Effect of exercise on chronic neck pain and central sensitization: A protocol for a randomized crossover trial.

Exercise-induced hypoalgesia (EIH) has been found to vary widely within individuals with chronic neck pain (NP). Research has suggested that the presence of central sensitization within a subgroup of individuals with chronic NP might be a mediating factor to explain the relationship between exercise and improvements in patient-reported outcomes. Furthermore, recent work has found that lactate might play a role in the development and maintenance of chronic pain. The immediate effect of a single bout of physical exercise on central sensitization in individuals with chronic NP and the relationship between lactate concentration, central sensitization and pain sensitivity are to be investigated. Eighty adult participants with chronic NP will be recruited for this randomized crossover trial. Outcome measures, including temporal summation, conditioned pain modulation, EIH and lactate concentration, will be assessed before and after low- and high-intensity bicycling exercise. The outcomes of this study will provide new insights into the mechanistic effect of exercise on central sensitization in individuals with chronic NP and have the potential to add important information to the current exercise prescription guidelines for individuals with chronic NP. This study has been approved by the Human Research Ethics Committee, The University of Adelaide (H-2022-082) and registered in the Australian New Zealand Clinical Trials Registry (ACTRN12622000642785p).

Phase I trial of Lipovaxin-MM, a novel dendritic cell-targeted liposomal vaccine for malignant melanoma.

INTRODUCTION: In this phase I study using a 3 + 3 dose escalation design, the safety, dose-limiting toxicity (DLT), immunogenicity and efficacy of intravenous Lipovaxin-MM-a multi-component dendritic cell-targeted liposomal vaccine against metastatic melanoma-was investigated. METHODS: Twelve subjects with metastatic cutaneous melanoma were recruited in three cohorts. Patients in Cohort A (n = 3) and Cohort B (n = 3) received three doses of 0.1 and 1 mL of Lipovaxin-MM, respectively, every 4 weeks. Patients in Cohort C (n = 6) received four doses of 3 mL vaccine weekly. Immunologic assessments of peripheral blood were made at regular intervals and included leukocyte subsets, cytokine levels, and Lipovaxin-MM-specific T-cell and antibody reactivities. Tumor responses were assessed by RECIST v1.0 at screening, then 8 weekly in Cohorts A and B and 6 weekly in Cohort C. RESULTS: Of a total of 94 adverse events (AEs) reported in ten subjects, 43 AEs in six subjects were considered to be possibly or probably vaccine-related. Most (95%) vaccine-related AEs were grade 1 or 2, two (5%) grade 3 vaccine-related AEs of anemia and lethargy were recorded, and higher grade AEs and DLTs were not observed. No consistent evidence of vaccine-specific humoral or cellular immune responses was found in post-immunization blood samples. One patient had a partial response, two patients had stable disease, and the remaining patients had progressive disease. CONCLUSIONS: Lipovaxin-MM was well tolerated and without clinically significant toxicity. Immunogenicity of Lipovaxin-MM was not detected. Partial response and stable disease were observed in one and two patients, respectively.

Glial Attenuation With Ibudilast in the Treatment of Medication Overuse Headache: A Double-Blind, Randomized, Placebo-Controlled Pilot Trial of Efficacy and Safety.

