alone exhibited an increase in spontaneous nociceptive behaviors, whereas coincubation of either acetoacetate or β-hydroxybutyrate reduced these behaviors. In summary, a ketogenic diet prevented the onset of methylglyoxal-evoked mechanical allodynia and increased scavenging of circulating methylglyoxal. Ketone bodies were individually capable of detoxifying methylglyoxal to prevent nociception. These findings provide insight to a potential mechanism by which a ketogenic diet improves DPN in mice and provide a rationale for exploring a ketogenic diet as a therapeutic intervention in other chronic pain conditions associated with elevated methylglyoxal. This work was supported by NIH grants RO1 NS043314 (DEW), the Kansas Institutional Development Award (IDeA) P20 GM103418, Kansas University Training Program in Neurological and Rehabilitation Sciences (NIH T32 award) supported by NIH Award Number T32HD057850, and core support from the Kansas IDDRC P30 HD00228. Methylglyoxal is a reactive dicarbonyl byproduct of glycolysis that has been implicated in a growing number of chronic pain conditions, including diabetic peripheral neuropathy (DPN). We previously demonstrated the efficacy of a ketogenic diet in reversing sensory symptoms in a rodent model of DPN. The purpose of this study was to determine whether a ketogenic diet modified methylglyoxal-evoked nociception as a potential mechanism of improving sensory symptoms of DPN. We delivered methylglyoxal to C57Bl/6 mice by intraperitoneal or intraplantar injections. Sensory behaviors were quantified for mechanical thresholds as assessed by von Frey filament testing and spontaneous nonreflexive nociceptive behaviors (shaking, biting, lifting, etc. of the injected paw). Intraperitoneal methylglyoxal injection induced lasting mechanical allodynia in standard chow-fed mice, while ketogenic diet-fed mice were protected. Importantly, ketogenic diet-fed mice exhibited significantly decreased methylglyoxylated-protein concentrations following injection relative to standard, chow-fed mice, and methylglyoxylated-protein concentration correlated negatively with blood ketones. A reaction between the ketone body acetoacetate and methylglyoxal was recently demonstrated in vivo as a potential mechanism of methylglyoxal detoxification, consistent with this observation. To assess whether ketone bodies modified methylglyoxal-evoked nociception by direct methylglyoxal detoxification, we incubated methylglyoxal with either β-hydroxybutyrate or acetoacetate overnight prior to intraplantar injection. Mice receiving an injection of methylglyoxal alone exhibited an increase in spontaneous nociceptive behaviors, whereas coincubation of either acetoacetate or β-hydroxybutyrate reduced these behaviors. In summary, a ketogenic diet prevented the onset of methylglyoxal-evoked mechanical allodynia and increased scavenging of circulating methylglyoxal. Ketone bodies were individually capable of detoxifying methylglyoxal to prevent nociception. These findings provide insight to a potential mechanism by which a ketogenic diet improves DPN in mice and provide a rationale for exploring a ketogenic diet as a therapeutic intervention in other chronic pain conditions associated with elevated methylglyoxal. This work was supported by NIH grants RO1 NS043314 (DEW), the Kansas Institutional Development Award (IDeA) P20 GM103418, Kansas University Training Program in Neurological and Rehabilitation Sciences (NIH T32 award) supported by NIH Award Number T32HD057850, and core support from the Kansas IDDRC P30 HD00228.

Neurotropin alleviates rat osteocarcinoma pain via P2X3 receptor activation in the midbrain periaqueductal gray.

