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Adequate management of acute pain in the older population is crucial. However, it is inherently complex because of multiple physiological changes that significantly impact both the pharmacokinetics and pharmacodynamics of medications. Current guidelines promote paracetamol as the first-line analgesic for acute pain in older adults, whereas opioids are advised cautiously for moderate to severe acute pain. However, opioids come with a significant array of side effects, which can be more pronounced in older individuals. Ketamine administered via intranasal (IN) and nebulised inhalation in the emergency department for managing acute pain in older patients shows promising potential for improving pain management and reducing opioid reliance Kampan, Thong-on, Sri-on (2024, Age Ageing, 53, afad255). Nebulised ketamine appears superior in terms of adverse event incidence. However, the adoption of IN or nebulised ketamine in older adult acute pain management remains unclear because of the lack of definitive conclusions and clear guidelines. Nevertheless, these modalities can be valuable options for patients where opioid analgesics are contraindicated or when intravenous morphine titration is impractical or contraindicated. Here, we review these concepts, the latest evidence and propose avenues for research., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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 (β = - 0.3, CI - 0.6-0.0), higher pain severity (β = 0.4, CI 0.1-0.6) and previous cannabis use (β = 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., (© 2024. The Author(s).)

Objective: To construct a new prediction nomogram to predict the risk of musculoskeletal pain in patients with primary osteoporosis who receive zoledronic acid intravenously for the first time., Method: Clinical data of 368 patients with primary osteoporosis who received the first intravenous injection of zoledronic acid in our hospital from December 2019 to December 2022 were studied. Patients were divided into a musculoskeletal pain group (n = 258) and a non-musculoskeletal pain group (n = 110) based on the presence or absence of musculoskeletal pain 3 days after injection. Statistically significant predictors were screened by logistic regression analysis and the minimum absolute contraction and selection operator (LASSO) to construct a nomogram. The nomogram was evaluated by the receiver operating characteristic (ROC) curve, the calibration curve, the C-index, and the decision curve analysis (DCA) and verified in a validation cohort., Results: The independent predictors of the nomogram were age, serum 25-hydroxyvitamin D, NSAIDs, prior Vitamin D intake, and BMI. The area under the ROC curve (AUC) was 0.980 (95% CI, 0.915-0.987), showing excellent predictive performance. The nomogram c index was 0.980, and the nomogram c index for internal verification remained high at 0.979. Moreover, calibration curves show that the nomogram has good consistency. Finally, the DCA showed that the net benefit of the nomogram was 0.20-0.49., Conclusion: Musculoskeletal pain is a common symptom of APR in OP patients treated with intravenous zoledronic acid. Risk factors for musculoskeletal pain after zoledronic acid injection in OP patients were: non-use of NSAIDs, youth (<80 years old), serum 25 (OH) D<30ng /mL, no prior intake of vitamin D, BMI<24 kg /m 2 . A nomogram constructed from the above predictors can be used to predict musculoskeletal pain after the first zoledronic acid injection., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., (© 2023 The American Geriatrics Society.)

Background: Osteoporosis is a disorder of bone mineralisation occurring in about one third of adults with cystic fibrosis. Bisphosphonates can increase bone mineral density and decrease the risk of new fractures in post-menopausal women and people receiving long-term oral corticosteroids. This is an updated version of a previous review., Objectives: To assess the effects of bisphosphonates on the frequency of fractures, bone mineral density, quality of life, adverse events, trial withdrawals, and survival in people with cystic fibrosis., Search Methods: We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register of references (identified from electronic database searches and hand searches of journals and abstract books) on 5 May 2022. We performed additional searches of PubMed, clinicaltrials.gov and the WHO ICTRP (International Clinical Trials Registry Platform) on 5 May 2022., Selection Criteria: Randomised controlled trials of at least six months duration studying bisphosphonates in people with cystic fibrosis., Data Collection and Analysis: Authors independently selected trials, extracted data and assessed risk of bias in included studies. Trial investigators were contacted to obtain missing data. We judged the certainty of the evidence using GRADE., Main Results: We included nine trials with a total of 385 participants (272 adults and 113 children (aged five to 18 years)). Trial durations ranged from six months to two years. Only two of the studies were considered to have a low risk of bias for all the domains.  Bisphosphonates compared to control in people with cystic fibrosis who have not had a lung transplant Seven trials included only adult participants without lung transplants, one trial included both adults and children without lung transplantation (total of 238 adults and 113 children). We analysed adults (n = 238) and children (n = 113) separately. Adults Three trials assessed intravenous bisphosphonates (one assessed pamidronate and two assessed zoledronate) and five trials assessed oral bisphosphonates (one assessed risedronate and four assessed alendronate). Bisphosphonates were compared to either placebo or calcium (with or without additional vitamin D). Data showed no difference between treatment or control groups in new vertebral fractures at 12 months (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.02 to 2.09; 5 trials, 142 participants; very low-certainty evidence) and two trials (44 participants) reported no vertebral fractures at 24 months. There was no difference in non-vertebral fractures at 12 months (OR 2.11, 95% CI 0.18 to 25.35; 4 trials, 95 participants; very low-certainty evidence) and again two trials (44 participants) reported no non-vertebral fractures at 24 months. There was no difference in total fractures between groups at 12 months (OR 0.57, 95% CI 0.13 to 2.50; 5 trials, 142 participants) and no fractures were reported in two trials (44 participants) at 24 months. At 12 months, bisphosphonates may increase bone mineral density at the lumbar spine (mean difference (MD) 6.31, 95% CI 5.39 to 7.22; 6 trials, 171 participants; low-certainty evidence) and at the hip or femur (MD 4.41, 95% 3.44 to 5.37; 5 trials, 155 participants; low-certainty evidence). There was no clear difference in quality of life scores at 12 months (1 trial, 47 participants; low-certainty evidence), but bisphosphonates probably led to more adverse events (bone pain) at 12 months (OR 8.49, 95% CI 3.20 to 22.56; 7 trials, 206 participants; moderate-certainty evidence). Children The single trial in 113 children compared oral alendronate to placebo. We graded all evidence as low certainty. At 12 months we found no difference between treatment and placebo in new vertebral fractures (OR 0.32, 95% CI 0.03 to 3.13; 1 trial, 113 participants) and non-vertebral fractures (OR 0.19, 95% CI 0.01 to 4.04; 1 trial, 113 participants). There was also no difference in total fractures (OR 0.18, 95% CI 0.02 to 1.61; 1 trial, 113 participants). Bisphosphonates may increase bone mineral density at the lumbar spine at 12 months (MD 14.50, 95% CI 12.91 to 16.09). There was no difference in bone or muscle pain (MD 3.00, 95% CI 0.12 to 75.22), fever (MD 3.00, 95% CI 0.12 to 75.22) or gastrointestinal adverse events (OR 0.67, 95% CI 0.20 to 2.26). The trial did not measure bone mineral density at the hip/femur or report on quality of life.  Bisphosphonates compared to control in people with cystic fibrosis who have had a lung transplant One trial of 34 adults who had undergone lung transplantation compared intravenous pamidronate to no bisphosphonate treatment. It did not report at 12 months and we report the 24-month data (not assessed by GRADE). There was no difference in the number of fractures, either vertebral or non-vertebral. However, bone mineral density increased with treatment at the lumbar spine (MD 6.20, 95% CI 4.28 to 8.12) and femur (MD 7.90, 95% CI 5.78 to 10.02). No participants in either group reported either bone pain or fever. The trial did not measure quality of life., Authors' Conclusions: Oral and intravenous bisphosphonates may increase bone mineral density in people with cystic fibrosis, but there are insufficient data to determine whether treatment reduces fractures. Severe bone pain and flu-like symptoms may occur with intravenous bisphosphonates. Before any firm conclusions can be drawn, trials in larger populations, including children, and of longer duration are needed to determine effects on fracture rate and survival. Additional trials are needed to determine if bone pain is more common or severe (or both) with the more potent zoledronate and if corticosteroids can ameliorate or prevent these adverse events. Future trials should also assess gastrointestinal adverse effects associated with oral bisphosphonates., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: At least 5 years of adjuvant endocrine therapy (ET) is recommended for patients with hormone receptor-positive invasive breast cancer to reduce cancer recurrence risk. Up to half of patients prematurely discontinue ET, often due to musculoskeletal pain. Nociplastic pain is abnormal central nervous system pain processing without evidence of tissue or neuronal damage. This study aimed to evaluate the relationship between baseline nociplastic pain and ET discontinuation., Methods: This was a retrospective, single center, cohort study. Included patients were female, had stage 0-III invasive breast cancer, did not receive neoadjuvant therapy, and completed quality of life questionnaires prior to breast surgery, including Fibromyalgia Survey for nociplastic pain. Clinical data including duration of ET were abstracted from the medical record. Patient characteristics were analyzed with t-tests and Chi-squared tests, as appropriate. Univariate and multivariable regressions were performed with Cox proportional hazard models., Results: Six hundred eighty-one patients diagnosed between 2012 and 2019 met inclusion criteria; 480 initiated ET and were included in the analysis. Of these 480 patients, 203 (42.3%) prematurely discontinued initial ET therapy. On univariate analysis, tamoxifen use (hazard ratio [HR] 0.70, p = 0.021) and premenopausal status (HR 0.73, p = 0.04) were inversely associated with ET discontinuation, while Fibromyalgia Score was positively associated (HR 1.04, p = 0.043). On multivariable analysis, baseline Fibromyalgia Score remained associated with ET discontinuation., Conclusion: Nociplastic pain present prior to surgery was associated with premature ET discontinuation. Fibromyalgia Score screening may be useful for evaluating ET discontinuation risk. Treatments targeting nociplastic pain may be more effective for treating ET-emergent pain., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

