Perceptions in orthopedic surgery on the use of cannabis in treating pain: a survey of patients with spine pain (POSIT Spine).

BACKGROUND: Back pain is the leading cause of disability worldwide. Despite guidelines discouraging opioids as first-line treatment, opioids remain the most prescribed drugs for back pain. There is renewed interest in exploring the potential medical applications of cannabis, and with the recent changes in national legislation there is a unique opportunity to investigate the analgesic properties of cannabis. METHODS: This was a multi-center survey-based study examining patient perceptions regarding cannabis for spine pain. We included patients presenting with back or neck pain to one of three Orthopedic clinics in Ontario. Our primary outcome was perceived effect of cannabis on back pain, while secondary outcomes were perceptions regarding potential applications and barriers to cannabis use. RESULTS: 259 patients participated in this study, 35.3% (90/255) stating they used cannabis medically. Average pain severity was 6.5/10 ± 0.3 (95% CI 6.2-6.8). Nearly three-quarters were prescribed opioids (73.6%, 148/201), with oxycodone/oxycontin (45.9% 68/148) being the most common, and almost half of (49.3%, 73/148) had used an opioid in the last week. Patients estimated cannabis could treat 54.3% ± 4.0 (95% CI 50.3-58.3%) of their spine pain and replace 46.2% ± 6. 6 (95% CI 39.6-52.8%) of their current analgesics. Age (ß = - 0.3, CI - 0.6-0.0), higher pain severity (ß = 0.4, CI 0.1-0.6) and previous cannabis use (ß = 14.7, CI 5.1-24.4) were associated with a higher perceived effect of cannabis. Patients thought cannabis would be beneficial to treat pain (129/146, 88.4%), and reduce (116/146, 79.5%) or eliminate opioids (102/146, 69.9%). Not considering using cannabis for medical purposes (65/150, 43.3%) was the number one reported barrier. CONCLUSIONS: Patients estimated medical cannabis could treat more than half of their spine pain, with one in three patients already using medical cannabis. 79% of patients also believe cannabis could reduce opioid usage. This data will help support more research into cannabis for musculoskeletal pain.

Oxygen-ozone autohemotherapy in breast cancer patients suffering from fatigue and musculoskeletal pain upon aromatase inhibitors treatment: a case-series study.

OBJECTIVE: In patients with breast cancer and positive hormone receptors, aromatase inhibitors are effective in reducing the risk of recurrences and are active in progressing the disease in this setting. On the other hand, fatigue and painful musculoskeletal side effects can significantly reduce treatment compliance. With no further treatment options to control these symptoms, non-pharmaceutical interventions, such as oxygen-ozone therapy, may play a role in managing rheumatologic symptomatology inasmuch. We have previously reported evidence on the effectiveness of oxygen-ozone in the treatment of pain and fatigue in chronic fatigue syndrome and fibromyalgia patients and in oncological patients as well. PATIENTS AND METHODS: In this study, we reported 6 cases of patients (mean age 64 yrs, all Caucasian females) with breast cancer upon treatment with anastrozole (Arimidex®), suffering from musculoskeletal pain, weakness and fatigue, and therefore treated with oxygen-ozone major autohemotherapy according to the Italian Scientific Society of Oxygen Ozone Therapy (SIOOT) protocol. Pain was measured with a 10-item Numerical Rating Scale (NRS) and fatigue with a 7-item Fatigue Scoring Scale (FSS). RESULTS: A reduction of at least 66% of pain (from 9.43 ±0.54 SD to 2.36 ±1.32 SD, p<0.001) and 66.26% of fatigue were obtained for all the cases. Pain and fatigue disappeared within one month from ozone therapy, and a healthy painless state lasted for many months following the oxygen-ozone therapy. CONCLUSIONS: The oxygen-ozone therapy is a sound opportunity for breast cancer patients to reduce anti-aromatase-induced pain, fatigue, and musculoskeletal symptoms.

Topical Chinese patent medicines for chronic musculoskeletal pain: systematic review and trial sequential analysis.