Objective(s):Clinically effective analgesia treatment for patients afflicted with osteocarcinoma lessens the intensity of pain. The midbrain periaqueductal gray (PAG) plays a critical role in pain modulation, and activation of P2X3 receptors in this region mediates pain processing. Neurotropin is a small molecule drug used for analgesic treatment of a number of chronic pain conditions. The present study aims at determining whether P2X3 receptor activation in PAG is responsible for the analgesic effect of neurotropin in rats with osteocarcinoma pain. Materials and Methods:The tibia of female Sprague-Dawley rats was inoculated with breast carcinoma cells to establish the osteocarcinoma pain model. The effects of intraperitoneal injection of 6, 12, and 18 neurotropin units (NU)/kg on pain threshold and receptor expression of P2X3 in the ventrolateral PAG (vlPAG) were assessed. The P2X3 receptor antagonist A-317491 (1.5 nmol/0.3 µl) was administered into vlPAG with a high-dose neurotropin (18 NU/kg) to determine the role of this receptor in the analgesic effect. Results:The pain thresholds of the rats with osteocarcinoma pain continuously decreased, whereas P2X3 receptor expression in vlPAG only slightly increased after osteocarcinoma cell inoculation. Neurotropin substantially elevated the pain threshold and P2X3 receptor expression in vlPAG in a dose-dependent manner. A-317491 microinjection into vlPAG significantly reduced the analgesic effects of neurotropin in the rats with osteocarcinoma pain.Conclusion:Through these findings, it is shown that vlPAG P2X3 receptor activation participates in neurotropin-mediated analgesia mechanism in osteocarcinoma pain.

Perceived Ineffectiveness of Pharmacological Treatments for Dysmenorrhea.

Background: Dysmenorrhea affects most reproductive-aged women. Common dysmenorrhea treatments vary in their effectiveness across individuals. Little is known about factors associated with perceived treatment ineffectiveness. The objectives of this study were to describe the perceived ineffectiveness of common pharmacological treatments for dysmenorrhea and investigate factors associated with perceived treatment ineffectiveness. Materials and Methods: In this cross-sectional study, 678 women with dysmenorrhea (aged 14-42) provided data on perceived treatment ineffectiveness, dysmenorrhea symptom-based phenotypes, demographics, clinical factors, and psychobehavioral characteristics. We used Fisher's exact tests to compare treatment ineffectiveness across three symptom-based phenotypes. We used logistic regressions to explore associations of phenotype, demographic, clinical, and psychobehavioral correlates of perceived treatment ineffectiveness. Results: Percentages perceiving treatments as ineffective were 29.3%-35.6% nonsteroidal anti-inflammatory drugs, 49.9% acetaminophen, and 39.3% combined oral contraceptive pills (OCPs). Factors associated with perceived ineffectiveness varied across treatments and included symptom-based phenotypes, clinical, and psychobehavioral factors. For ibuprofen and acetaminophen, women with severe (vs. mild) pain phenotype and higher number of chronic pain conditions were more likely to perceive the treatments as ineffective. For OCPs, women with severe pain (vs. mild) phenotype, comorbid gynecological condition, less anxiety, and worse depressive symptoms were more likely to perceive the treatment as ineffective. Conclusion: A significant percentage of women reported ineffectiveness of dysmenorrhea treatments. Phenotypes, clinical, and psychobehavioral factors were associated with treatment ineffectiveness. Future research should test if symptom-based phenotypes are associated with treatment effectiveness in clinical trials and investigate other factors that affect dysmenorrhea treatment effectiveness, so treatments can be tailored to individuals.

Effects of neurofeedback in the management of chronic pain: A systematic review and meta-analysis of clinical trials.