For patients with optimally treated chronic myeloid leukemia (CML), discontinuation of tyrosine kinase inhibitor (TKI) therapy can lead to treatment-free remission. In previous trials, TKI discontinuation has been associated with increased musculoskeletal pain in some patients ("withdrawal syndrome"), based on physician-reported adverse events (AE). Patient-reported pain has not been described. The Life After Stopping TKI study was a 14-site prospective, non-randomized clinical trial of TKI discontinuation. We defined increased pain after discontinuation as: (i) a physician-reported pain AE, (ii) a 2-level increase in self-reported musculoskeletal pain (4-level single item), or (iii) initiation of a medication for pain. We plotted the trajectory of patient-reported pain over time using a piecewise mixed-effects ordinal logistic model. Within 3 months of discontinuation, 35 of 172 patients (20.3%) had a physician-reported pain AE, 22 of 172 (12.8%) had an increase in self-reported pain, and 18 of 154 (11.7%) initiated a pain medication. Agreement among these measures was limited; overall, 60 of 172 patients (34.9%) had increased pain. Three patients (1.7%) restarted a TKI because of pain. The modelpredicted trajectory showed an increase in pain in the first 3 months followed by a decrease, returning to baseline levels by 6 months and further decreasing after that. This trajectory was similar among patients who did and did not restart TKI, suggesting that resuming a TKI for withdrawal syndrome may be necessary for some, but other approaches to manage pain should be tried so that patients can remain in treatment-free remission when possible.

Joint and muscle pain, including arthralgia, myalgia, and musculoskeletal pain, are among the common adverse events (AEs) reported for ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). This pooled analysis from nine clinical trials of ibrutinib in CLL and MCL ( N  = 1178) evaluated patterns of these AEs. Any grade arthralgia, myalgia, and musculoskeletal pain occurred in 18%, 10%, and 6% of patients, respectively. AEs were primarily low-grade (grade 1/2: 97‒99%) and occurred during the first year of treatment; most resolved (67%-80%) at first occurrence. Few (<5%) patients required ibrutinib dose modification; no patients discontinued ibrutinib due to these AEs. Among patients evaluated for concomitant medication use, all those receiving concomitant medications after the first AE occurrence experienced AE resolution. These data suggest that these AEs were not treatment-limiting during ibrutinib therapy.