BACKGROUND: Medication overuse headache (MOH) is a condition bordering between a chronic pain condition and a substance dependence disorder. Activation of immunocompetent glial cells in the central nervous system has been linked to both pathological pain and drug addiction/reward. Preclinically, ibudilast attenuates glial activation and is able to reduce neuropathic pain and markers of substance dependence. We therefore hypothesized ibudilast would reduce headache burden and opioid analgesic requirements in patients with opioid overuse headache. OBJECTIVE: To determine if treatment with ibudilast provides a greater reduction in headache index than placebo in MOH patients consuming opioids. METHODS: Participants with MOH who were using opioids were randomized via computer-generated code to ibudilast 40 mg or placebo twice daily for 8 weeks in a double-blind, parallel groups study. Before randomization participants completed a 4-week baseline headache diary. During treatment, headache diary data collection continued and participants attended 4 study visits during which quantitative sensory testing was performed. Blood samples for immune biomarker analyses were collected before and after treatment in a subgroup of participants. RESULTS: Thirty-four participants were randomized, 13 of 15 randomized to ibudilast and 17 of 19 randomized to placebo completed treatment. Ibudilast was generally well-tolerated with mild, transient nausea reported as the most common adverse event (66.7% vs 10.5% in placebo group). Results are shown as mean (SD). At the end of treatment no differences in the primary outcome average daily headache index (placebo 62 [44] vs ibudilast 77 [72] groups, difference -15, CI -65 to 35 h × numerical rating scale), or secondary outcomes headache frequency (placebo 23 [8.1] vs ibudilast 24.5 [6.2], difference -1.5, CI -7.7 to 4.8 days/month) and opioid intake (placebo 20.6 [43] vs ibudilast 19 [24.3], difference 1.6, CI -31.5 to 34.8 mg morphine equivalent) were observed between placebo and ibudilast groups. CONCLUSIONS: Using the current dosing regimen, ibudilast does not improve headache or reduce opioid use in patients with MOH without mandated opioid withdrawal. However, it would be of interest to determine in future trials if ibudilast is able to improve ease of withdrawal during a forced opioid down-titration when incorporated into an MOH detoxification program.

The absolute bioavailability of racemic ketamine from a novel sublingual formulation.

AIM: The principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability. METHODS: The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg intravenous dose as a constant rate 30 min infusion or a 25mg sublingual dose of ketamine wafer in two treatment periods with a 7 day wash out. Pharmacokinetic blood sampling and local tolerability and safety assessments were carried out during 24 h following both dosing occasions. Plasma concentrations were analyzed by non-compartmental methods and local tolerability was assessed using modified Likert scales. RESULTS: The median (90% CI lower, upper limit) absolute bioavailability of sublingual ketamine was 29% (27, 31%). The first quantifiable plasma ketamine concentration was observed within 5 min for all eight participants for both routes of administration and the median (min­max) time of the peak plasma concentration was 0.75 h (0.25­1.0 h) after sublingual administration. The ketamine wafer had very good local tolerability. CONCLUSION: Sublingual administration of the ketamine wafer resulted in rapid absorption. The ketamine wafer has comparable bioavailability with other oral transmucosal formulations of ketamine but with markedly reduced inter-subject variability, warranting further evaluation as an analgesic adjunct.

Reduced response to the thermal grill illusion in chronic pain patients.

OBJECTIVE: Sensory illusions may reveal fundamental features of the nervous system. The thermal grill illusion is such a pain illusion, where interlaced warm and cool temperature bars (thermal grill) produce a paradoxical burning sensation. Previous studies have only systematically investigated the thermal grill illusion in pain-free volunteers. The objective of this study was to investigate whether the response to the thermal grill illusion was tolerable in patients with chronic pain and whether the response differed between patients with chronic pain and pain-free volunteers. SUBJECTS: Sixteen pain-free participants and 18 chronic pain patients (seven not receiving opioids and 11 receiving opioids). METHODS: The thermal grill response was investigated using a custom-built thermal grill. Heat and cold pain thresholds were also determined. RESULTS: Chronic pain patients reported less intense pain, heat, and unpleasantness to the thermal grill compared with pain-free participants; in particular, there was an overall main effect for significantly less heat from the thermal grill compared with pain-free participants (P = 0.016). At the 22/38°C combination, although the majority of pain-free participants experienced the illusion to some degree, the majority of pain patients in both groups did not (median pain score 0). Although perceived heat from the thermal grill was significantly lower in chronic pain patients, both heat and cold pain thresholds did not differ among the three populations. CONCLUSIONS: This preliminary data suggest that the thermal grill response may provide insights into pain sensitivity that are not detected by conventional thermal quantitative sensory testing.

Exercise-induced changes in central sensitization outcomes in individuals with chronic musculoskeletal pain: A systematic review with meta-analysis.

