Treatment Of Pain Research Articles

Efficacy of platelet rich plasma (PRP) injection in the treatment of knee pain in patients with osteoarthritis knee.

Objective: To assess the efficacy of intra-articular PRP injections in patients with knee osteoarthritis. Study Design: Cross Sectional. Setting: Orthopedic Department of Mardan Medical Complex. Period: 13th August to 14th December 2023. Methods: Involving 50 diagnosed osteoarthritis patients at demographic data, grades of osteoarthritis, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were recorded pre-treatment. Patients received PRP injections at three intervals, and post-treatment WOMAC scores were assessed. Statistical analysis included mean, standard deviations, and a paired t-test. Results: The study comprised 66% female patients, with a mean age of 50.08±5.82 and mean BMI of 27.16±3.53. Regarding grades of osteoarthritis, grade 1, grade 2 and grade 3 comprised of n=14(28%), 19(38%), 17(34%) respectively PRP treatment significantly reduced WOMAC scores from a pre-treatment mean of 56.62±5.70 to 27.54±4.79 (p < 0.001). Conclusion: The significant reduction in WOMAC scores post-treatment suggests that intra-articular PRP injections may serve as a valuable intervention in the short term management of knee osteoarthritis.

Randomized feasibility study of an autologous protein solution versus corticosteroids injection for treating subacromial pain in the primary care setting - the SPiRIT trial.

The primary aim of this study was to assess the feasibility of recruiting and retaining patients to a patient-blinded randomized controlled trial comparing corticosteroid injection (CSI) to autologous protein solution (APS) injection for the treatment of subacromial shoulder pain in a community care setting. The study focused on recruitment rates and retention of participants throughout, and collected data on the interventions' safety and efficacy. Participants were recruited from two community musculoskeletal treatment centres in the UK. Patients were eligible if aged 18 years or older, and had a clinical diagnosis of subacromial impingement syndrome which the treating clinician thought was suitable for treatment with a subacromial injection. Consenting patients were randomly allocated 1:1 to a patient-blinded subacromial injection of CSI (standard care) or APS. The primary outcome measures of this study relate to rates of recruitment, retention, and compliance with intervention and follow-up to determine feasibility. Secondary outcome measures relate to the safety and efficacy of the interventions. A total of 53 patients were deemed eligible, and 50 patients (94%) recruited between April 2022 and October 2022. Overall, 49 patients (98%) complied with treatment. Outcome data were collected in 100% of participants at three months and 94% at six months. There were no significant adverse events. Both groups demonstrated improvement in patient-reported outcome measures over the six-month period. Our study shows that it is feasible to recruit to a patient-blinded randomized controlled trial comparing APS and CSI for subacromial pain in terms of clinical outcomes and health-resource use in the UK. Safety and efficacy data are presented.

Substantial discrepancies exist between registered protocol and published manuscript in trials on exercise interventions for chronic low back pain: a meta-research study

Reporting bias, prevalent in biomedical fields, can undermine evidence credibility. Our objective was to evaluate the proportion of discrepancies between registered protocols and published manuscripts in randomized controlled trials (RCTs) on exercise interventions for patients with chronic low back pain (CLBP). Cross-sectional meta-research study. We started from the 2021 'Exercise therapy for chronic low back pain' Cochrane Review to select all RCTs reporting a protocol registration on a primary register of the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) or in ClinicalTrials.gov. We extracted data from both registered protocol and published manuscript of RCTs, collecting recruitment and administrative information (e.g., record dates) and details of trial characteristics (e.g., outcomes, arms, statistical analysis plan details). Independent pairs of reviewers assessed discrepancies between registered protocol and published manuscript for the reporting of primary and secondary outcomes domains, measurement instruments, time-points, number of arms and statistical analysis plans (if attached). Outcome discrepancies were characterized as addition, omission, upgrade or downgrade. We included 116 RCTs reporting an available protocol registration. Overall, 100 RCTs (86.2%) distinguished between primary and secondary outcomes. Of these, 39 RCTs (39.0%) reported one or more discrepancies in primary outcomes, and 78 RCTs (78.0%) reported one or more discrepancies in secondary outcomes. Focusing on discrepancies for the primary outcome, 64.5% of added, upgraded or downgraded outcomes favored statistically significant effects. Few RCTs (n=6) reported discrepancies in the number of arms. Statistical analysis plans were poorly reported in the registered protocols (n=3) for being compared to the publications. We found substantial outcome discrepancies comparing registered protocols and published manuscripts in RCTs assessing exercise interventions for patients with CLBP, with some impacting the statistical significance of the effects. Readers are encouraged to approach RCTs results in this field with caution.