Objectives: ketamine has potential advantages over morphine for musculoskeletal pain relief. The aim of this study was to compare the analgesic efficacy and safety of intranasal (IN) ketamine to intravenous (IV) morphine for older adults with musculoskeletal pain in the emergency department (ED)., Methods: this was a non-inferiority, double-blind, randomised controlled trial of ED patients aged of 65 and older presenting with acute moderate to severe musculoskeletal pain defined as a score ≥5 on an 11-point numeric rating scale (NRS). Patients were randomly assigned to receive IN ketamine or IV morphine. The primary outcome was comparative reduction of NRS pain scores between ketamine and morphine groups at 30 min post-treatment. Secondary outcomes were incidence of adverse events and requirement for rescue therapy., Results: seventy-four patients were eligible for analysis (37 in the IN ketamine and 37 in the IV morphine group). Mean pain score at 30 min did not differ significantly between IN ketamine and IV morphine groups (6.03 versus 5.81). Similarly, the difference in mean NRS change from baseline between IN ketamine and IV morphine groups [(-2.14, 95% CI: -2.79 to -1.48) and (-0.81, 95% CI: -2.36 to -1.26) = -0.32, 95% CI: -1.17 to -0.52] did not reach the non-inferiority margin of 1.3. Adverse events and incidence of rescue therapy also did not differ between groups., Conclusions: intranasal ketamine can provide a non-inferior analgesic effect compared to intravenous morphine for acute musculoskeletal pain in older adults with mild adverse effects and low incidence of rescue analgesic treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Almost one-half of aromatase inhibitor (AI)-treated breast cancer patients experience AI-associated musculoskeletal symptoms (AIMSS); 20%-30% discontinue treatment because of severe symptoms. We hypothesized that we could identify predictors of pain reduction in AIMSS intervention trials by combining data from previously conducted trials., Methods: We pooled patient-level data from 3 randomized trials testing interventions (omega-3 fatty acids, acupuncture, and duloxetine) for AIMSS that had similar eligibility criteria and the same patient-reported outcome measures. Only patients with a baseline Brief Pain Inventory average pain score of at least 4 of 10 were included. The primary outcome examined was 2-point reduction in average pain from baseline to week 12. Variable cut-point selection and logistic regression were used. Risk models were built by summing the number of factors statistically significantly associated with pain reduction. Analyses were stratified by study and adjusted for treatment arm., Results: For the 583 analyzed patients, the 4 factors statistically significantly associated with pain reduction were Functional Assessment of Cancer Therapy Functional Well-Being greater than 24 and Physical Well-Being greater than 14 (higher scores reflect better function), and Western Ontario and McMaster Universities Osteoarthritis Index less than 50 and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands less than 33 (lower scores reflect less pain). Patients with all 4 factors were greater than 6 times more likely to experience at least a 2-point pain reduction (odds ratio = 6.37, 95% confidence interval = 2.31 to 17.53, 2-sided P < .001); similar results were found for secondary 30% and 50% pain reduction endpoints., Conclusions: Patients with AIMSS who have lower symptom and functional distress at study entry on AIMSS intervention trials are more likely to experience meaningful pain reduction. Baseline symptom and functional status should be considered as stratification factors in future interventional trials., (© The Author(s) 2021. Published by Oxford University Press.)

Exercise-induced hypoalgesia (EIH) describes acute reductions in pain that occur following exercise. Current evidence suggests that the magnitude of EIH is small-to-moderate at best, warranting exploration of novel avenues to bolster these effects. Transcranial direct current stimulation (tDCS) has been shown to relieve pain and represents a promising intervention that may enhance EIH. This study aimed to determine whether anodal tDCS of the primary motor cortex (M1) can augment EIH in healthy individuals experiencing experimentally-induced musculoskeletal pain. Twenty-four healthy subjects attended 2 experimental sessions ("Day 0" and "Day 2"). On Day 0, subjects were injected with nerve growth factor into their right extensor carpi radialis brevis to induce persistent elbow pain. On Day 2, each subject received active or sham tDCS over M1 followed by an isometric grip exercise. Pain intensity, muscle soreness, sensitivity (pressure pain thresholds), and conditioned pain modulation were assessed prior to the nerve growth factor injection, on Day 2 before tDCS, immediately post-exercise, and 15 minutes post-exercise. Active tDCS expedited the onset of EIH, inducing immediate reductions in pain intensity that were not present until 15 minutes post-exercise in the sham group. However, active tDCS did not reduce muscle soreness or sensitivity when compared to sham tDCS. PERSPECTIVE: These findings suggest that active tDCS accelerates the onset of EIH in healthy individuals experiencing experimentally-induced pain. This may represent a promising means of enhancing adherence to exercise protocols. However, larger randomised controlled trials in persistent pain populations are required to confirm the clinical impact of these findings., (Copyright © 2020 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

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.

Purpose: To evaluate the efficacy of testosterone supplementation for improving aromatase inhibitor musculoskeletal symptoms (AIMSS)., Methods: Postmenopausal women experiencing moderate-to-severe arthralgias while taking adjuvant aromatase inhibitors for breast cancer were enrolled in this trial. Initially, patients were randomly allocated to receive either a subcutaneous testosterone pellet versus a placebo pellet. Due to slow accrual, the protocol was modified such that additional participants were randomized to receive either a topical testosterone gel or a placebo gel. Changes in patient-reported joint pain were compared between patients receiving testosterone and those receiving placebo using a two-sample t test. Changes in hot flashes and other vasomotor symptoms were also analyzed. Further analyses were conducted to evaluate whether 27 single nucleotide polymorphisms (SNPs) in 14 genes previously associated with AIMSS were associated with testosterone supplementation benefit., Results: While 64% of patients reported an improvement in joint pain at 3 months, there were no significant differences in average pain or joint stiffness at 3 or 6 months between testosterone and placebo arms. Patients receiving testosterone did report improvements in strength, lack of energy, urinary frequency, and stress incontinence (p < 0.05). The subset of patients receiving subcutaneous testosterone also experienced improvements in hot flashes and mood swings. An inherited variant (rs7984870 CC genotype) in TNFSF11 was more likely to be associated with improvements in hot flashes in patients receiving testosterone., Conclusion: The doses of testosterone supplementation used in this study did not significantly improve AIMSS., Trial Registration: ClinicalTrials.gov Identifier: NCT01573442.