PURPOSE: Chronic musculoskeletal pain (CMP) is defined as persistent or recurrent pain that occurs in the joints, musculo-soft tissue, spine or bones for more than three months and is not completely curable. Although topical Chinese patent medicine (CPM) is the most extensively utilized medication in Asia and is widely used for pain management, its efficacy remains controversial. This article presents a systematic review of clinical studies on the therapeutic properties of topical CPM for CMP patients to better inform clinical decision-making and provide additional and safer treatment options for patients with CMP. METHOD: We performed a comprehensive search on PubMed, Cochrane Library, web of science and Chinese databases (CNKI and WanFang data) from 2010 to 2022. In all the studies, knee osteoarthritis, cervical spondylosis, low back pain, and periarthritis of shoulder met the International Pain Association definition of chronic musculoskeletal pain. We included only randomized controlled trials (RCTs) using topical CPM primarily for chronic musculoskeletal pain in adults. To determine the effect of topical CPM on clinical symptoms, we extracted the Visual Analog Scale (VAS, range 0-10) and the Western Ontario and McMaster Universities Arthritis Index pain scores (WOMAC pain, range 0-20), in which the lower the score, the better the results. We also accepted the comprehensive outcome criteria developed by the Chinese National Institute of Rheumatology as an endpoint (total effectiveness rate, range 0-100%, higher score = better outcome), which assesses the overall pain, physical function and wellness. Finally, trial sequential analysis of VAS pain score and total effectiveness rate was performed using TSA software. RESULTS: Twenty-six randomized controlled trials (n = 3180 participants) compared topical CPM with oral Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (n = 15), topical NSAIDs (n = 9), physiotherapy (n = 5), exercise therapy (n = 4), and intra-articular Sodium hyaluronate injection (n = 2). Sixteen studies found that topical CPM was statistically significant in improving CMP pain (measured by VAS pain and Womac pain scores)(p < 0.05), and 12 studies found topical CPMs to be more clinically effective (assessed by ≥ 30% reduction in symptom severity) in treating patients with CMP (p < 0.05). Trial sequential analysis indicates that the current available evidence is robust, and further studies cannot reverse this result. In most of the studies, randomisation, allocation concealment and blinding were not sufficiently described, and no placebo-controlled trials were identified. CONCLUSION: Most studies showed superior analgesic effects of topical CPM over various control treatments, suggesting that topical CPM may be effective for CMP and is an additional, safe and reasonable treatment option. These reported benefits should be validated in higher-quality RCTs.

Factors affecting the intensity of chronic musculoskeletal pain in patients with cardiovascular disease and evaluation of the efficacy of magnesium emulsion cream for muscle cramps.

Chronic musculoskeletal pain (CMP) is associated with an increased risk of cardiovascular disease (CVD). This study aimed to determine the factors associated with the intensity of CMP in patients with underlying CVD and to evaluate the efficacy of Ice Power Magnesium In Strong Cream in patients with muscle cramps. We investigated 396 patients with or without CMP who visited an outpatient cardiology clinic and analyzed the features of CMP and factors associated with pain intensity and specific types of CVD in study 1. We also analyzed 73 patients who had muscle cramps in the lower extremities in study 2 to evaluate the efficacy of Ice Power Magnesium In Strong Cream in reducing pain intensity. In study 1, multivariable linear regression analysis showed that older age (regression coefficient [B] = 0.66, 95% confidence interval [CI], 0.07-1.24), female sex (B = 1.18, 95% CI, 0.59-1.76), presence of hypertension (B = 0.69, 95% CI, 0.05-1.33), and use of calcium supplements (B = 1.27, 95% CI, 0.31-2.24) were significantly associated with a higher intensity of CMP. In study 2, the mean pain scores at baseline, week 2 and week 4 after treatment were 5.99 ± 2.12, 2.92 ± 2.63, and 1.90 ± 2.41, respectively, and the reductions were significant at both week 2 and week 4 after treatment (P < .05). Older age, female sex, hypertension, and use of calcium supplements were associated with an increased intensity of CMP. Ice Power Magnesium In Strong Cream was effective in reducing the pain intensity of muscle cramps in the lower extremities.

Prevalence of opioid and nonopioid pain management therapies among Medicare beneficiaries with musculoskeletal pain conditions from 2016 to 2019.

INTRODUCTION: Pain treatment guidelines prioritize nonopioid therapies over opioid medications to prevent opioid-related harms. We examined trends in receipt and intensity of nonpharmacologic, nonopioid medication, and opioid therapies among Medicare beneficiaries. METHODS: Using a 20% national random sample of Medicare data from 2016 to 2019, we identified fee-for-service beneficiaries with ≥2 diagnoses of back, neck, fibromyalgia, or osteoarthritis/joint pain annually. We excluded beneficiaries with cancer. We calculated annual proportions of beneficiaries who received physical therapy (PT), chiropractic care, gabapentin, and opioids, overall and in demographic, geographic, and clinical subgroups. We estimated the intensity of therapies using the annual number of visitsor prescription fills, prescription days' supply, and opioid dose. RESULTS: During 2016-2019, PT receipt increased (22.8% to 25.5%) and the mean number of visits among recipients of PT went from 12 to 13. Chiropractic receipt (~18%) and mean annual visits (~10) remained unchanged. The prevalence of gabapentin receipt was stable at ~22% and the mean annual number of fills was unchanged though gabapentin days increased slightly. Opioid prescribing decreased (56.7% to 46.5%) and reductions in opioid dose and duration were observed. Opioid receipt was high among beneficiaries who were under 65 years, American Indian/Alaska Native, Black/African American, or had opioid use disorder (OUD), in whom nonpharmacologic therapies were also received the least. CONCLUSION: Utilization of nonopioid therapies lagged opioids among Medicare beneficiaries with musculoskeletal pain, with limited changes from 2016 to 2019. As opioid prescribing declines and alternative pain therapy receipt remains low, there are potential increasing risks of pain going untreated or undertreated and individuals seeking illicit opioids to alleviate their pain.