Temporal Summation but not Expectations of Pain Relief Predict Response to Acupuncture Treatment in Fibromyalgia

Fibromyalgia (FM) is a common chronic pain condition for which acupuncture treatment is increasingly utilized. However, there is no universally accepted measure to predict whether a specific patient will benefit from acupuncture. This is a single center, single-blind, sham-controlled, randomized, non-crossover, longitudinal trial of 76 subjects with FM, assigned to either electroacupuncture or a placebo control, mock laser acupuncture. Outcome measures included: clinical pain severity (Brief Pain Inventory, BPI), degree of nociplastic pain (Fibromyalgia Survey Questionnaire, FSQ), and pressure pain tolerance. Baseline measures of temporal summation of pain and expectations for treatment relief were used as predictors. Individuals in both treatment groups experienced significant reductions in BPI (electroacupuncture: p<0.001; mock laser: p=0.018) and FSQ (electroacupuncture: p=0.032; mock laser: p=0.002) after treatment; however, neither group showed a significant increase in pressure pain tolerance. Lower temporal summation at baseline was correlated with greater post-treatment improvement in BPI in the electroacupuncture group (rho=0.389, p=0.025) but not in the mock laser group (rho=-0.272, p=0.109). Lower baseline temporal summation was correlated with greater decreases in pressure pain tolerance following electroacupuncture (rho=0.400, p=0.040), whereas the opposite was seen for mock laser (rho=-0.562, p=0.001). Treatment expectancy at baseline was not correlated with any outcome after electroacupuncture or mock laser treatments. Our results support using a quantitative sensory testing metric, temporal summation of pain, but not expectations, to predict analgesia following acupuncture treatment for pain. Clinical trial registrationRegistered under ClinicalTrials.gov identifier NCT02064296. PerspectiveA randomized study of acupuncture in fibromyalgia found baseline temporal summation, but not expectations of pain relief, to be predictive of treatment response.

M41 - Do People With Substance Misuse (SM) Use Distinct Pain Treatment Modalities?

M41 - Do People With Substance Misuse (SM) Use Distinct Pain Treatment Modalities?

Pain management treatments and opioid use disorder risk in Medicaid patients

IntroductionPeople with chronic pain are at increased risk of opioid-misuse. Less is known about the unique risk conferred by each pain management treatment, as treatments are typically implemented together, confounding their independent effects. This study estimated the extent to which pain management treatments were associated with risk of opioid use disorder (OUD) for those with chronic pain, controlling for baseline demographic and clinical confounding variables and holding other pain management treatments at their observed levels. MethodsData were analyzed in 2024 from two chronic pain subgroups within a cohort of non-pregnant Medicaid patients aged 35-64 years, 2016-2019, from 25 states: those with 1) chronic pain and physical disability (CPPD) (N=6,133) or 2) chronic pain without disability (CP) (N=67,438). Nine pain management treatments were considered: prescription opioid i) dose and ii) duration; iii) number of opioid prescribers; opioid co-prescription with iv) benzo- diazepines, v) muscle relaxants, and vi) gabapentinoids; vii) non-opioid pain prescription, viii) physical therapy, and ix) other pain treatment modality. The outcome was OUD risk. ResultsHaving opioids co-prescribed with gabapentin or benzodiazepine was statistically significantly associated with a 37-45% increased OUD risk for the CP subgroup. Opioid dose and duration also were significantly associated with increased OUD risk in this subgroup. Physical therapy was significantly associated with an 18% decreased risk of OUD in the CP subgroup. ConclusionsCo-prescription of opioids with either gabapentin or benzodiazepines may substantially increase OUD risk. More positively, physical therapy may be a relatively accessible and safe pain management strategy.