Neurofeedback (NFB) provides real-time feedback about neurophysiological signals to patients, thereby encouraging modulation of pain-associated brain activity. This review aims to evaluate the effectiveness and safety of NFB in alleviating pain and pain-associated symptoms in chronic pain patients. MEDLINE, PUBMED, Web of Science and PsycINFO databases were searched using the strategy: ("Neurofeedback" OR "EEG Biofeedback" OR "fMRI Biofeedback") AND ("Pain" or "Chronic Pain"). Clinical trials reporting changes in pain following electroencephalogram (EEG) or functional magnetic resonance imaging (fMRI) NFB in chronic pain patients were included. Only Randomized-controlled trials (RCT), non-randomized controlled trials (NRCT) and case series were included. Effect size was pooled for all RCTs in a meta-analysis. Twenty-one studies were included. Reduction in pain following NFB was reported by one high-quality RCT, five of six low-quality RCT or NRCT and 13 of 14 case-series. Pain reduction reported by studies ranged from 6% to 82%, with 10 studies reporting a clinically significant reduction in pain of >30%. The overall effect size was medium (cohen's d -0.76, 95% confidence interval -1.31 to -0.20). Studies were highly heterogeneous (Q [df=5]=18.46, p=.002, I2 =73%). Improvements in depression, anxiety, fatigue and sleep were also seen in some studies. Common side-effects included headache, nausea and drowsiness. These generally did not lead to withdrawal of therapy except in one study. Neurofeedback is a safe and effective therapy with promising but largely low-quality evidence supporting its use in chronic pain. Further high-quality trials comparing different protocols is warranted to determine the most efficacious way to deliver NFB. Neurofeedback is a novel neuromodulatory approach which can be used to reduce the severity of pain and pain-associated symptoms such as sleep disturbances, mood disturbances, fatigue and anxiety in a number of chronic pain conditions. It has a potential to provide integrative non-pharmacological management for chronic pain patients with pain refractory to pharmacological agents with high side-effect profiles. Further high-quality double-blinded randomized sham-controlled trials are needed in order to fully explore the potential of this therapy.

Primary Motor Cortex Transcranial Direct Current Stimulation Modulates Temporal Summation of the Nociceptive Withdrawal Reflex in Healthy Subjects.

Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has shown efficacy in a number of chronic pain conditions. Despite attempts to dissect the analgesic mechanisms, it is unknown whether M1 tDCS modulates the central integration of spinal nociception. To test this, we investigated the top-down modulation of spinal excitability using temporal summation (TS) of the nociceptive withdrawal reflex (NWR). In this randomized, blinded, cross-over study, eight healthy subjects received electrically evoked TS of the NWR, which was delivered at 5 Hz at a threshold and a suprathreshold (1.1× threshold) to elicit TS resulting in different levels of pain. Subjects were asked to rate their pain after each stimulation. Changes in the TS of the NWR and pain ratings were investigated following 20 minutes of 2-mA anodal tDCS or sham stimulation applied over M1. Baseline recordings showed that TS of the NWR was induced with both threshold and suprathreshold stimulation. Suprathreshold stimulation was also associated with a higher pain intensity rating. After brain stimulation, there was no effect over the lower-intensity TS of the NWR or pain ratings in both the tDCS and sham conditions. However, tDCS reduced TS of the NWR and associated pain ratings following higher-intensity suprathreshold stimulation. These results indicate that M1 tDCS can indirectly modulate the central integration of suprathreshold nociceptive processing in the spinal cord. It is possible that the analgesic efficacy of tDCS is dependent on plasticity induced within pain pathways following repeated, high-intensity stimulation, which may explain the beneficial effects seen in chronic pain patients.

Mexiletine Usage in a Chronic Pain Clinic: Indications, Tolerability, and Side Effects