Safety of baclofen versus tizanidine for older adults with musculoskeletal pain.

BACKGROUND: Baclofen and tizanidine are both muscle relaxants that carry the risk for neuropsychiatric events in older adults but there is a lack of data directly comparing their safety. This study aimed to investigate the relative risk between these two medications in causing injury and delirium in older adults. METHODS: This was a retrospective cohort study that was completed in an integrated healthcare system in the United States and included patients aged 65 years or older who started baclofen or tizanidine for the treatment of musculoskeletal pain from January 2016 through December 2018. Outcomes included new incidence of injury (concussion, contusion, dislocation, fall, fracture, or other injuries) and delirium. The cohort was followed from the initiation of therapy until the first occurrence of any of the following events: end of the index drug exposure, end of health plan membership, death, or the study end date of December 31st, 2019. Descriptive statistics were used to compare baseline patient characteristics between baclofen and tizanidine treatment groups. Cox proportional hazards model was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals. RESULTS: The final study cohort included 12,101 and 6,027 older adults in the baclofen and tizanidine group respectively (mean age 72.2 ± 6.2 years old, 59% female). Older adults newly started on baclofen had a greater risk of injury (HR = 1.54, 95% CI = 1.21-1.96, P = < 0.001) and delirium (HR = 3.33, 95% CI = 2.11-5.26, p = <0.001) compared to those started on tizanidine. CONCLUSION: The results of this study suggest that baclofen is associated with higher incidences of injury and delirium compared to tizanidine when used for the treatment of musculoskeletal pain. Future studies should investigate if these risks are dose-related and include a comparison group not exposed to either drug.

Efficacy of Kampo medicine Kakkonto as acute medication to treat tension-type headache among musculoskeletal pain patients using regular analgesics.

OBJECTIVES: Tension-type headache (TTH) is the most prevalent type of primary headache disorder. Its acute pharmacotherapy is acetaminophen or non-steroidal anti-inflammatory drugs based on the Japanese Clinical Practice Guideline for Headache Disorders 2021. With Japan's aging population, however, the number of TTH patients with comorbidities that have been treated by analgesics is increasing. Under this context, it is sometimes difficult to select an acute pharmacotherapy for TTH. Kakkonto, Japanese traditional herbal kampo medicine, is empirically used for TTH. We hypothesized that kakkonto has efficacy for TTH with painful comorbidities. MATERIALS AND METHODS: We prospectively collected 10 consecutive TTH patients who had already taken analgesics for comorbidities. We prescribed 2.5 g of kakkonto (TJ-1), and patients took it. A numerical rating scale for pain before and 2 hours after kakkonto intake was evaluated. RESULTS: Eight women and 2 men were included. The mean age was 71.0 ± 13.4 years old. Four patients had lower back pain, 2 had lumbar spinal stenosis, 2 had knee pain, 1 had neck pain, and 1 had shoulder myofasciitis. Celecoxib was used for 4 patients, acetaminophen for 3, loxoprofen for 2, and a combination of tramadol and acetaminophen for 1, as routinely used analgesics. The median numerical rating scale statistically improved from the median of 4 to that of 0. There were no side effects of kakkonto. CONCLUSION: Kakkonto showed efficacy as an acute medication for TTH with comorbidities that have been treated by analgesic.

Effects of vitamin D on insulin resistance and fasting blood glucose in pregnant women with insufficient or deficient vitamin D: a randomized, placebo-controlled trial.

BACKGROUND: Gestational diabetes is one of the most common metabolic disorders during pregnancy. Some studies have reported the effect of vitamin D deficiency on the incidence of this disorder. Therefore, the purpose of the present study was to determine the effect of vitamin D supplementation on fasting blood glucose (FBG) levels, fasting blood insulin (FBI) levels and insulin resistance index (HOMA-IR) (primary outcomes) and symptoms of depression, musculoskeletal pain, frequency of gestational diabetes and the frequency of abortion (secondary outcomes). METHODS: In this triple-blind randomized controlled trial, 88 pregnant women at 8-10 weeks of pregnancy who had the vitamin D of less than 30 ng/ml were randomly assigned to the vitamin D group (n = 44) and control group (n = 44) using block randomization. The vitamin D group received 4,000 units of vitamin D tablets daily and the control group received placebo tablets for 18 weeks. Independent t-test, Mann-Whitney U and ANCOVA tests were used to analyze the data. RESULTS: After the intervention, there was no statistically significant difference between the two groups in terms of FBG (P = 0.850), FBI (P = 0.353), HOMA-IR (P = 0.632), mean score of depressive symptoms (P = 0.505), frequency of gestational diabetes (P = 0.187) and frequency of abortion (P = 1.000) and there was only a difference in terms of serum vitamin D level (P = 0.016) and musculoskeletal pain including knee pain (P = 0.025), ankle pain (P < 0.001) and leg pain (P < 0.001). CONCLUSION: Vitamin D could improve the musculoskeletal pain in pregnant women but couldn't decrease FBG, FBI, HOMA-IR, depression symptoms score, incidence of GDM and abortion. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT): IRCT20120718010324N59. Date of registration: 4/11/2020. URL: https://en.irct.ir/user/trial/50973/view ; Date of first registration: 21/11/2020.