Virtual reality for postsurgical pain management: An explorative randomized controlled study

BackgroundVirtual reality (VR) is a promising tool in a multimodal analgesic approach; however, evidence regarding virtual reality for postsurgical pain is limited. This study investigates the initial effectiveness and feasibility of self-administered virtual reality in postsurgical pain management. MethodsPatients reporting a postsurgical pain score ≥4 were randomized for control or VR, stratified for 3 interventions with varying levels of immersion and interaction. Subjects were instructed to use virtual reality as add-on treatment at least 3 times a day for 10 minutes on days 2 till 4 postoperatively. Primary outcome was the mean daily pain intensity. Results of pain scores were related to patient and intervention characteristics, to explore which characteristics interact with virtual reality effects. Secondary outcomes were analgesic use, anxiety, stress, and feasibility. ResultsOne hundred patients were included in the analyses: 37 in the control group and 63 for VR. VR did not demonstrate a significant effect on self-reported pain scores (P = .43), nor were specific patient or intervention characteristics associated with greater VR effects. Analgesic usage did not differ between groups. However, there was a trend toward greater cumulative percentages of patients achieving a 30% pain reduction, and significantly lower daily experienced stress (P = .01) and anxiety (P = .03) levels in VR intervention groups. VR was used less than prescribed, mainly because of illness and pain. Adverse events included disorientation, nausea, and fatigue. ConclusionsThis explorative study did not demonstrate initial effectiveness of VR as add-on pain treatment regarding pain and analgesic use; however, VR positively affected stress and anxiety. VR is safe and suitable for a wide target audience, and feasibility differed between interventions. Personalizing and improving VR technology may enhance its effectiveness.

Evaluation of the Therapeutic Potential of Amantadine in a Vincristine-Induced Peripheral Neuropathy Model in Rats.

This study aimed to evaluate the therapeutic potential of amantadine in a vincristine-induced peripheral neuropathy model in rats. Forty-eight male Wistar rats were used. The treated groups received oral amantadine at doses of 2, 5, 12, 25 and 50 mg/kg, with daily applications for 14 days. The mechanical paw withdrawal threshold was measured using a digital analgesimeter. Immunohistochemical analysis of IL-6, TNFα, MIP1α, IL-10, CX3CR1, CXCR4, SOD, CAT and GPx, and enzymatic activity analysis of CAT, SOD and GPx were performed, in addition to quantitative PCR of Grp78, Chop, Ho1, Perk, Bax, Bcl-xL, Casp 3, Casp 9, IL-6, IL-10, IL-18 and IL-1β. The results showed an increase in nociceptive thresholds in animals that received 25 mg/kg and 50 mg/kg amantadine. Immunohistochemistry showed a decrease in the immunostaining of IL-6, TNFα, MIP1α and CX3CR1, and an increase in IL-10. CAT and SOD showed an increase in both immunochemistry and enzymatic analysis. qPCR revealed a reduced expression of genes related to endoplasmic reticulum stress and regulation in the expression of immunological and apoptotic markers. Amantadine demonstrated antinociceptive, anti-inflammatory and antioxidant effects in the vincristine-induced peripheral neuropathy model in rats, suggesting that amantadine may be considered an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.