BACKGROUND AND OBJECTIVE: INTP5 has been developed as a pegfilgrastim biosimilar. Single-dose, crossover study compared the pharmacokinetics and pharmacodynamics (PK/PD) of INTP5 (pegfilgrastim biosimilar) with reference pegfilgrastim (Neulasta ® , pegfilgrastim-ref) and a multiple-dose, parallel-group study compared the immunogenicity of INTP5 with pegfilgrastim-ref in healthy subjects as part of a complete clinical development plan., Methods: In the PK/PD study, subjects received a single subcutaneous 6 mg dose of INTP5 and pegfilgrastim-ref (N = 142) separated by a 6-week washout period. The primary endpoints were area under the serum concentration-time curve measured from time zero to infinity (AUC 0-∞ ) and maximum measured serum concentration (C max ) of pegfilgrastim and area under the absolute neutrophil count (ANC) versus time curve from time zero to t (AUEC 0-t ) and maximum measured ANC (E max ) of baseline non-adjusted ANCs. In the immunogenicity study, subjects received two 6 mg doses of INTP5 (N = 100) or pegfilgrastim-ref (N = 100) separated by 21 days. The primary endpoints were incidence of anti-drug antibodies (ADAs) in the two treatment groups., Results: The primary PK endpoints [AUC 0-∞ (90% CI 108.59-123.11) and C max (106.24-118.99)] and the primary PD endpoints [AUEC 0-t (99.07-102.32) and E max (100.24-104.25)] met the acceptance criteria of 80-125%. The incidence of ADAs was 10.6% in the INTP5 arm and 9.0% in the pegfilgrastim-ref arm. The 90% CI for risk difference of the ADA incidence between INTP5 and pegfilgrastim-ref was 1.64% (- 5.40 to 8.68) and was within the 10% margin. No neutralizing antibodies were reported. Immunogenicity did not impact PK/PD parameters and subjects with aberrant PK/PD/safety did not show immunogenicity concerns. Incidence of adverse events (AEs) was similar with INTP5 and pegfilgrastim-ref in both studies. The most common AEs were musculoskeletal pain and headache., Conclusion: INTP5 showed PK/PD equivalence with pegfilgrastim-ref following a single dose, no clinically meaningful difference in the immune response following multiple doses, and a comparable safety profile.

Introduction : Tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity, have significantly prolonged the overall survival of patients affected by chronic myeloid leukemia (CML) and changed drastically the outcome. Evidences from several studies suggest that in patients who have achieved a sustained, stable and deep molecular response, TKI treatment can be safely discontinued with a close subsequent monitoring. Thus, a stable deep molecular response (DMR) has become a feasible treatment goal in CML. Areas covered : In this review, the main findings extrapolated from sponsored and real-life evidences regarding TKI discontinuation were discussed, through a broad research on Medline, Embase and archives from EHA and ASH congresses (including words such as discontinuation, treatment-free remission, TFR, etc). Moreover, suggestions emerged from international guidelines about treatment-free remission (TFR) are presented. Expert opinion : With the growing availability of clinical trials and real-life data on TFR, in recent years the possibility of offering to CML patients a safe, informed and shorter path to TFR, through the achievement of a stable deep molecular response (DMR), has become an increasing option. However, many controversial aspects remain regarding treatment choices and timings, predictive factors, patient communication and optimal strategies aimed at achieving a successful TFR.

Despite broad clinical implications, the mechanisms linking inflammation and pain remain incompletely understood. Using human experimental endotoxemia as a translational model of systemic inflammation, we aimed to elucidate putative vulnerability factors of inflammation-induced musculoskeletal hyperalgesia. We pooled data from three published randomized controlled trials, resulting in a sample of N = 98 healthy volunteers who received either low-dose endotoxin (lipopolysaccharide) or vehicle (saline) intravenously. As measure of musculoskeletal pain sensitivity, pressure pain thresholds (PPTs) were assessed at baseline and 3 h post injection with a handheld algometer for the low back (erector spinae muscle), calf (gastrocnemius muscle), and shoulder region (deltoid muscle). Implementing multiple regression models, we tested the contribution of putative vulnerability factors on musculoskeletal hyperalgesia during systemic inflammation, including acute changes in pro-inflammatory cytokines, state anxiety and mood, as well as pre-existing symptoms of anxiety and depression. Endotoxin application led to significant increases in plasma cytokines, state anxiety, and negative mood, and significantly decreased PPTs for all muscle groups. Regression models revealed that greater M. erector spinae PPT changes were predicted by higher HADS-anxiety scores. Higher TNF-α concentration emerged as predictor for M. gastrocnemius PPT changes, and more pronounced TNF-α increase and higher HADS-anxiety were predictive for M. deltoideus PPTs. HADS scores emerged as predictor for a mean PPT score (computed across all body sites). Together, our results indicate that musculoskeletal hyperalgesia during systemic inflammation is related to pro-inflammatory cytokines, specifically TNF-α. Importantly, subclinical anxiety symptoms (even though in a low and normal range in this cohort of healthy volunteers) may contribute to inflammation-induced hyperalgesia, making individuals more vulnerable to the detrimental effects of systemic inflammation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with breast cancer (BC) show strong interest in complementary and alternative medicine (CAM), particularly for adverse effects of adjuvant endocrine treatment - e.g., with letrozole. Letrozole often induces myalgia/limb pain and arthralgia, with potential noncompliance and treatment termination. This analysis investigated whether CAM before aromatase inhibitor (AI) therapy is associated with pain development and the intensity of AI-induced musculoskeletal syndrome (AIMSS) during the first year of treatment., Patients and Methods: The multicenter phase IV PreFace study evaluated letrozole therapy in postmenopausal, hormone receptor-positive patients with early BC. Patients were asked about CAM use before, 6 months after, and 12 months after treatment started. They recorded pain every month for 1 year in a diary including questions about pain and numeric pain rating scales. Data were analyzed for patients who provided pain information for all time points., Results: Of 1396 patients included, 901 (64.5%) had used CAM before AI treatment. Throughout the observation period, patients with CAM before AI treatment had higher pain values, for both myalgia/limb pain and arthralgia, than non-users. Pain increased significantly in both groups over time, with the largest increase during the first 6 months. No significant difference of pain increase was noted regarding CAM use., Conclusions: CAM use does not prevent or improve the development of AIMSS. Pain intensity was generally greater in the CAM group. Therefore, because of the risk of non-compliance and treatment discontinuation due to the development of higher pain levels, special attention must be paid to patient education and aftercare in these patients., Competing Interests: Declaration of competing interest S·Y.B. has received honoraria from Pfizer and Novartis. W.J. has received honoraria and research grants from Novartis. A.D.H. has received honoraria from AstraZeneca, Genomic Health, Roche, Novartis, Celgene, and Pfizer. R.W. has received honoraria and research funds from Novartis. S.K. has received honoraria from Roche, Celgene, Amgen, and AstraZeneca and funding support from Roche. C.T. has received honoraria from Novartis, Pfizer, and AstraZeneca. M.P.L. has participated on advisory boards for AstraZeneca, MSD, Novartis, Pfizer, Genomic Health, and Roche and has received honoraria for lectures from Lilly, Roche, Novartis, Pfizer, Genomic Health, AstraZeneca, medac, and Eisai. P.G. has received honoraria from Novartis and financial support for symposia from Novartis, Roche, and PharmaMar. H.-C.K. has received honoraria from Carl Zeiss meditec, TEVA, Theraclion, Novartis, Amgen, Astra Zeneca, Pfizer, Janssen-Cilag, GSK, LIV Pharma, Roche, and Genomic Health. D.S.-B. has received honoraria from Novartis. M.W.B.‘s institution has received research grants from Novartis. T.F. has received honoraria from Pfizer, Novartis, Roche, and Amgen. P.A.F. has received honoraria from Roche, Pfizer, Novartis, and Celgene. His institution conducts research for Novartis. N.N. has received honoraria from Janssen-Cilag, Novartis and Teva. All of the remaining authors have declared that they have no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Musculoskeletal pain (MSKP) is the most reported symptom during treatment with aromatase inhibitors (AIs) for breast cancer. The mechanisms underlying MSKP are multidimensional and not well understood. The goals of this biological pathway analysis were to (1) gain an understanding of the genetic variation and biological mechanisms underlying MSKP with AI therapy and (2) identify plausible biological pathways and candidate genes for future investigation., Method: Genes associated with MSKP during AI therapy or genes involved in drug metabolism of and response to AIs were identified from the literature. Studies published through February 2019 were queried in PubMed®. The genes identified from the literature were entered into QIAGEN's Ingenuity® Pathway Analysis (IPA) software to generate canonical pathways, upstream regulators, and networks through a core analysis., Results: The 17 genes identified were ABCB1 , ABCG1 , CYP17A1 , CYP19A1 , CYP27B1 , CYP2A6 , CYP3A4 , CYP3A5 , ESR1 , OATP1B1 , OPG , RANKL, SLCO3A1 , TCL1A , UGT2A1 , UGT2B17 , and VDR . These genes are involved in encoding bone-remodeling regulators, drug-metabolizing enzymes (cytochrome P450 family, UDP-glucuronosyltransferases family), or drug transporters (ATP-binding cassette transporters, organic anion transporters). Multiple plausible biological pathways (e.g., nicotine degradation, melatonin degradation) and candidate genes (e.g., NFKB , HSP90 , AKT , ERK1/2 , FOXA2 ) are proposed for future investigation based on the IPA results., Conclusion: Multiple genes and molecular-level etiologies may contribute to MSKP with AI therapy in women with breast cancer. Our innovative combination of gene identification from the literature plus biological pathway analysis allowed for the emergence of novel candidate genes and biological pathways for future investigations.