Fast pain relief in exercise-induced acute musculoskeletal pain by turmeric-boswellia formulation: A randomized placebo-controlled double-blinded multicentre study.

BACKGROUND: Plant extracts with analgesic properties are seldom considered for treatment of acute musculoskeletal pain due to delay in onset of analgesia. Turmeric (Curcuma longa) and boswellia (Boswellia serrata) extracts are well-studied anti-inflammatory compounds gaining in popularity and used as an alternative to conventional treatments for musculoskeletal pain. This study analyzed the analgesic effect of a formulation of turmeric and boswellia extracts in sesame oil (Rhuleave-K, TBF) in reducing exercise-induced acute musculoskeletal pain in healthy participants. METHODS: In this randomized double-blinded placebo-controlled, single-dose, single-day, multicentre study, a total of 232 participants (TBF n = 116; placebo n = 116) having moderate-to-severe exercise-induced acute musculoskeletal pain were randomized in an allocation concealed 1:1 ratio to receive a single dose of 1000 mg of TBF or placebo. The outcome measures were numerical rating scale (NRS), categorical pain relief scale (PRS), onset of analgesia, and short form of McGill questionnaire (SF-MPQ). NRS and PRS were measured from predose to every 30 minutes interval of postdose up to 6 hours at rest, with movement and applying pressure on the affected part. The onset of analgesia was measured from the time of dosage and censored at 6 hours of postdose. The sum of pain intensity difference (SPID6) and total pain relief (TOTPAR6) at 6 hours was, respectively, analyzed from NRS and PRS scores. RESULTS: TBF showed a significant reduction in pain intensity (SPID6rest) with 97.85% improvement in cumulative responder analysis compared with 2.46% in placebo. The onset of pain relief was fast and highly significant in the TBF group with 99% of participants having a mean perceptible pain relief at 68.5 minutes (95% confidence interval, 59.5-77.4) and 96% of participants having a mean meaningful pain relief at 191.6 minutes (95% confidence interval, 176.7-206.4) compared to the placebo group. Highly significant and continuous improvement in pain relief was observed in the TBF group with 93% of participants having ≥ 50% of maximum TOTPAR6 with a number needed to treat of 1.1 at rest. CONCLUSION: Exercise-induced acute musculoskeletal pain can be effectively relieved by TBF (Rhuleave-K) in about 3 hours signifying its strong analgesic activity.

The Efficacy of Vitamin D Supplementation in the Treatment of Fibromyalgia Syndrome and Chronic Musculoskeletal Pain.

Fibromyalgia syndrome (FMS) and chronic widespread musculoskeletal pain (CMP) are diffuse suffering syndromes that interfere with normal activities. Controversy exists over the role of vitamin D in the treatment of these diseases. We carried out a systematic literature review of randomized controlled trials (RCT) to establish whether vitamin D (25OHD) deficiency is more prevalent in CMP patients and to assess the effects of vitamin D supplementation in pain management in these individuals. We searched PubMed, Physiotherapy Evidence Database (PEDro), and the Cochrane Central Register of Controlled Trials (CENTRAL) for RCTs published in English from 1 January 1990 to 10 July 2022. A total of 434 studies were accessed, of which 14 satisfied the eligibility criteria. In our review three studies, of which two had the best-quality evidence, a correlation between diffuse muscle pain and 25OHD deficiency was confirmed. Six studies, of which four had the best-quality evidence, demonstrated that appropriate supplementation may have beneficial effects in patients with established blood 25OHD deficiency. Eight studies, of which six had the best-quality evidence, demonstrated that 25OHD supplementation results in pain reduction. Our results suggest a possible role of vitamin D supplementation in alleviating the pain associated with FMS and CMP, especially in vitamin D-deficient individuals.

The Effect of Vitamin D Supplementation on Treatment-Induced Pain in Cancer Patients: A Systematic Review.

OBJECTIVES: Despite the widespread use of complementary and alternative medicine by patients and physicians alike, there is no accurate evidence regarding the effects of vitamin D supplementation on treatment-induced pain in cancer patients. Thus, the aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the impact of vitamin D administration on therapy-related pain in subjects diagnosed with malignant disorders. REVIEW ANALYSIS METHODS: We searched the Web of Science, Scopus, PubMed/Medline, Embase, and Google Scholar databases up to October 2020 to identify published RCTs that investigated the use of vitamin D in the management of treatment-induced pain in individuals with cancer. RESULTS: Nine RCTs were detected. The median duration of the intervention was of 24 weeks (range 12-52 weeks) and dose of vitamin D employed was 2000-50000 IU of vitamin D3 weekly orally each day. Six RCTs reported a significant reduction in pain, whereas three did not detect a notable decrease of this variable. Of the six studies that reported an alleviation of pain, an RCT which recruited 60 participants and lasted for 24 weeks consisted of supplementation with high doses of vitamin D2 weekly for 8 weeks in women receiving anastrozole as adjuvant therapy, then supplementation with vitamin D2 monthly for 4 months, effectively alleviated the aromatase inhibitor-associated musculoskeletal syndrome (AIMSS). The results of the same RCT also suggested a beneficial effect of vitamin D on musculoskeletal pain. CONCLUSIONS: Our results suggest that the supplementation with high doses of vitamin D in cancer patients with low serum levels of vitamin D, can be effective in reducing treatment-related pain.