Benefits of Lavender Aromatherapy in Reducing Menstruation Pain in Teenage Women

Adolescence is a transition stage that causes physical, emotional, and psychological changes. A disorder that often occurs in young women is menstrual pain which can change a woman's emotions in a short time, disrupting her routine and learning process. Aromatherapy can be applied directly through direct massage on the skin using plant extracts. Aromatherapy can treat respiratory problems, and pain, and reduce stress levels. Lavender oil is rich in analgesic essentials which can stimulate the nervous system to bring a feeling of calm to pain sufferers. The main aim of the research was to see how to reduce pain intensity in teenagers before and after being given lavender aromatherapy. The objective of implementing this PkM activity is so that young women at SMA Negeri 1 Perbaungan can experience increased knowledge and be able to carry out appropriate treatment for menstrual pain through the use of lavender aromatherapy. PkM activities were conducted through socialization, where the participants were young women at SMA Negeri 1 Perbaungan, totaling 30 participants. The PkM results show that many young women's menstrual pain conditions change from severe pain to mild and moderate pain after being given lavender aromatherapy therapy. This proves that giving lavender aromatherapy can reduce menstrual pain in young women. Apart from that, the socialization of PkM has been proven to be able to increase the knowledge of young women in understanding and applying it when menstrual pain occurs.

Benefits of Lavender Aromatherapy in Reducing Menstruation Pain in Teenage Women

Adolescence is a transition stage that causes physical, emotional, and psychological changes. A disorder that often occurs in young women is menstrual pain which can change a woman's emotions in a short time, disrupting her routine and learning process. Aromatherapy can be applied directly through direct massage on the skin using plant extracts. Aromatherapy can treat respiratory problems, and pain, and reduce stress levels. Lavender oil is rich in analgesic essentials which can stimulate the nervous system to bring a feeling of calm to pain sufferers. The main aim of the research was to see how to reduce pain intensity in teenagers before and after being given lavender aromatherapy. The objective of implementing this PkM activity is so that young women at SMA Negeri 1 Perbaungan can experience increased knowledge and be able to carry out appropriate treatment for menstrual pain through the use of lavender aromatherapy. PkM activities were conducted through socialization, where the participants were young women at SMA Negeri 1 Perbaungan, totaling 30 participants. The PkM results show that many young women's menstrual pain conditions change from severe pain to mild and moderate pain after being given lavender aromatherapy therapy. This proves that giving lavender aromatherapy can reduce menstrual pain in young women. Apart from that, the socialization of PkM has been proven to be able to increase the knowledge of young women in understanding and applying it when menstrual pain occurs.

Dietary Walnuts Prevented Indomethacin-Induced Gastric Damage via AP-1 Transcribed 15-PGDH, Nrf2-Mediated HO-1, and n-3 PUFA-Derived Resolvin E1.

Non-steroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, cause gastric mucosal damage, including ulcers, directly or indirectly, by which the development of GI-safer (-sparing) NSAIDs relates to unmet medical needs. This study aimed to document the preventive effects of walnut polyphenol extracts (WPEs) against NSAID-induced gastric damage along with the molecular mechanisms. RGM-1 gastric mucosal cells were administered with indomethacin, and the expressions of the inflammatory mediators between indomethacin alone or a combination with WPEs were compared. The expressions of the inflammatory mediators, including COX-1 and COX-2, prostaglandin E2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and antioxidant capacity, were analyzed by Western blot analysis, RT-PCR, and ELISA, respectively. HO-1, Nrf-2, and keap1 were investigated. The in vivo animal models were followed with in vitro investigations. The NSAIDs increased the expression of COX-2 and decreased COX-1 and 15-PGDH, but the WPEs significantly attenuated the NSAID-induced COX-2 expression. Interestingly, the WPEs induced the expression of 15-PGDH. By using the deletion constructs of the 15-PGDH promoter, we found that c-Jun is the most essential determinant of the WPE-induced up-regulation of 15-PGDH expression. We confirmed that the knockdown of c-Jun abolished the ability of the WPEs to up-regulate the 15-PGDH expression. In addition, the WPEs significantly increased the HO-1 expression. The WPEs increased the nuclear translocation of Nrf2 by Keap-1 degradation, and silencing Nrf2 markedly reduced the WPE-induced HO-1 expression. We found that the WPE-induced HO-1 up-regulation was attenuated in the cells harboring the mutant Keap1, in which the cysteine 151 residue was replaced by serine. These in vitro findings were exactly validated in indomethacin-induced gastric rat models. Daily walnut intake can be a promising nutritional supplement providing potent anti-inflammatory, antioxidative, and mucosa-protective effects against NSAID-induced GI damage.