Background: Survival for stage I to III, hormone receptor-positive, breast cancer has substantially improved over time due to advances in screening, surgery and adjuvant therapy. However many adjuvant therapies have significant treatment-related toxicities, which worsen quality of life for breast cancer survivors. Postmenopausal women with hormone receptor-positive breast cancer are now prescribed aromatase inhibitors (AI) as standard, with longer durations of therapy, up to 10 years, being considered for certain women. AI treatment is associated with a high incidence of AI-induced musculoskeletal symptoms (AIMSS), often described as symmetrical pain and soreness in the joints, musculoskeletal pain and joint stiffness. AIMSS reduces compliance with AI therapy in up to one half of women undergoing adjuvant AI therapy, potentially compromising breast cancer outcomes. Exercise has been investigated for the prevention and treatment of AIMSS but the effect of this intervention remains unclear., Objectives: To assess the effects of exercise therapies on the prevention or management of aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) in women with stage I to III hormone receptor-positive breast cancer., Search Methods: We searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases up to 13 December 2018. We also searched two conference proceedings portals and two clinical trials registries for ongoing studies or unpublished trials, or both, in August 2019. We also reviewed reference lists of the included studies., Selection Criteria: We included randomised controlled trials that compared exercise versus a comparator arm. We did not impose any restriction on the comparator arm, which could include an alternative type of exercise, no exercise or a waiting list control. Both published and non-peer-reviewed studies were eligible., Data Collection and Analysis: Two review authors independently extracted data, assessed risk of bias and certainty of the evidence using the GRADE approach. The outcomes investigated were pain, joint stiffness, grip strength, health-related quality of life, cancer-specific quality of life, adherence to AI therapy, adverse events, incidence of AIMSS, breast cancer-specific survival and overall survival. For continuous outcomes that were assessed with the same instrument, we used the mean difference (MD); for those outcomes that used different instruments, we used the standardised mean difference (SMD) for the analysis. For dichotomous outcomes, we reported outcomes as an odds ratio (OR)., Main Results: We included seven studies with 400 randomised participants; one study assessed exercise for preventing AIMSS and six studies assessed treating AIMSS. For preventing AIMSS, the single study reported no difference in pain scores, grip strength or compliance to taking AI medication between groups. Data values were not provided in the study and no other outcomes were reported. For managing AIMSS, we found that the evidence for the effect of exercise therapies on overall change in worst pain scores was very uncertain (SMD -0.23, 95% confidence interval (CI) -0.78 to 0.32; 4 studies, 284 women; very low-certainty evidence). The evidence suggested that exercise therapies result in little to no difference in overall change in stiffness scores (Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) stiffness score MD -0.76, 95% CI -1.67 to 0.15 and Visual Analogues Scale (VAS) stiffness score MD -0.42, 95% CI -2.10 to 1.26; 1 study, 53 women; low-certainty evidence). The evidence was very uncertain for the outcomes of overall change in grip strength (MD 0.30, 95% CI -0.55 to 1.15; 1 study, 83 women; very low-certainty evidence); overall change in health-related quality of life (subscales of SF-36 tool ranged from least benefit of MD 1.88, 95% CI -2.69 to 6.45 to most benefit of MD 9.70, 95% CI 1.67 to 17.73; 2 studies, 123 women, very low-certainty evidence); overall change in cancer-specific quality of life (MD 4.58, 95% CI -0.61 to 9.78; 2 studies, 136 women; very low-certainty evidence); and adherence to aromatase inhibitors (OR 2.43, 95% CI 0.41 to 14.63; 2 studies, 224 women; very low-certainty evidence). There were no adverse events identified across four studies in either arm (0 events reported; 4 studies; 331 participants; low-certainty evidence). There were no data reported on incidence of AIMSS, breast cancer-specific survival or overall survival., Authors' Conclusions: Given the wide-ranging benefits of exercise for people affected by cancer, it was surprising that this review provided no clear evidence of benefit for exercise therapies in women with early breast cancer with AIMSS. This review only yielded seven eligible studies with 400 participants, which is likely to have underpowered the findings. The meta-analysis was challenging due to the considerable heterogeneity amongst the trials, with a wide range of exercise regimens and follow-up periods. Despite these inconclusive findings, exercise needs to be part of routine care for women with breast cancer due to its wide-ranging benefits. Future research in this area would be enhanced with further understanding of the mechanism of AIMSS, a single clear definition of the condition, and phase III randomised controlled trials that are adequately powered to test targeted exercise interventions on the key clinical outcomes in this condition., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