Systemic therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer.

BACKGROUND: Adjuvant aromatase inhibitors (AI) improve survival compared to tamoxifen in postmenopausal women with hormone receptor-positive stage I to III breast cancer. In approximately half of these women, AI are associated with aromatase inhibitor-induced musculoskeletal symptoms (AIMSS), often described as symmetrical pain and soreness in the joints, musculoskeletal pain and joint stiffness. AIMSS may have significant and prolonged impact on women's quality of life. AIMSS reduces adherence to AI therapy in up to a half of women, potentially compromising breast cancer outcomes. Differing systemic therapies have been investigated for the prevention and treatment of AIMSS, but the effectiveness of these therapies remains unclear. OBJECTIVES: To assess the effects of systemic therapies on the prevention or management of AIMSS in women with stage I to III hormone receptor-positive breast cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, WHO International Clinical Trials Registry Platform (ICTRP) and Clinicaltrials.gov registries to September 2020 and the Cochrane Breast Cancer Group (CBCG) Specialised Register to March 2021.  SELECTION CRITERIA: We included all randomised controlled trials that compared systemic therapies to a comparator arm. Systemic therapy interventions included all pharmacological therapies, dietary supplements, and complementary and alternative medicines (CAM). All comparator arms were allowed including placebo or standard of care (or both) with analgesia alone. Published and non-peer-reviewed studies were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies, extracted data, and assessed risk of bias and certainty of the evidence using the GRADE approach. Outcomes assessed were pain, stiffness, grip strength, safety data, discontinuation of AI, health-related quality of life (HRQoL), breast cancer-specific quality of life (BCS-QoL), incidence of AIMSS, breast cancer-specific survival (BCSS) and overall survival (OS). For continuous outcomes, we used vote-counting by reporting how many studies reported a clinically significant benefit within the confidence intervals (CI) of the mean difference (MD) between treatment arms, as determined by the minimal clinically importance difference (MCID) for that outcome scale. For dichotomous outcomes, we reported outcomes as a risk ratio (RR) with 95% CI. MAIN RESULTS: We included 17 studies with 2034 randomised participants. Four studies assessed systemic therapies for the prevention of AIMSS and 13 studies investigated treatment of AIMSS. Due to the variation in systemic therapy studies, including pharmacological, and CAM, or unavailable data, meta-analysis was limited, and only two trials were combined for meta-analysis. The certainty of evidence for all outcomes was either low or very low certainty. Prevention studies The evidence is very uncertain about the effect of systemic therapies on pain (from baseline to the end of the intervention; 2 studies, 183 women). The two studies, investigating vitamin D and omega-3 fatty acids, showed a treatment effect with 95% CIs that did not include an MCID for pain. Systemic therapies may have little to no effect on grip strength (RR 1.08, 95% CI 0.37 to 3.17; 1 study, 137 women) or on women continuing to take their AI (RR 0.16, 95% 0.01 to 2.99; 1 study, 147 women). The evidence suggests little to no effect on HRQoL and BCS-QoL from baseline to the end of intervention (the same single study; 44 women, both quality of life outcomes showed a treatment effect with 95% CIs that did include an MCID). The evidence is very uncertain for outcomes assessing incidence of AIMSS (RR 0.82, 95% CI 0.63 to 1.06; 2 studies, 240 women) and the safety of systemic therapies (4 studies, 344 women; very low-certainty evidence). One study had a US Food and Drug Administration alert issued for the intervention (cyclo-oxygenase-2 inhibitor) during the study, but there were no serious adverse events in this or any study. There were no data on stiffness, BCSS or OS. Treatment studies The evidence is very uncertain about the effect of systemic therapies on pain from baseline to the end of intervention in the treatment of AIMSS (10 studies, 1099 women). Four studies showed an MCID in pain scores which fell within the 95% CI of the measured effect (vitamin D, bionic tiger bone, Yi Shen Jian Gu granules, calcitonin). Six studies showed a treatment effect with 95% CI that did not include an MCID (vitamin D, testosterone, omega-3 fatty acids, duloxetine, emu oil, cat's claw).  The evidence was very uncertain for the outcomes of change in stiffness (4 studies, 295 women), HRQoL (3 studies, 208 women) and BCS-QoL (2 studies, 147 women) from baseline to the end of intervention. The evidence suggests systemic therapies may have little to no effect on grip strength (1 study, 107 women). The evidence is very uncertain about the safety of systemic therapies (10 studies, 1250 women). There were no grade four/five adverse events reported in any of the studies. The study of duloxetine reported more all-grade adverse events in this treatment group than comparator group. There were no data on the incidence of AIMSS, the number of women continuing to take AI, BCCS or OS from the treatment studies. AUTHORS' CONCLUSIONS: AIMSS are chronic and complex symptoms with a significant impact on women with early breast cancer taking AI. To date, evidence for safe and effective systemic therapies for prevention or treatment of AIMSS has been minimal. Although this review identified 17 studies with 2034 randomised participants, the review was challenging due to the heterogeneous systemic therapy interventions and study methodologies, and the unavailability of certain trial data. Meta-analysis was thus limited and findings of the review were inconclusive. Further research is recommended into systemic therapy for AIMSS, including high-quality adequately powered RCT, comprehensive descriptions of the intervention/placebo, and robust definitions of the condition and the outcomes being studied.