BACKGROUND AND OBJECTIVE: Temporal summation of pain (TSP) and conditioned pain modulation (CPM) are the two most commonly used clinical measures of central sensitization (CS). However, the effectiveness of exercise on TSP and CPM has yet to be evaluated. This review aims to investigate the effect of exercise alone on CS outcomes in individuals with chronic musculoskeletal pain. DATABASES AND DATA TREATMENT: This is a systematic review and meta-analysis. MEDLINE, EMBASE, CINAHL, PEDro and Cochrane databases were searched. Data were extracted based on the exercise modality and grouped into aerobic, resistance, isometric, or motor control modalities. Risk of bias was assessed using RoB2, RoB2 for crossover trials and ROBINS-I tools. Quality of evidence was assessed using GRADE. Random-effects meta-analyses were conducted, with subgroup analysis conducted for each exercise modality. RESULTS: The meta-analyses included thirteen studies, consisting of eight non-randomized studies, three randomized controlled trials and three randomized crossover trials. Data were categorized into four subgroups for analyses based on exercise modality. No statistically significant effect existed for both TSP and conditioned pain modulation. However, motor control exercise was found to have a significant enhancing effect on conditioned pain modulation. No significant differences were found between the exercise subgroup for both TSP and conditioned pain modulation. CONCLUSIONS: We did not find an overall effect of physical exercise on TSP and CPM. However, subgroup analysis shows favourable effects of motor control exercise in individuals with chronic neck pain. Future research should focus on exercise modality and dosage and their role in the mechanism involved in TSP and CPM in predefined populations. SIGNIFICANCE STATEMENT: Results from this study found that motor control exercise has a significant enhancing effect on conditioned pain modulation, with subgroup analysis showing favourable effects of motor control exercise in individuals with chronic neck pain. This indicates that physical exercise may have a positive effect on central sensitisation in individual with chronic neck pain. However, differential effects may exist between different types of exercise. These findings will inform understanding of neurobiological effects underlying chronic neck pain and may guide the development of more effective, personalised treatments.

Low-dose endotoxin potentiates capsaicin-induced pain in man: evidence for a pain neuroimmune connection.

Despite the wealth of evidence in animals that immune activation has a key role in the development and maintenance of chronic pain, evidence to support this in humans is scant. We have sought such evidence by examining the effect of a subtle immunological stimulus, low dose intravenous endotoxin, on the allodynia, hyperalgesia, flare and pain produced by intradermal capsaicin in healthy volunteers. Here we provide evidence of immune priming of this neuropathic-like pain response in humans. Specifically, in 12 healthy volunteers, activation of Toll-Like Receptor 4 by endotoxin (0.4ng/kg IV) caused significant 5.1-fold increase in the 90-min integral of areas of capsaicin-induced allodynia (95% CI 1.3-9.1), 2.2-fold increase in flare (95% CI 1.9-2.6) and 1.8-fold increase in hyperalgesia (95% CI 1.1-2.5) following 50µg intradermal capsaicin injected into the forearm 3.5h after endotoxin. These data demonstrate clinically a significant role for the neuroimmune pain connection in modifying pain, thus providing evidence that immune priming may produce pain enhancement in humans and hence offer a novel range of pharmacological targets for anti-allodynics and/or analgesics. Additionally, the simplicity of the model makes it suitable as a test-bed for novel immune-targeted pain therapeutics.

Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment.

INTRODUCTION: Patients with chronic headache who consume large amounts of analgesics are often encountered in clinical practice. Excessive intake of analgesics is now considered to be a cause, rather than simply a consequence, of frequent headaches, and as such the diagnosis "medication-overuse headache" (MOH) has been formulated. Despite the prevalence and clinical impact of MOH, the pathophysiology behind this disorder remains unclear and specific mechanism-based treatment options are lacking. DISCUSSION: Although most acute headache treatments have been alleged to cause MOH, here we conclude from the literature that opioids are a particularly problematic drug class consistently associated with worsening headache. MOH may not be a single entity, as each class of drug implicated may cause MOH via a different mechanism. Recent evidence indicates that chronic opioid administration may exacerbate pain in the long term by activating toll-like receptor-4 on glial cells, resulting in a pro-inflammatory state that manifests clinically as increased pain. Thus, from the available evidence it seems opioid-overuse headache is a phenomenon similar to opioid-induced hyperalgesia, which derives from a cumulative interaction between central sensitisation, due to repeated activation of nociceptive pathways by recurrent headaches, and pain facilitation due to glial activation. CONCLUSION: Treatment strategies directed at inhibiting glial activation may be of benefit alongside medication withdrawal in the management of MOH.