Intramuscular Pulsed Radiofrequency Upregulates BNDF-TrKB Expression in the Spinal Cord in Rats as an Alternative Treatment for Complicated Pain.

Two cases of complicated pain exist: posterior screw fixation and myofascial pain. Intramuscular pulsed radiofrequency (PRF) may be an alternative treatment for such patients. This is a two-stage animal study. In the first stage, two muscle groups and two nerve groups were subdivided into a high-temperature group with PRF at 58 °C and a regular temperature with PRF at 42 °C in rats. In the second stage, two nerve injury groups were subdivided into nerve injury with PRF 42 °C on the sciatic nerve and muscle. Blood and spinal cord samples were collected. In the first stage, the immunohistochemical analysis showed that PRF upregulated brain-derived neurotrophic factor (BDNF) in the spinal cord in both groups of rats. In the second stage, the immunohistochemical analysis showed significant BDNF and tropomyosin receptor kinase B (TrkB) expression within the spinal cord after PRF in muscles and nerves after nerve injury. The blood biomarkers showed a significant increase in BDNF levels. PRF in the muscle in rats could upregulate BDNF-TrkB in the spinal cord, similar to PRF on the sciatica nerve for pain relief in rats. PRF could be considered clinically for patients with complicated pain and this study also demonstrated the role of BDNF in pain modulation. The optimal temperature for PRF was 42 °C.

Comparison of grapiprant and meloxicam for management of postoperative joint pain in dogs: A randomized, double-blinded, prospective clinical trial.

Grapiprant is a novel anti-inflammatory drug approved for the treatment of pain associated with osteoarthritis in dogs. Compare the efficacy of grapiprant vs meloxicam for the management of postoperative joint pain in dogs. Forty-eight dogs presented with cranial cruciate ligament disease and treated by tibial plateau leveling osteotomy (TPLO) between May 2020 and May 2022. In this randomized, double blinded, prospective clinical trial, client-owned dogs with naturally occurring unilateral cruciate ligament rupture were enrolled on the day of surgery. The day after surgery, all animals received a subcutaneous injection of 0.2 mg/kg of meloxicam and were randomly assigned to receive either oral grapiprant (2 mg/kg) or meloxicam (0.1 mg/kg), once a day for 14 days, in a blinded manner. The primary endpoint of the study was the pain severity (PSS) and interference (PIS) scores, assessed by the Canine Brief Pain Inventory (CBPI) at day 3, 7, 10 and 15 after the surgery. Three days after surgery, grapiprant treated dogs had lower PSS compared to meloxicam treated dogs with a mean ± SD of 2.76 ± 0.18 vs 3.25 ± 0.23, respectively (difference of -0.49 [95% CI -0.94 to -0.04], P = .032). Pain Interference Score was also lower in grapiprant group at day 3 (4.11 ± 0.18 vs 4.69 ± 0.16 in meloxicam group [difference of -0.58 {95% CI -1.03 to -0.13}, P = .013]) and at day 10 (2.23 ± 0.13 vs 2.72 ± 0.28 [difference of -0.49 {95% CI -0.92 to -0.01}, P = .049]). Our study supports the use of grapiprant as an alternative analgesic to meloxicam for management of postoperative joint pain in dogs.