One of the most common adverse events (AEs) occurring during treatment with aromatase inhibitors (AIs) is musculoskeletal pain. The aim of our study was to analyze the influence of preexisting muscle/limb pain and joint pain on the development of AI-induced musculoskeletal AEs. Women eligible for upfront adjuvant endocrine therapy with letrozole were included in the PreFace study, a multicenter phase IV trial. During the first treatment year, they were asked to record musculoskeletal AEs monthly by answering questions regarding pain symptoms and rating the pain intensity on a numeric rating scale from 0 (no pain) to 10 (very strong pain). Pain values were compared using nonparametric statistical tests. Overall, 1,416 patients were evaluable. The average pain value over all time points in women with preexisting muscle/limb pain was 4.3 (median 4.3); in those without preexisting pain, it was 2.0 (median 1.7). In patients without preexisting muscle/limb pain, pain levels increased relatively strongly within the first 6 months (mean increase +0.9, p < 0.00001) in comparison with those with preexisting pain (mean increase +0.3, p < 0.001), resulting in a statistically significant difference (p < 0.00001) between the two groups. The development of joint pain was similar in the two groups. Women without preexisting muscle/limb pain or joint pain have the greatest increase in pain after the start of adjuvant AI therapy. Women with preexisting pain have significantly higher pain values. The main increase in pain values takes place during the first 6 months of treatment., (© 2019 UICC.)

Background: Low-level laser therapy (LLLT) is widely used in pain control in the field of physical medicine and rehabilitation and is effective for fibromyalgia pain. However, its analgesic mechanism remains unknown. A possible mechanism for the effect of LLLT on fibromyalgia pain is via the antinociceptive signaling of substance P in muscle nociceptors, although the neuropeptide has been known as a neurotransmitter to facilitate pain signals in the spinal cord., Objective: To establish an animal model of LLLT in chronic muscle pain and to determine the role of substance P in LLLT analgesia., Methods: We employed the acid-induced chronic muscle pain model, a fibromyalgia model proposed and developed by Sluka et al., and determined the optimal LLLT dosage., Results: LLLT with 685 nm at 8 J/cm2 was effective to reduce mechanical hyperalgesia in the chronic muscle pain model. The analgesic effect was abolished by pretreatment of NK1 receptor antagonist RP-67580. Likewise, LLLT showed no analgesic effect on Tac1-/- mice, in which the gene encoding substance P was deleted. Besides, pretreatment with the TRPV1 receptor antagonist capsazepine, but not the ASIC3 antagonist APETx2, blocked the LLLT analgesic effect., Conclusions: LLLT analgesia is mediated by the antinociceptive signaling of intramuscular substance P and is associated with TRPV1 activation in a mouse model of fibromyalgia or chronic muscle pain. The study results could provide new insight regarding the effect of LLLT in other types of chronic pain., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Nivolumab demonstrated durable responses and safety in patients with hepatocellular carcinoma (HCC) with Child-Pugh class A cirrhosis in the CheckMate 040 trial, with rates of hepatotoxicity that were similar to those of non-HCC populations. To the authors' knowledge, the safety and efficacy of nivolumab has not been established in patients with Child-Pugh class B (CPB) cirrhosis, a population with limited therapeutic options and a poor prognosis., Methods: The authors conducted a retrospective case series of patients with advanced HCC and CPB cirrhosis who were treated with nivolumab and enrolled in the University of California at San Francisco Hepatobiliary Tissue Bank and Registry. Safety endpoints included rates of grade ≥3 adverse events (AEs) (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]) and serious AEs, immune-related AEs (irAE), steroid requirement, and discontinuation. Efficacy endpoints included time on treatment, the objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, overall survival, and progression-free survival., Results: A total of 18 patients were included, with 72% of them (13 of 18 patients) previously treated with sorafenib. The majority of patients (94%; 17 of 18 patients) experienced a grade ≥3 AE, with treatment-related grade ≥3 AEs reported in 28% of patients (5 of 18 patients). irAEs were reported to occur in approximately 50% of patients (9 of 18 patients), and 28% (5 of 18 patients) required steroids. Treatment-related AEs required discontinuation in 4 patients (22%). The median time on treatment was 2.3 months (95% CI, 1.9 months to upper bound not estimable). The objective response rate was 17% (3 of 18 patients), including 2 partial responses and 1 complete response. The median overall survival from the time of nivolumab initiation was 5.9 months (95% CI, 3 months to upper bound not estimable), with a median progression-free survival of 1.6 months (95% CI, 1.4-3.5 months)., Conclusions: Patients with CPB HCC experienced high rates of AEs, although the frequency of irAEs was similar to that of patients with Child-Pugh class A HCC in the CheckMate 040 trial. A subset of patients experienced prolonged tumor responses. Nivolumab warrants further study in patients with CPB HCC., (© 2019 American Cancer Society.)

Clinical trials have shown that for some patients with chronic myeloid leukemia in chronic phase receiving tyrosine kinase inhibitors (TKIs), treatment-free remission (TFR) is achievable and safe. TFR is now a treatment goal for select patients who have experienced a sustained deep molecular response. An expected result of TFR would be a decrease in the frequency or intensity of adverse events (AEs) associated with TKI therapy. Unexpectedly, however, some clinical trials have reported new or worsening AEs, typically described as musculoskeletal pain, in patients attempting TFR. These AEs are hypothesized to be a TKI withdrawal syndrome, although the underlying mechanism is not known. Overall, musculoskeletal pain has been reported in approximately 20% to 30% of patients attempting TFR and is typically transient and easily managed. TKI cessation would be expected to improve patients' quality of life (QOL); however, in studies assessing QOL, patients have reported little change after ceasing TKI therapy, perhaps because they must tolerate long-term TKI therapy before they can attempt TFR. Here we review reports of musculoskeletal pain during TFR and changes in QOL after TKI cessation in clinical trials. As more patients attempt TFR in routine practice, the health care community will play an important role in helping these patients understand the benefits and risks of TFR, the effect it may have on their QOL, and the potential for musculoskeletal pain., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Tiger dancing or Hulivesha, where the volunteers paint their bare body like a tiger and dance in a ritual during the Navarathri festival in Mangalore, India. There are no scientific studies done with the Hulivesha dancers at all, and therefore, we investigated the adverse effects of painting body like a tiger and dancing in the volunteers., Objective/aim: In this study, we investigated the clinico-haematological effects of topical application of lead-containing paint and dancing for three consecutive days in these dancers to ascertain the toxic effects of whole body painting and dancing., Materials and Methods: This was a case-control study and was conducted during the Dasara festival in 2013 in the Huliveshadaris (study group) and the accompanying drummers (controls). Clinical, dermatological, and musculoskeletal examination were done before (day 0) and after the three days of the function (day 3). Blood was also collected and examined for alterations in the hematological parameters, lead, antioxidant glutathione, and lipid peroxidation levels., Results: The results indicated that the all Hulivesha volunteers had severe musculoskeletal pain, while few also complained of skin reactions (61.6%), headache (25%) and nausea, and vomiting (18.75%). The results also indicated that topical application increased the levels of blood lead, caused a change in the haematological profile, decreased glutathione and increased lipid peroxidation (p < 0.03-0.0001)., Conclusions: The results from this study clearly shows that topical application of the acrylic paint increases lead, changes haematological parameters and imparts adverse skin reactions.