Chronic tension-type headache is associated with impaired motor learning.

BACKGROUND: Supraspinal activity-dependent neuroplasticity may be important in the transition from acute to chronic pain. We examined neuroplasticity in a cortical region not considered to be a primary component of the central pain matrix in chronic tension-type headache (CTTH) patients. We hypothesised that neuroplasticity would be exaggerated in CTTH patients compared to healthy controls, which might explain (in part) the development of chronic pain in these individuals. METHODS: Neuroplasticity was examined following a ballistic motor training task in CTTH patients and control subjects (CS). Changes in peak acceleration (motor learning) and motor-evoked potential (MEP) amplitude evoked by single-pulse transcranial magnetic stimulation were compared. RESULTS: CTTH patients showed significantly less motor learning on the training task than CS (mean acceleration increase 87% CTTH, 204% CS, P < .05), and CS but not CTTH patients showed a significant increased MEP amplitude following training (CS: F = 2.9, P < .05; CTTH: F = 1.6, P > .05). CONCLUSIONS: These findings suggest a deficit in use-dependent neuroplasticity within networks responsible for task performance in CTTH patients which might reflect reciprocal influences between primary motor cortex and interconnected pain processing networks. These findings may help explain the positive effects of facilitatory non-invasive brain stimulation targeting motor areas on chronic pain and help elucidate the mechanisms mediating chronic pain.

The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype.

AIMS: 1) To determine the pharmacokinetics and pharmacodynamics of (R)- and (S)-warfarin given alone and in combination and 2) to determine whether the relative potency of (R)- and (S)-warfarin is dependent on VKORC1 genotype. METHODS: A three way crossover study was conducted in which 17 healthy male subjects stratified by VKORC1 1173 C>T genotype and all CYP2C9 1*/1* received (R)-warfarin 80 mg, (S)-warfarin 12.5 mg and rac-warfarin sodium 25 mg. Plasma (R)- and (S)-warfarin unbound and total concentrations and prothrombin time were determined at multiple time points to 168 h. RESULTS: Pharmacokinetic parameters for (R)- and (S)-warfarin were similar to the literature. (R)-warfarin 80 mg alone resulted in a mean AUC(PT) (0,168 h) of 3550 s h (95% CI 3220, 3880). Rac-warfarin sodium 25 mg containing (S)-warfarin 11.7 mg produced a greater effect on AUC(PT) (0,168 h) than (S)-warfarin 12.5 mg (mean difference 250 s.h, 95% CI 110, 380, P < 0.002) given alone. In a mixed effects model the ratio of response between (R)- and (S)-warfarin (AUC(PT((R)-warfarin)) : AUC(PT((S)-warfarin))) was 1.21 fold higher (95% CI 1.05, 1.41, P < 0.02) in subjects of VKORC1 TT genotype compared with the CC genotype. CONCLUSIONS: (R)-warfarin has a clear PD effect and contributes to the hypoprothrombinaemic effect of rac-warfarin. VKORC1 genotype is a covariate of the relative R/S potency relationship. Prediction of drug interactions with warfarin needs to consider effects on (R)-warfarin PK and VKORC1 genotype.

Harnessing pain heterogeneity and RNA transcriptome to identify blood-based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury model.

A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats, by integrating graded chronic constriction injury (CCI), ipsilateral lumbar dorsal quadrant (iLDQ) and whole blood transcriptomes, and pathway analysis with pain behavior. Correlational bioinformatics identified a range of putative biomarker genes for allodynia intensity, many encoding for proteins with a recognized role in immune/nociceptive mechanisms. A selection of these genes was validated in a separate replication study. Pathway analysis of the iLDQ transcriptome identified Fcγ and Fcε signaling pathways, among others. This study is the first to employ the whole blood transcriptome to identify pain biomarker panels. The novel correlational bioinformatics, developed here, selected such putative biomarkers based on a correlation with pain behavior and formation of signaling pathways with iLDQ genes. Future studies may demonstrate the predictive ability of these biomarker genes across other models and additional variables.