Nurses’ Awareness and Practice Toward Pain Assessment and Management as Fifth Vital Sign in Sudan: A Cross-sectional Study

Background: Pain is globally prevalent, affecting quality of life and driving most people to seek medical care. Nurses are essential for pain assessment and treatment. Adequate nursing awareness, attitudes, and skills are vital for optimal management. This study investigates nurses’ awareness and practice toward pain assessment and management as the fifth vital sign in Sudan. Methods: This study was a cross-sectional, hospital-based study. Convenience sampling was performed to collect information from nurses working at four government hospitals using a self-administered questionnaire 24 November 2020 and 18 April 2021. The study utilized descriptive and inferential statistics for data analysis. Results: A total of 393 registered nurses participated in this study. Most (66.7%) were women, 46.6% were aged 20–25 years, and 69.2% had a bachelor degree. More than half of the nurses had low awareness of pain assessment (51.7%) and management practices (53.7%). A weak positive correlation was observed between awareness and practice (r = 0.280, P = 0.000). Women nurses showed a higher awareness (204.80, P = 0.048). Nurses with a high level of education showed higher awareness (249.32, P = 0.031) and higher practice (272.00, P = 0.029). Nurses working in the critical care unit performed significantly better than others (234.61, P = 0.001). Conclusion: There is a low level of awareness regarding pain assessment and management practices. This study suggests the need for more research and training programs, especially for nurses with low educational levels.

Nurses’ Awareness and Practice Toward Pain Assessment and Management as Fifth Vital Sign in Sudan: A Cross-sectional Study

Background: Pain is globally prevalent, affecting quality of life and driving most people to seek medical care. Nurses are essential for pain assessment and treatment. Adequate nursing awareness, attitudes, and skills are vital for optimal management. This study investigates nurses’ awareness and practice toward pain assessment and management as the fifth vital sign in Sudan. Methods: This study was a cross-sectional, hospital-based study. Convenience sampling was performed to collect information from nurses working at four government hospitals using a self-administered questionnaire 24 November 2020 and 18 April 2021. The study utilized descriptive and inferential statistics for data analysis. Results: A total of 393 registered nurses participated in this study. Most (66.7%) were women, 46.6% were aged 20–25 years, and 69.2% had a bachelor degree. More than half of the nurses had low awareness of pain assessment (51.7%) and management practices (53.7%). A weak positive correlation was observed between awareness and practice (r = 0.280, P = 0.000). Women nurses showed a higher awareness (204.80, P = 0.048). Nurses with a high level of education showed higher awareness (249.32, P = 0.031) and higher practice (272.00, P = 0.029). Nurses working in the critical care unit performed significantly better than others (234.61, P = 0.001). Conclusion: There is a low level of awareness regarding pain assessment and management practices. This study suggests the need for more research and training programs, especially for nurses with low educational levels.

Intravenous Ketamine for Cancer Pain: A Single-Center Retrospective Analysis Comparing Fixed-Rate Versus Weight-Based Dosing

Although weak evidence exists to support subanesthetic ketamine for cancer pain treatment, successful use may be hindered in the absence of standardized dosing guidance. We aimed to compare the success rates of intravenous ketamine fixed-rate versus weight-based dosing strategies for cancer pain treatment, and to assess patient characteristics that correlate with treatment success. We conducted a single-center retrospective review including non-critically ill adults with cancer pain who received subanesthetic ketamine for at least 24-h. All patients received fixed-rate ketamine; weight-based doses were retrospectively determined using total body weight. Treatment was considered successful if after reaching the maximum prescribed ketamine dose the patient had a 30% reduction in: baseline pain score, as-needed opioid use, or total morphine equivalent daily dose over a standardized 24-h. Of 105 included patients, 51 (48.6%) successfully responded to ketamine. Responders had lower fixed-rate ketamine doses compared to non-responders (median[IQR] 15 mg/hr[10-15] vs. 15 mg/hr[15-20], p = 0.043), but no difference in retrospectively calculated weight-based doses (0.201 ± 0.09 mg/kg/hr vs. 0.209 ± 0.08 mg/kg/hr, p = 0.59). Responders had higher daily opioid requirements at baseline compared to non-responders (p = 0.04). Though underpowered, our findings suggest that weight-based ketamine dosing may not convey additional benefit over fixed-rate dosing.