Intravenous lidocaine has multiple applications in the management of acute and chronic pain. Mexiletine, an oral lidocaine analogue, has been used in a number of chronic pain conditions although its use is not well characterized. To report our experience using mexiletine in a chronic pain population, specifically looking at tolerability, side effects, and EKG changes. Retrospective, cohort study. Three chronic pain clinics within a hospital system in Detroit, MI. All patients who had a mexiletine prescription between August 2015 and August 2016 were queried via the electronic medical record. Each chart was examined for demographics, QTc changes on EKG, length of use, and reasons for stoppage. There were 74 total patients identified in the chronic pain management clinics as receiving at least 1 mexiletine prescription over the 1-year time period. Twice as many women as men received mexiletine prescriptions. Neuropathic pain was the most common primary diagnosis (64%) which included diabetic neuropathy, radiculopathy, and others. Fibromyalgia was the next most common primary diagnosis (28%). A QTc change on the EKG showed a mean decrease of 0.1 ms and median increase of 1.5 ms. At 6 months (180 days), approximately 30% of the patients remained on mexiletine therapy, and 28% remained on the therapy at 1 year (360 days). Median duration of use was 60 days and the mean was 288 days. Neurologic and gastrointestinal side effects were the most commons reason for stoppage. All side effects were mild and resolved with stoppage. After side effects, lack of response, or loss of efficacy, were the next most common reasons for stoppage. Pain relief and outcomes were not specifically examined due to confounding factors including interventional treatments and multiple treatment modalities. This was a retrospective, cohort study limited to our specific clinic population with a relatively high loss to follow-up rate. Mexiletine is rarely a first line option for chronic pain management and is often used when multiple other modalities have failed. By reporting our experience, we hope other clinicians may have more familiarity with the drug's use in a chronic pain practice. It appears reasonably tolerable, may not require frequent EKG monitoring, and can be an appropriate adjunct in the chronic pain population. More research is needed regarding efficacy and dose titration for mexiletine in chronic pain. Chronic pain, mexiletine, IV lidocaine, pain, neuropathic pain, neuropathy, fibromyalgia, QTc, tolerability.

Frequency-dependent top-down modulation of temporal summation by anodal transcranial direct-current stimulation of the primary motor cortex in healthy adults.

Transcranial direct-current stimulation (tDCS) applied over the primary motor cortex has been shown to be effective in the treatment of a number of chronic pain conditions. However, there is a lack of understanding of the top-down analgesic mechanisms involved. In this study, we investigated the effects of tDCS on the facilitation of subjective sensory and pain scores using a transcutaneous electrically evoked measure of temporal summation. In this randomized, blinded, cross-over study healthy subjects received a single stimulus given at 0.9× pain threshold (pTh) over the L5 dermatome on the lateral aspect of the right leg, followed by a train of 5 stimuli given at 0.5, 1, 5 and 20Hz before and after 20min of sham or anodal tDCS (2mA) applied over the primary motor cortex. Ratings of sensation and pain intensity were scored on a visual analogue scale (VAS). Temporal summation leading to pain only occurred at higher frequencies (5 and 20Hz). Sham or real tDCS had no effect over temporal summation evoked at 5Hz; however, there was a significant analgesic effect at 20Hz. Sham or real tDCS had no effect over acute, single stimuli-evoked responses. These results indicate that anodal tDCS applied to the primary motor cortex preferentially modulates temporal summation induced by high-frequency electrical stimulation-induced pain. The inhibitory effects of tDCS appear to be dynamic and dependent on the degree of spinal cord excitability and may explain the higher analgesic efficacy in patients with moderate to severe chronic pain symptoms. The analgesic effects of tDCS are dependent on spinal cord excitability. This work provides insight into top-down modulation during acute pain and temporal summation. This knowledge may explain why tDCS has a higher analgesic efficacy in chronic pain patients.

Adverse Childhood Experiences and Symptoms of Urologic Chronic Pelvic Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study

Adverse Childhood Experiences (ACEs) such as sexual and physical violence, serious illness, and bereavement have been linked to number of chronic pain conditions in adulthood, and specifically to urologic chronic pelvic pain syndrome (UCPPS). We sought to characterize the prevalence of ACEs in UCPPS using a large well-characterized cohort in comparison with a group of healthy controls. We also sought to determine the association of ACE severity with psychological factors known to impact pain and to determine whether ACEs are associated with patterns of improvement or worsening of symptom over a year of naturalistic observation. For longitudinal analyses we used functional clusters identifying broad classes of (a) improved, (b) worsened, and (c) stable groups for genitourinary pain and urinary symptoms. We employed a mediation/path analysis framework to determine whether ACEs influenced 1 year outcomes directly, or indirectly through worse perceptions of physical well-being. ACE severity was elevated in UCPPS (n = 421) participants compared with healthy controls (n = 414; p < .001), and was most strongly associated with factors associated with complex chronic pain, including more diffuse pain, comorbid functional symptoms/syndromes, and worse perceived physical well-being (all p < .001). Finally, worse physical well-being mediated the relationship between ACE severity and less likelihood of painful symptom improvement (OR = .871, p = .007)) and a greater likelihood of painful symptom worsening (OR = 1.249, p = .003) at 1 year. These results confirm the association between ACEs and UCPPS symptoms, and suggest potential targets for therapeutic interventions in UCPPS. NCT01098279.