Intradermal capsaicin as a neuropathic pain model in patients with unilateral sciatica.

AIM: This study compared the responses between patients with unilateral sciatica and pain-free volunteers following administration of intradermal capsaicin. METHODS Fourteen patients with unilateral sciatica and 12 pain-free volunteers received one injection per hour over 4 h of 1 µg and 10 µg capsaicin, into each calf. For each dose, spontaneous pain (10 cm VAS), area of flare (cm²) and the sum of allodynia and hyperalgesia radii across eight axes (cm) were recorded pre-injection and at 5, 15, 30, 45 and 60 min post injection. RESULTS: Sciatica subjects experienced higher spontaneous pain and hyperalgesia responses in both legs compared with pain-free volunteers. The largest mean difference in spontaneous pain was 2.8 cm (95% CI 1.6, 3.9) at 5 min in the unaffected leg following 10 µg. The largest mean difference in hyperalgesia was 19.7 cm (95% CI 12.4, 27.0) at 60 min in the unaffected leg following 10 µg. Allodynia was greater in patients than in controls with the largest mean difference of 2.9 cm (95% CI 1, 4.8) at 5 min following 10 µg in the affected leg. Allodynia was also higher in the affected leg compared with the unaffected leg in sciatica patients with the highest mean difference of 3.0 cm (95% CI 1.2, 4.7) at 5 min following 10 µg. CONCLUSIONS: The responses to intradermal capsaicin are quantitatively and qualitatively different in unilateral sciatica patients compared with pain-free controls.

Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain.

Recent evidence implicates an adaptive immune response in the central nervous system (CNS) mechanisms of neuropathic pain. This review identifies how neuropathic pain alters CNS immune privilege to facilitate T cell infiltration. Once in the CNS, T cells may interact with the local antigen presenting cells, microglia, via the major histocompatibility complex and the costimulatory molecules CD40 and B7. In this way, T cells may contribute to the maintenance of neuropathic pain through pro-inflammatory interactions with microglia and by facilitating the activation of astrocytes in the spinal dorsal horn. Based on the evidence presented in this review, we suggest that this bidirectional, pro-inflammatory system of neurons, glia and T cells in neuropathic pain should be renamed the pentapartite synapse, and identifies the latest member as a potential disease-modifying therapeutic target.

Adoptive transfer of peripheral immune cells potentiates allodynia in a graded chronic constriction injury model of neuropathic pain.

Recent evidence demonstrates that peripheral immune cells contribute to the nociceptive hypersensitivity associated with neuropathic pain by infiltrating the central nervous system (CNS). We have recently developed a rat model of graded chronic constriction injury (CCI) by varying the exposure of the sciatic nerve and control non-nerve tissue to surgical placement of chromic gut. We demonstrate that splenocytes can contribute significantly to CCI-induced allodynia, as adoptive transfer of these cells from high pain donors to low pain recipients potentiates allodynia (P<0.001). The phenomenon was replicated with peripheral blood mononuclear cells (P<0.001). Adoptive transfer of allodynia was not achieved in sham recipients, indicating that peripheral immune cells are only capable of potentiating existing allodynia, rather than establishing allodynia. As adoptively transferred cells were found by flow cytometry to migrate to the spleen (P<0.05) and potentiation of allodynia was prevented in splenectomised low pain recipients, adoptive transfer of high pain splenocytes may induce the migration of host-derived immune cells from the spleen to the CNS as observed by flow cytometry (P<0.05). Importantly, intrathecal transfer of CD45(+) cells prepared from spinal cords of high pain donors into low pain recipients led to potentiated allodynia (P<0.001), confirming that infiltrating immune cells are not passive bystanders, but actively contribute to nociceptive hypersensitivity in the lumbar spinal cord.

Androgens, Endometriosis and Pain.