Sex and gender differences in pain perception and management in clinical settings

Sex and gender differences in pain perception and management in clinical settings

Harnessing the ocean’s pharmacy: marine bioactive compounds as next-generation therapeutics

The ocean’s vast and diverse ecosystem offers a rich reservoir of bioactive compounds with immense clinical potential. Marine organisms produce structurally unique and biologically active compounds, leading to breakthroughs in therapeutic development. Notable examples include anticancer agents like trabectedin and cytarabine, and the analgesic ziconotide. Marine compounds also exhibit potent antimicrobial and antiviral properties, addressing critical challenges like antibiotic resistance and emerging viral infections. Despite the promise, challenges such as sustainable harvesting and complex extraction processes persist. Advances in synthetic biology and metabolic engineering provide solutions for sustainable production, ensuring a stable supply of these valuable compounds. The integration of marine bioactives into modern medicine could revolutionize treatments for cancer, chronic pain, and infectious diseases, underscoring the need for continued investment in marine bioprospecting and biotechnological innovation.

Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment

Opioids are the gold standard for the treatment of chronic pain but are limited by adverse side effects. In our earlier work, we showed that Heat shock protein 90 (Hsp90) has a crucial role in regulating opioid signaling in spinal cord; Hsp90 inhibition in spinal cord enhances opioid anti-nociception. Building on these findings, we injected the non-selective Hsp90 inhibitor KU-32 by the intrathecal route into male and female CD-1 mice, showing that morphine anti-nociceptive potency was boosted by 1.9–3.5-fold in acute and chronic pain models. At the same time, tolerance was reduced from 21-fold to 2.9 fold and established tolerance was rescued, while the potency of constipation and reward was unchanged. These results demonstrate that spinal Hsp90 inhibition can improve the therapeutic index of morphine. However, we also found that systemic non-selective Hsp90 inhibition blocked opioid pain relief. To avoid this effect, we used selective small molecule inhibitors and CRISPR gene editing to identify 3 Hsp90 isoforms active in spinal cord (Hsp90α, Hsp90β, and Grp94) while only Hsp90α was active in brain. We thus hypothesized that a systemically delivered selective inhibitor to Hsp90β or Grp94 could selectively inhibit spinal cord Hsp90 activity, resulting in enhanced opioid therapy. We tested this hypothesis using intravenous delivery of KUNB106 (Hsp90β) and KUNG65 (Grp94), showing that both drugs enhanced morphine anti-nociceptive potency while rescuing tolerance. Together, these results suggest that selective inhibition of spinal cord Hsp90 isoforms is a novel, translationally feasible strategy to improve the therapeutic index of opioids.

Treadmill running on neuropathic pain: via modulation of neuroinflammation.

Neuropathic pain is a type of chronic pain caused by an injury or somatosensory nervous system disease. Drugs and exercise could effectively relieve neuropathic pain, but no treatment can completely stop neuropathic pain. The integration of exercise into neuropathic pain management has attracted considerable interest in recent years, and treadmill training is the most used among exercise therapies. Neuropathic pain can be effectively treated if its mechanism is clarified. In recent years, the association between neuroinflammation and neuropathic pain has been explored. Neuroinflammation can trigger proinflammatory cytokines, activate microglia, inhibit descending pain modulatory systems, and promote the overexpression of brain-derived neurotrophic factor, which lead to the generation of neuropathic pain and hypersensitivity. Treadmill exercise can alleviate neuropathic pain mainly by regulating neuroinflammation, including inhibiting the activity of pro-inflammatory factors and over activation of microglia in the dorsal horn, regulating the expression of mu opioid receptor expression in the rostral ventromedial medulla and levels of γ-aminobutyric acid to activate the descending pain modulatory system and the overexpression of brain-derived neurotrophic factor. This article reviews and summarizes research on the effect of treadmill exercise on neuropathic pain and its role in the regulation of neuroinflammation to explore its benefits for neuropathic pain treatment.