Spinal Cord Stimulator Implant Infection Rates and Risk Factors: A Multicenter Retrospective Study

Spinal cord stimulation is an evidence-based treatment for a number of chronic pain conditions. While this therapy offers improvement in pain and function it is not without potential complications. These complications include device failure, migration, loss of therapeutic paresthesia, and infection. This article looked to establish a modern infection rate for spinal cord stimulators, assess the impact of known risk factors for surgical site infections and to determine the impact of certain preventative measures on the rate of infection. After institutional review board approval, a multisite, retrospective review was conducted on 2737 unique implants or revisions of SCS systems. Patient demographics, risk factors including diabetes, tobacco use, obesity, revision surgery, trial length, implant location, implant type, surgeon background, prophylactic antibiotic use, utilization of a occlusive dressing, and post-operative antibiotic use were recorded and analyzed. The overall infection rate was 2.45% (n = 67). Diabetes, tobacco use, and obesity did not independently increase the rate of infection. Revision surgeries had a trend toward higher infection rate; however, this did not meet statistical significance. There was no difference in the rate of infection between implants performed by physicians of different base specialties, cylinder leads vs. paddle leads, or between different prophylactic antibiotics. Implants performed at academic centers had a higher rate of infection when compared to implants performed in nonacademic settings. When patients received an occlusive dressing or post-operative antibiotics they had a lower rate of infection. The infection rate (2.45%) reported in this study is lower than the previously reported rates (3-6%) and are on par with other surgical specialties. This study did not show an increased rate of infection for patients that used tobacco, had diabetes or were obese. It's possible that given the low overall infection rate a larger study is needed to establish the true impact of these factors on infection. In addition, this study did not address the impact of poorly controlled diabetes mellitus (elevated hemoglobin A1c) vs. well-controlled diabetes. It can be concluded from this study that utilizing an occlusive dressing over the incision in the post-operative period decreases the rate of infection and should become the standard of care. This study also demonstrated the positive impact of post-operative antibiotics in decreasing the rate of infection. Studies in other surgical specialties have not shown this impact which would suggest that further research is needed.

Surfen is a broad-spectrum calcium channel inhibitor with analgesic properties in mouse models of acute and chronic inflammatory pain.

Multiple voltage-gated calcium channels (VGCCs) contribute to the processing of nociceptive signals in primary afferent fibers. In addition, alteration of calcium channel activity is associated with a number of chronic pain conditions. Therefore, VGCCs have emerged as prime target for the management of either neuropathic or inflammatory pain, and selective calcium channel blockers have been shown to have efficacy in animal models and in the clinic. However, considering that multiple calcium channels contribute pain afferent signaling, broad-spectrum inhibitors of several channel isoforms may offer a net advantage in modulating pain. Here, we have analyzed the ability of the compound surfen to modulate calcium channels, and assessed its analgesic potential. We show that surfen is an equipotent blocker of both low- and high-voltage-activated calcium channels. Furthermore, spinal (intrathecal) delivery of surfen to mice produces sustained analgesia against both acute and chronic pain. Collectively, our data establish surfen as a broad-spectrum calcium channel inhibitor with analgesic potential, and raise the possibility of using surfen-derived compounds for the development of new pain-relieving drugs.

Temporal analysis of pain responders and common adverse events: when do these first appear following treatment with pregabalin.