The intriguing relationship between androgens, endometriosis and chronic pain continues to unfold. Determining this relationship is of crucial importance to gynecologists managing people with these conditions, as common treatments dramatically alter her hormonal profiles, with both intended and unintended consequences. Although they may be present in the same individual, there is a recognized disconnect between pain or pain-related symptoms, and the presence or extent of endometriosis lesions. Reduced androgen levels provide a potential mechanism to link the development of endometriosis lesions and the presence of chronic pain. This research paper expands the presentation of our research at the World Endometriosis Congress in 2021, subsequently published in the Journal of Pain Research which demonstrated a strong inverse relationship between androgen levels and days per month of pelvic and period pain. Here we extend and further explore the evidence for a role for androgens in the etiology and management of dysmenorrhea and pelvic pain in women, both with and without endometriosis. We explore the potential for inflammation to induce low androgen levels and consider ways in which clinicians can optimize levels of androgens when treating women with these conditions. This article prompts the question: Is it estrogens that predispose people to a life of pain, or androgens that are protective?

The Relationship Between Androgens and Days per Month of Period Pain, Pelvic Pain, Headache, and TLR4 Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhoea.

PURPOSE: Women bear a disproportionate burden of persistent pain conditions when compared to men. To determine whether the hormonal environment affects the clinical experience of pain, as measured by the days per month of pelvic pain (DPelvicPM), period pain (DPeriodPM), headache (DHeadachePM) or the in vitro EC50 for Interleukin-1ß (IL-1ß) release following TLR4 stimulation with Lipopolysaccharide from Peripheral Blood Mononuclear Cells (PBMCs). Findings were stratified according to use or non-use of the oral contraceptive pill. PATIENTS AND METHODS: Fifty-six women aged 16-35 years, with minimal or severe dysmenorrhea, and use or non-use of the OC, were enrolled. Blood was collected on two occasions in a single menstrual cycle: Days 1-2 and Days 7-10. Hormonal analysis for testosterone, dihydrotestosterone, dehydroepiandrosterone, Androstenedione, 3α-Androstanediol, 3ß-androstanediol, estradiol, estrone, 17α-hydroxyprogesterone, progesterone, cortisol and sex-hormone binding globulin was undertaken using ultra-sensitive Liquid Chromatography Mass-Spectrometry (LC-MS). PBMCs were exposed to lipopolysaccharide (LPS) and the resulting Interleukin-1ß output was determined. RESULTS: Non-users of the OC showed a strongly inverse correlation between a reducing free androgen index (FAI) and increasing DPelvicPM (p=0.0032), DPeriodPM (p=0.013), DHeadachePM (p=0.041). Non-users of the OC showed a significant increase in DPelvicPM (p=0.049) on Days 7-10. Modestly significant associations were found between reduced androgens and potentiated LPS-induced IL-1ß (lower EC50). CONCLUSION: This is the first study to investigate the relationship between the hormonal environment and activation of the immune system in young women with dysmenorrhoea-related pain conditions. Low androgen levels were consistently associated with increased pain. Translational implications for the findings are discussed.

Stress and tension-type headache mechanisms.

Stress is widely demonstrated as a contributing factor in tension-type headache (TTH). The mechanisms underlying this remain unclear at present. Recent research indicates the importance of central pain processes in tension-type headache (TTH) pathophysiology. Concurrently, research with animals and healthy humans has begun to elucidate the relationship between stress and pain processing in the central nervous system, including central pain processes putatively dysfunctional in TTH. Combined, these two fields of research present new insights and hypotheses into possible mechanisms by which stress may contribute to TTH. To date, however, there has been no comprehensive review of this literature. The present paper provides such a review, which may be valuable in facilitating a broader understanding of the central mechanisms by which stress may contribute to TTH.

Noxious inhibition of temporal summation is impaired in chronic tension-type headache.