Effectiveness of maturity of Rubus occidentalis on hyperalgesia induced by acidic saline injection in rats.

BACKGROUND: Rubus occidentalis, also known as black raspberry, contains several bioactive components that vary depending on the maturity of the fruit. The goal of this study was to evaluate the efficacy of immature Rubus occidentalis extract(iROE) on acid-induced hyperalgesia, investigate the mechanism involved, and compare the antihyperalgesic effect of immature and mature ROEs. METHODS: In adult male Sprague-Dawley rats, chronic muscle pain was induced via two injections of acidic saline into one gastrocnemius muscle. To evaluate the dose response, the rats were injected intraperitoneally with 0.9% saline or iROE (10, 30, 100, or 300 mg/kg) following hyperalgesia development. To evaluate the mechanism underlying iROE-induced analgesia, the rats were injected intraperitoneally with saline, yohimbine 2 mg/kg, dexmedetomidine 50 µg/kg, prazosin 1 mg/kg, atropine 5 mg/kg, mecamylamine 1 mg/kg, or naloxone 5 mg/kg 24 h after hyperalgesia development, followed by iROE 300 mg/kg administration. To compare immature versus mature ROE, the rats were injected with mature ROE 300 mg/kg and immature ROE 300 mg/kg after hyperalgesia development. For all experiments, the mechanical withdrawal threshold(MWT) was evaluated using von Frey filaments before the first acidic saline injection, 24 h after the second injection, and at various time points after drug administration. Data were analysed using multivariate analysis of variance(MANOVA) and the linear mixed-effects model(LMEM). We compared the MWT at each time point using analysis of variance with the Bonferroni correction. RESULTS: The iROE 300 mg/kg injection resulted in a significant increase in MWT compared with the control, iROE 30 mg/kg, and iROE 100 mg/kg injections at ipsilateral and contralateral sites. The iROE injection together with yohimbine, mecamylamine, or naloxone significantly decreased the MWT compared with iROE alone, whereas ROE together with dexmedetomidine significantly increased the MWT. According to MANOVA, the effects of immature and mature ROEs were not significantly different; however, the LMEM presented a significant difference between the two groups. CONCLUSIONS: Immature R. occidentalis showed antihyperalgesic activity against acid-induced chronic muscle pain, which may be mediated by the α2-adrenergic, nicotinic cholinergic, and opioid receptors. The iROE displayed superior tendency regarding analgesic effect compared to mature ROE.

The therapeutic effect of Värska mud and Värska mineral water baths on the overuse pain and muscle tension syndromes in the working age population.

The effects of bath therapy are complex and result from a unique interaction between the aquatic environment and the human body functions. The effect of bath therapy depends on both water temperature and chemical additives (mineral substances and humic substances). Värska Resort Centre, in south-eastern Estonia, uses for the balneotherapy the local curative mud and mineral water. The aim of the study was to evaluate and compare the effects of Värska's local mud bath and mineral water bath on moderate musculoskeletal pains in working-age people. The study involved 64 working-age subjects: within two weeks, 32 of them received five general mineral water baths, and another 32 received five general curative mud baths. Pain was assessed with the Nordic Musculosceletal Questionnaire, and muscle tension was measured with a myotonometer in m. erector spinae and m. trapezius. Measurements were performed three times: before the start of the study, immediately after the last procedure, and 2-3 weeks after the last procedure. Both the Värska curative mud bath and the Värska mineral water bath showed a positive effect on musculoskeletal pain and muscle tension. Both procedures can be recommended as drug-free interventions for mild to moderate musculoskeletal pain syndrome and muscle tensions, in both prevention and treatment.

Evaluation of a nutritional supplement for the alleviation of pain associated with feline degenerative joint disease: a prospective, randomized, stratified, double-blind, placebo-controlled clinical trial.