BackgroundPregabalin is an α2δ ligand indicated in the USA for treatment of a number of chronic pain conditions, including diabetic peripheral neuropathy, postherpetic neuralgia, pain associated with spinal cord injury, and fibromyalgia. A greater understanding of when patients first respond to treatment with pregabalin and when adverse events emerge, or worsen, could aid design of new proof-of-concept studies and help guide treatment of patients.MethodsThis was an analysis of five randomized, placebo-controlled, double-blind trials (between 8 and 16 weeks in duration) of flexible-dose pregabalin (150–600 mg/day). Individual patient data were pooled into three groups by disease condition: diabetic peripheral neuropathy or postherpetic neuralgia (n=514), spinal cord injury (n=356), and fibromyalgia (n=498). Responders were classified as having a ≥30% and/or ≥50% reduction in mean pain score from baseline; once a patient responded, they were not scored subsequently (and were excluded from the responder analysis). The emergence of adverse events at each week was also recorded.ResultsThe majority of the 30% and 50% responders emerged within the first 3–4 weeks with pregabalin, but were more uniformly distributed across the 6 weeks of the analysis with placebo. The majority of common adverse events also emerged within the first 3–4 weeks of pregabalin treatment.ConclusionThese data suggest that the majority of pain responders and common adverse events emerge within 3–4 weeks of treatment with pregabalin. These data could advise new proof-of-concept studies and guide clinical management.

Principles of Electrical Stimulation and Dorsal Column Mapping as it Relates to Spinal Cord Stimulation: An Overview

The last 30 years have witnessed the growth of spinal cord stimulation as a treatment modality for an increasing number of chronic pain conditions. In spite of this growth, one of the greatest criticisms is the lack of concrete evidence for the mechanism of action. With the ever increasing enlightenment with regards to the neurophysiology of pain, and the development of more dynamic neuroimaging techniques, the opportunity to better define the mechanism of action of the spinal cord stimulator will continue to expand. In the interim, clinicians will benefit from the consolidation of the available knowledge that will enhance the effective use of the device. This review serves to provide an overview of the key principles of electrical stimulation and dorsal column mapping as it relates to spinal cord stimulation. We aim at enhancing the understanding regarding the basis for successful placement of leads and manipulation of electrical parameters.

Brain imaging reveals that engagement of descending inhibitory pain pathways in healthy women in a low endogenous estradiol state varies with testosterone

The combined oral contraceptive pill (COCP) has been implicated in the development of a number of chronic pain conditions. Modern COCP formulations produce a low endogenous estradiol, low progesterone environment similar to the early follicular phase of the natural menstrual cycle, with a variable effect on serum androgen levels. We used behavioural measures and functional magnetic resonance imaging to investigate the response to experimental thermal stimuli in healthy women, in both a natural and COCP-induced low endogenous estradiol state, to investigate whether alterations in central pain processing may underlie these observations in COCP users. Although COCP users overall did not require lower temperatures to obtain a fixed pain intensity, alterations in the brain response to these stimuli were observed. In a subgroup of COCP users with significantly reduced serum testosterone, however, lower temperatures were required. Region-of-interest analysis revealed that within key regions of the descending pain inhibitory system, activity in response to noxious stimulation varied with serum testosterone levels in both groups of women. Of particular interest, in COCP users, activity in the rostral ventromedial medulla increased with increasing testosterone and in those women with low testosterone, was significantly reduced compared to controls. These findings suggest that, in a low endogenous estradiol state, testosterone may be a key factor in modulating pain sensitivity via descending pathways. Specifically, failure to engage descending inhibition at the level of the rostral ventromedial medulla may be responsible for the reduction in temperature required by COCP users with low circulating testosterone.

Tetrodotoxin (TTX) as a Therapeutic Agent for Pain

Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured) nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed.