Purpose: Breast cancer patients receiving hormonal therapies face risks of relapse, increased rates of cardiovascular events, and toxicities of therapy such as aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS). C-reactive protein (CRP), a marker for inflammation, is associated with breast cancer outcomes. We evaluated whether the olive-derived polyphenol hydroxytyrosol combined with omega-3 fatty acids and curcumin would reduce CRP and musculoskeletal symptoms in breast cancer patients receiving adjuvant hormonal therapies., Experimental Design: This prospective, multicenter, open-label, single arm, clinical trial enrolled post-menopausal breast cancer patients (n = 45) with elevated C-reactive protein (CRP) taking predominantly aromatase inhibitors to receive a combination of hydroxytyrosol, omega-3 fatty acids, and curcumin for 1 month. CRP, other inflammation-associated cytokines, and pain scores on the Brief Pain Inventory were measured before therapy, at the end of therapy and 1 month after completion of therapy., Results: CRP levels declined during the therapy [from 8.2 ± 6.4 mg/L at baseline to 5.3 ± 3.2 mg/L (p = 0.014) at 30 days of treatment], and remained decreased during the additional 1 month off therapy. Subjects with the highest baseline CRP levels had the greatest decrease with the therapy. Pain scores also decreased during the therapy. There were no significant adverse events., Conclusions: The combination of hydroxytyrosol, omega-3 fatty acids, and curcumin reduced inflammation as indicated by a reduction in CRP and reduced pain in patients with aromatase-induced musculoskeletal symptoms. Longer studies comparing this combination to other anti-inflammatories in larger groups of patients with clinical outcome endpoints are warranted.

In light of waning immunity to pertussis following receipt of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine, maintaining protection may require repeated Tdap vaccination. We evaluated the safety of repeated doses of tetanus-containing vaccine in 68 915 nonpregnant adolescents and adults in the Vaccine Safety Datalink population who had received an initial dose of Tdap. Compared with 7521 subjects who received a subsequent dose of tetanus toxoid, reduced diphtheria (Td) vaccine, the 61 394 subjects who received a subsequent dose of Tdap did not have significantly elevated risk of medical visits for seizure, cranial nerve disorders, limb swelling, pain in limb, cellulitis, paralytic syndromes, or encephalopathy/encephalitis/meningitis. These results suggest that repeated Tdap vaccination has acceptable safety relative to Tdap vaccination followed by Td vaccination., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: Chemotherapy for breast cancer is associated with a high risk of neutropenia. Pegfilgrastim reduces the risk of neutropenic fever but commonly causes bone pain., Objective: Evaluate whether a reduced dose of pegfilgrastim (3 mg) reduced the frequency of bone pain without compromising efficacy., Methods: Records reviewed from breast cancer patients who received at least one 3 mg dose of pegfilgrastim, white blood count (WBC), and absolute granulocyte counts (AGC) were collected. Musculoskeletal pain scale was collected at each visit., Results: 265 treatments from 36 women were analyzed. There was no difference in post-treatment AGC between 3 versus 6 mg. Leukocytosis (WBC > 20,000 cells/cu mm) was more likely for those treated with 6 mg (chi-square 5.265, p = 0.0215). There was higher change in bone pain in patients who received 6 mg doses compared to none or 3 mg., Limitations: In this retrospective, non-randomized study, we found the majority of patients received the reduced 3 mg dose after intolerance to the 6 mg dose. It is unknown if smaller or larger doses than 3 mg would achieve similar results or whether 3 mg dose would be effective as an initial therapy or for patients receiving different chemotherapy regimens. Pain is observed despite premedication with naproxen and/or loratidine., Conclusion: Reduced dose of pegfilgrastim 3 mg was less likely to cause bone pain. The reduced dose was not associated with a significant difference in post-treatment AGC or rate of serious infection.

As individuals with musculoskeletal disorders often experience motor impairments, contemporary rehabilitation relies heavily on the use of motor learning principles. However, motor impairments are often associated with pain. Although there is substantial evidence that muscle pain interferes with motor control, much less is known on its impact on motor learning. The objective of the present study was to assess the effects of muscle pain on locomotor learning. Two groups (Pain and Control) of healthy participants performed a locomotor adaptation task (robotized ankle-foot orthosis perturbing ankle movements during swing) on two consecutive days. On day 1 (acquisition), hypertonic saline was injected in the tibialis anterior (TA) muscle of the Pain group participants, while Control group participants were pain free. All participants were pain free on day 2 (retention). Changes in movement errors caused by the perturbation were assessed as an indicator of motor performance. Detailed analysis of kinematic and electromyographic data provided information about motor strategies. No between-group differences were observed on motor performance measured during the acquisition and retention phases. However, Pain group participants had a residual movement error later in the swing phase and smaller early TA activation than Control group participants, thereby suggesting a reduction in the use of anticipatory motor strategies to overcome the perturbation. Muscle pain did not interfere with global motor performance during locomotor adaptation. The different motor strategies used in the presence of muscle pain may reflect a diminished ability to anticipate the consequences of a perturbation. NEW & NOTEWORTHY This study shows that experimental muscle pain does not influence global motor performance during the acquisition or next-day retention phases of locomotor learning. This contrasts with previous results obtained with cutaneous pain, emphasizing the risk of directly extrapolating from one pain modality to another. Muscle pain affected motor strategies used when performing the task, however: it reduced the ability to use increased feedforward control to overcome the force field.