OBJECTIVES: The purpose of this study was to evaluate the pain-alleviating and activity-enhancing effects of glucosamine/chondroitin sulfate (Dasuquin) in cats that had degenerative joint disease (DJD) and owner-noted mobility/activity impairment. We hypothesized that the nutritional supplement would produce pain-relieving and activity-enhancing effects in cats with painful DJD. METHODS: In this prospective, randomized, stratified, double-blind, placebo-controlled clinical trial, 59 cats with DJD pain were assigned to receive a placebo (n = 30) or supplement (n = 29) for 6 weeks after 2 weeks of placebo. Outcome measures (at-home accelerometry and client-specific outcome measures [feline (CSOMf); Feline Musculoskeletal Pain Index (FMPI); quality of life (QoL)]; and veterinarian examination) were collected at days 14, 28, 42 and 56. RESULTS: Twenty-seven cats in the treatment group and 30 in the placebo group completed the trial. Within the first 2 weeks (placebo administration to all cats), 78% of all cats had an improvement in CSOMf scores. Both groups showed significant improvement at most time points in CSOMf, FMPI, QoL and pain scores, with the placebo group showing greater improvement than the supplement group (significant for CSOMf [P = 0.01]). Overall, no differences in activity were seen between the groups. Cumulative distribution function analysis indicated that for most levels of activity, the placebo-treated cats were more active; however, the least active cats were more active on the supplement (P = 0.013). CONCLUSIONS AND RELEVANCE: This study showed a strong placebo effect. The glucosamine/chondroitin sulfate supplement did not show pain-relieving effects when compared with placebo.

Substitution of Nonpharmacologic Therapy With Opioid Prescribing for Pain During the COVID-19 Pandemic.

Importance: During the pandemic, access to medical care unrelated to COVID-19 was limited because of concerns about viral spread and corresponding policies. It is critical to assess how these conditions affected modes of pain treatment, given the addiction risks of prescription opioids. Objective: To assess the trends in opioid prescription and nonpharmacologic therapy (ie, physical therapy and complementary medicine) for pain management during the COVID-19 pandemic in 2020 compared with the patterns in 2019. Design, Setting, and Participants: This retrospective, cross-sectional study used weekly claims data from 24 million US patients in a nationwide commercial insurance database (Optum's deidentified Clinformatics Data Mart Database) from January 1, 2019, to September 31, 2020. Among patients with diagnoses of limb, extremity, or joint pain, back pain, and neck pain for each week, patterns of treatment use were identified and evaluated. Data analysis was performed from April 1, 2021, to September 31, 2021. Main Outcomes and Measures: The main outcomes of interest were weekly rates of opioid prescriptions, the strength and duration of related opioid prescriptions, and the use of nonpharmacologic therapy. Transition rates between different treatment options before the outbreak and during the early months of the pandemic were also assessed. Results: A total of 21 430 339 patients (mean [SD] age, 48.6 [24.0] years; 10 960 507 [51.1%] female; 909 061 [4.2%] Asian, 1 688 690 [7.9%] Black, 2 276 075 [10.6%] Hispanic, 11 192 789 [52.2%] White, and 5 363 724 [25.0%] unknown) were enrolled during the first 3 quarters in 2019 and 20 759 788 (mean [SD] age, 47.0 [23.8] years; 10 695 690 [51.5%] female; 798 037 [3.8%] Asian; 1 508 023 [7.3%] Black, 1 976 248 [9.5%] Hispanic, 10 059 597 [48.5%] White, and 6 417 883 [30.9%] unknown) in the first 3 quarters of 2020. During the COVID-19 pandemic, the proportion of patients receiving a pain diagnosis was smaller than that for the same period in 2019 (mean difference, -15.9%; 95% CI, -16.1% to -15.8%). Patients with pain were more likely to receive opioids (mean difference, 3.5%; 95% CI, 3.3%-3.7%) and less likely to receive nonpharmacologic therapy (mean difference, -6.0%; 95% CI, -6.3% to -5.8%), and opioid prescriptions were longer and more potent during the early pandemic in 2020 relative to 2019 (mean difference, 1.07 days; 95% CI, 1.02-1.17 days; mean difference, 0.96 morphine milligram equivalents; 95% CI, 0.76-1.20). Analysis of individuals' transitions between treatment options for pain found that patients were more likely to transition out of nonpharmacologic therapy, replacing it with opioid prescriptions for pain management during the COVID-19 pandemic than in the year before. Conclusions and Relevance: Nonpharmacologic therapy is a benign treatment for pain often recommended instead of opioid therapy. The decrease in nonpharmacologic therapy and increase in opioid prescription during the COVID-19 pandemic found in this cross-sectional study, especially given longer days of prescription and more potent doses, may exacerbate the US opioid epidemic. These findings suggest that it is imperative to investigate the implications of limited medical access on treatment substitution, which may increase patient risk, and implement policies and guidelines to prevent those substitutions.

Do nonpharmacological services offset opioids in pain treatment for soldiers?