OBJECTIVE: To examine effects of stress on noxious inhibition and temporal summation (TS) in tension-type headache. BACKGROUND: Stress is the most commonly reported trigger of a chronic tension-type headache (CTH) episode; however, the mechanisms underlying this are unclear. Stress affects pain processing throughout the central nervous system, including, potentially, mechanisms of TS and diffuse noxious inhibitory controls (DNIC), both of which may be abnormal in CTH sufferers (CTH-S). No studies have examined TS of pressure pain or DNIC of TS in CTH-S to date. Similarly, effects of stress on TS or DNIC of TS have not been reported in healthy subjects or CTH-S to date. METHODS: The present study measured TS and DNIC of TS in CTH-S and healthy controls (CNT) exposed to an hour-long stressful mental task, and in CTH-S exposed to an hour-long neutral condition. TS was elicited at finger and shoulder via 10 pulses from a pressure algometer, applied before and during stimulation from an occlusion cuff at painful intensity. RESULTS: Algometer pain ratings increased more in the CTH compared with the CNT group, and were inhibited during occlusion cuff more in the CNT compared with CTH groups. Task effects on TS or DNIC were not significant. CONCLUSIONS: The results indicate increased TS to pressure pain and impaired DNIC of TS in CTH-S. Stress does not appear to aggravate abnormal TS or DNIC mechanisms in CTH-S.

Toll-Like Receptor Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhea.

PURPOSE: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. To determine whether there is evidence of activation of the innate immune system in dysmenorrhea and whether the degree of activation may be used as a biomarker for pain, we compared the responsiveness of peripheral blood mononuclear cells (PBMCs) to toll-like receptor (TLR) 2 or 4 stimulation. We also investigated whether this effect is modulated by the use of the oral contraceptive pill (OC). PATIENTS AND METHODS: Fifty-six women aged 16-35 years, with either severe or minimal dysmenorrhea, and use or non-use of the OC, were enrolled. PBMCs were collected on two occasions in a single menstrual cycle: the menstrual phase and the mid-follicular phase. PBMCs were exposed to lipopolysaccharide (LPS), a TLR4 agonist, and PAM3CSK4 (PAM), a TLR2 agonist, and the resulting interleukin-1beta (IL-1ß) output was determined. Statistical analysis compared the EC50 between groups as a measure of TLR responsiveness of PBMCs. RESULTS: The key finding following LPS stimulation was a pain effect of dysmenorrhea (p=0.042) that was independent of use or non-use of OC, and independent of day of testing. Women with dysmenorrhea showed a large 2.15-fold (95% CI -4.69, -0.09) increase in IL-1ß release when compared with pain-free participants across both days. CONCLUSION: This is the first study to demonstrate an ex vivo immune relationship in women with dysmenorrhea-related pelvic pain. It provides evidence for the potential of immune modulation as a novel pharmacological target for future drug development in the management of dysmenorrhea.

A comparison of two formulations of intradermal capsaicin as models of neuropathic pain in healthy volunteers.

AIMS: To compare the dose-response relationships of two formulations [Tween- or hydroxypropyl-b-cyclodextrin (HP-b-CD)-based] of intradermal capsaicin in healthy volunteers and to assess the effect of potential covariates of response. One, 10, 30 and 100 microg in 10 ml were compared for the outcomes of flare, spontaneous pain, mechanical allodynia and hyperalgesia in eight healthy men and eight healthy women. RESULTS: The formulations produced comparable responses at doses 1, 10 and 30 microg, but in all parameters the response was less at 100 microg with the Tween formulation.Mean area for hyperalgesia was 9 cm(2) [95% confidence interval (CI) 5, 13] higher with the HP-beta-CD formulation. Flare area was 5 cm(2) (95% CI 8, 13) greater with the HP-beta-CD formulation. There was a significant difference between pain responses from the injection site on the upper forearm compared with the lower forearm on all four pain assessments. In contrast, significant differences were seen in pain response between nondominant and dominant arm for flare, allodynia and hyperalgesia but not for spontaneous pain. A significant difference in sex was seen only for hyperalgesia. The nominal 100-microg dose of the Tween formulation contained only 39% of label strength in the aqueous phase, which may explain the lower pharmacodynamic response. CONCLUSION: The formulations are comparable over the dose range 1-30 microg. The significantly lower pain response at the 100 microg dose in the Tween compared with the HP-beta-CD formulation is likely to be due to limitations in solubility at the 100 microg level. Given the greater ease of formulation and the superior dose-response relationship, the HP-beta-CD formulation is preferable for use in the model in future studies.