Estrogen effects on pain sensitivity and neuropeptide expression in rat sensory neurons

While a number of chronic pain conditions are much more prevalent in women than men, the role of estrogen in regulating nociception remains unclear. Estrogen receptors (ER) are known to be expressed in various parts of the nociceptive pathway, including in the small-sized primary sensory neurons of the dorsal root ganglion (DRG). This study evaluated the effects of long term estrogen replacement on pain sensitivity and neuropeptide expression in the DRG of female Sprague Dawley rats. The goal was to evaluate whether estrogen modulates nociceptive neuropeptides in the DRG in a manner consistent with its effects on pain sensitivity. Our results show that long term (28 days) ovariectomy (ovx) of adult rats induces a profound thermal and mechanical hyperalgesia of the hindpaw and tail compared to ovariectomized animals that were continuously estrogen-treated (ovx + E). Significant changes in the expression of two neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP), were observed using immunocytochemistry and in situ hybridization (ISH) in the small lumbar DRG neurons which contain ER. CGRP and SP were differentially regulated by estrogen, with SP showing a significant downregulation at both the peptide and mRNA levels while CGRP and its mRNA were increased in the DRG of estrogen-treated animals. We also evaluated the development of mechanical allodynia after partial sciatic nerve injury and found that both ovx and ovx + E animals developed significant allodynia within a week of the partial nerve injury, which continued for at least one month. The estrogen-treated animals showed a partial amelioration of the extent of the allodynia at 2 weeks post injury. Overall, the results suggest that estrogen has significant anti-nociceptive actions that can be directly correlated with changes in expression of two peptides in the small nociceptive ERα expressing neurons of the DRG.

Relationships among alexithymia and pain intensity, pain interference, and vitality in persons with neuromuscular disease: Considering the effect of negative affectivity

Alexithymia, the inability to identify or label emotions, has been shown to be associated with pain in patients with a number of chronic pain conditions. We sought to: (1) replicate this association in samples of persons with chronic pain secondary to neuromuscular disease, (2) extend this finding to other important pain-related measures, and (3) to determine whether relationships among alexithymia and study variables existed after controlling for negative affect. One hundred and twenty-nine individuals with muscular dystrophy and chronic pain were administered measures of alexithymia (Toronto Alexithymia Scale, TAS-20), pain intensity (0–10 NRS), pain interference (Brief Pain Inventory Interference scale), mental health (SF-36 Mental Health scale; as a proxy measure of negative affect) and vitality (SF-36 Vitality scale). Higher TAS scores were associated significantly with higher pain intensity and interference, and less vitality. Although the strengths of these associations were reduced when mental health was used as a control, the associations between the Difficulty Identifying Feelings scale and vitality, and the Externally Oriented Thinking and Total TAS scales and pain intensity remained statistically significant. The findings replicate and extend previous findings concerning the associations between alexithymia and important pain-related variables in a sample of persons with chronic pain and neuromuscular disease. Future research is needed to determine the extent to which the associations are due to (1) a possible causal effect of alexithymia on patient functioning that is mediated via its effects on negative affect or (2) the possibility that alexithymia/outcome relationships reflect response bias caused by general negative affectivity.

Adenine-Based Acyclic Nucleotides as Novel P2X3 Receptor Ligands

A new series of acyclic nucleotides based on the adenine skeleton and bearing in 9-position a phosphorylated four carbon chain has been synthesized. Various substituents were introduced in 2-position of the adenine core. The new compounds were evaluated on rat P2X3 receptors, using patch clamp recording from HEK transfected cells and the full P2X3 agonist alpha,beta-meATP as reference compound. The results suggest that certain acyclic nucleotides, in particular compounds 28 and 29, are endowed with modest partial agonism on P2X3 receptors. This is an interesting property that can depress the function of P2X3 receptors, whose activation is believed to be involved in a number of chronic pain conditions including neuropathic pain and migraine. In fact, the new acyclic nucleotides are able to persistently block (by desensitization) P2X3 receptor activity after a brief, modest activation, yet leaving the ability of sensory neurons to mediate responses to standard painful stimuli via a lower level of signaling.