OBJECTIVE: To examine the relationships between nonpharmacological treatment (NPT) utilization and opioid prescriptions and doses and whether these relationships vary according to the type of NPT service received. DATA SOURCE: Secondary data from the US Military Health System, nationwide. STUDY DESIGN: Patterns of NPT utilization and opioid prescriptions were analyzed over the 23 months after initial pain treatment (index visit). Regression models were used to examine the relationship between opioid prescription use in a given month and NPT service utilization in the three preceding months, using person fixed effects to control for time-invariant patient characteristics, as well as time fixed effects. Analyses were stratified by whether the patient filled an opioid prescription in the first 30 days post index visit. DATA EXTRACTION METHODS: Administrative data on health care utilization were extracted from the US Military Health System Data Repository for Army service members who returned from deployments in Afghanistan and Iraq that ended in fiscal years 2008 to 2014 and had at least one outpatient visit with a primary diagnosis of musculoskeletal pain in the subsequent year. PRINCIPAL FINDINGS: Utilization of any NPT service in the past 3 months was positively associated with filling an opioid prescription in the given month, regardless of whether the patient was initially prescribed opioids (percentage point difference [PP] =2.87, P < 0.01) or not (PP = 0.83, P < 0.01). However, for those not initially prescribed opioids, use of any NPT service in the past 3 months was negatively associated with mean daily opioid dose in the given month (morphine milligram equivalent dose = -0.4017, P < 0.01). For those initially prescribed opioids, NPT was not associated with opioid dose. CONCLUSIONS: NPT only reduced the prescription opioid daily dose for some patients, whereas the probability of receiving an opioid prescription was positively associated with NPT. Future research should assess whether recent system-level policies and program changes influence referral and opioid prescribing patterns.

The good and the bad of cupping therapy: case report and review of the literature.

Cupping therapy (CT) represents a cornerstone of traditional Chinese and Persian medicine, but it has its roots in the history of therapy. Although its exact mechanisms of action have been not fully understood, it is widely used as an alternative or complementary treatment of a broad spectrum of diseases, mainly musculoskeletal pain and muscular tension. Some practitioners use CT to cure dermatoses, but the most common adverse events occur at the skin level. We describe a case and briefly review the related literature.

Involvement of Oxidative Stress and Nerve Growth Factor in Behavioral and Biochemical Deficits of Experimentally Induced Musculoskeletal Pain in Mice: Ameliorative Effects of Heraclin.

Musculoskeletal pain is a widespread complex regional pain syndrome associated with altered emotional and cognitive functioning along with heightened physical disability that has become a global health concern. Effective management of this disorder and associated disabilities includes accurate diagnosis of its biomarkers and instituting mechanism-based therapeutic interventions. Herein, we explored the role of heraclin, a plant-derived molecule, in musculoskeletal pain and its underlying mechanistic approaches in an experimental mouse model. Reserpine (0.5 mg/kg) for 3 consecutive days evoked hyperalgesia, motor incoordination, lack of exploratory behavior, anxiety, and cognition lapse in mice. Reserpine-challenged mice displayed higher serum cytokine level, altered brain neurotransmitter content, elevated brain and muscle oxidative stress, and upregulated brain nerve growth factor receptor expression. Treatment with heraclin (10 mg/kg for 5 consecutive days) exerted analgesic effect and improved motor coordination and memory deficits in mice. Heraclin arrested serum cytokine rise, normalized brain neurotransmitter content, reduced tissue oxidative stress, and downregulated the nerve growth factor receptor expression. Therefore, it may be suggested that heraclin exerts beneficial effects against reserpine-induced musculoskeletal pain disorder possibly through the attenuation of NGFR-mediated pain and inflammatory signaling. Graphical Abstract.

A Systematic Review of CheeZheng Pain Relieving Plaster for Musculoskeletal Pain: Implications for Oncology Research and Practice.

BACKGROUND: Musculoskeletal pain is a common and debilitating condition for cancer patients. Existing therapies for these pain conditions have substantial limitations. To identify an integrative approach to pain management, we conducted a systematic review to evaluate the safety and efficacy of a Tibetan herbal-based topical agent, CheeZheng Pain Relieving Plaster (PRP), for the treatment of osteoarthritis (OA) pain. METHODS: We extracted citations from PubMed and Chinese databases (CNKI, WanFang Data, and CQVIP). We included randomized clinical trials evaluating the effectiveness and safety of CheeZheng PRP compared to conventional OA pain treatments. RESULTS: Twenty-two randomized clinical trials (n = 2556 participants) compared CheeZheng PRP against nonsteroidal anti-inflammatory drugs (11), glucosamine (2), intraarticular corticosteroid (2), hyaluronic acid injections (6), and acetaminophen (1). Ten studies found a statistically greater effectiveness (assessed by ≥30% reduction in symptom severity) of CheeZheng PRP in improving OA pain (measured by the Visual Analogue Scale), stiffness, and function compared to control. Ten studies reported that 4.8% of participants experienced application site skin irritation that resolved after discontinuing the plaster. Randomization was not sufficiently described in most studies, and no placebo-controlled trials were identified. CONCLUSIONS: There is promising evidence for the safety and clinical effectiveness of CheeZheng PRP to treat OA; however, lack of placebo control and unclear descriptions of randomization increase the potential risk for bias. Future randomized, placebo-controlled trials are needed to establish the safety and efficacy of CheeZheng PRP for pain management in oncology settings.