Introduction: Adherence to aromatase inhibitor (AI) therapy is poor, often because of treatment-emergent side effects, including musculoskeletal symptoms, fatigue, and insomnia. In the present analysis, we examined the sleep patterns and daytime function both objectively using actigraphy and subjectively using validated questionnaires in women initiating AI therapy., Patients and Methods: Postmenopausal women with stage 0-III hormone receptor-positive breast cancer who were initiating AI therapy were eligible. The patients wore actigraphy devices for 10 consecutive days and completed questionnaires at baseline before the initiation of AI and after 3 months of AI therapy. Associations between the baseline demographics and symptoms, changes in patient-reported outcomes and actigraphy measures from baseline to 3 months of AI therapy and discontinuation of AI therapy were examined using sign tests, logistic regression models, Spearman's correlation, and linear mixed models., Results: Forty-two patients (86%) completed the baseline assessments and 23 patients (47%) completed both the baseline and the 3-month assessments. Objectively measured daytime function as measured by total daytime activity decreased during the 3 months after starting AI (232,566 activity count vs. 204,205 activity count; P = .023), and the decrease was more evident in women with higher baseline physical function. Reduced daytime activity correlated with increased fatigue (ρ = -0.49; P = .017)., Conclusion: Daytime function decreased after initiation of AI therapy and correlated moderately with increased fatigue, although no association was identified with changes in pain or sleep quality. Additional studies are required to understand why function is reduced, which could have implications for interventions to improve patient tolerance of, and persistence with, AI therapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n - 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms., Methods: We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n - 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks., Results: Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n - 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n - 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n - 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n - 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks., Conclusion: High-dose n - 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are prevalent among patients on AI therapy, which leads to a lower quality of life and poor adherence to AI treatment. We evaluated whether Yi Shen Jian Gu granules (YSJG) is effective and safe to relieve AIMSS in patients with breast cancer. Eligible participants were randomly assigned to the YSJG group or the placebo group. Both groups had a 12-week treatment period and a 12-week follow-up period. Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index, and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M-SACRAH) were obtained at baseline and at 4, 8, 12 and 24 weeks. Of 146 participants enrolled, 84 were randomly assigned, and 77 were evaluable at 12 weeks. Baseline characteristics were comparable between two groups. The primary outcome was the differences in mean BPI-SF scores at 12 weeks. The worst pain scores decreased by 3.10 points (50.2%; 95% CI, 2.50 to 3.65) for YSJG group compared with a 1.63-point decrease (26.9%; 95% CI, 3.86 to 4.97) for the placebo group (P = 0.001). Significantly improvements were also observed for the WOMAC and M-SACRAH. Possibly YSJG-related side effects were grade 1 nausea (10%) and grade 2 diarrhea (2%). Serum follicle-stimulating hormone and serum estradiol were kept in the postmenopausal range before and after YSJG treatment. Patients with AIMSS treated with YSJG granules had significant improvements in musculoskeletal symptoms. YSJG is effective, safe and well-tolerated in managing AIMSS., Trial Registration: ISCTN: ISRCTN06129599 (assigned 14 August 2013)., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) frequently occur in women being treated for breast cancer. Prior studies suggest high prevalence of vitamin D deficiency in breast cancer patients with musculoskeletal (MS) pain. We conducted a randomized, placebo-controlled trial to determine if 30,000 IU vitamin D3 per week (VitD3) would prevent worsening of AIMSS in women starting adjuvant letrozole for breast cancer., Methods: Women with stage I-III breast cancer starting adjuvant letrozole and 25(OH)D level ≤40 ng/ml were eligible. All subjects received standard daily supplement of 1200 mg calcium and 600 IU vitamin D3 and were randomized to 30,000 IU oral VitD3/week or placebo. Pain, disability, fatigue, quality of life, 25(OH)D levels, and hand grip strength were assessed at baseline, 12, and 24 weeks. The primary endpoint was incidence of an AIMSS event., Results: Median age of the 160 subjects (80/arm) was 61. Median 25OHD (ng/ml) was 25 at baseline, 32 at 12 weeks, and 31 at 24 weeks in the placebo arm and 22, 53, and 57 in the VitD3 arm. There were no serious adverse events. At week 24, 51% of women assigned to placebo had a protocol defined AIMSS event (worsening of joint pain using a categorical pain intensity scale (CPIS), disability from joint pain using HAQ-II, or discontinuation of letrozole due to MS symptoms) vs. 37% of women assigned to VitD3 (p = 0.069). When the brief pain inventory (BPI) was used instead of CPIS, the difference was statistically significant: 56 vs. 39% (p = 0.024)., Conclusions: Although 30,000 IU/week of oral vitamin D3 is safe and effective in achieving adequate vitamin D levels, it was not associated with a decrease in AIMSS events based on the primary endpoint. Post-hoc analysis using a different tool suggests potential benefit of vitamin D3 in reducing AIMSS.

Objectives: To investigate the effects of experimental adductor pain on the pain referral pattern, mechanical sensitivity and muscle activity during common clinical tests., Design: Repeated-measures design., Methods: In two separate sessions, 15 healthy males received a hypertonic (painful) and isotonic (control) saline injection to either the adductor longus (AL) tendon to produce experimental groin pain or into the rectus femoris (RF) tendon as a painful control. Pain intensity was recorded on a visual analogue scale (VAS) with pain distribution indicated on body maps. Pressure pain thresholds (PPT) were assessed bilaterally in the groin area. Electromyography (EMG) of relevant muscles was recorded during six provocation tests. PPT and EMG assessment were measured before, during and after experimental pain., Results: Hypertonic saline induced higher VAS scores than isotonic saline (p<0.001), and a local pain distribution in 80% of participants. A proximal pain referral to the lower abdominal region in 33% (AL) and 7% (RF) of participants. Experimental pain (AL and RF) did not significantly alter PPT values or the EMG amplitude in groin or trunk muscles during provocation tests when forces were matched with baseline., Conclusions: This study demonstrates that AL tendon pain was distributed locally in the majority of participants but may refer to the lower abdomen. Experimental adductor pain did not significantly alter the mechanical sensitivity or muscle activity patterns., (Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Chronic musculoskeletal pain is one of the main symptoms found in Fibromyalgia with unclear etiology and limited pharmacological treatment. The aim of this study was to complex LIM in β-cyclodextrin (LIM-βCD) and then evaluate its antihyperalgesic effect in an animal model of chronic musculoskeletal pain. Differential scanning calorimetry and scanning electron microscopy was used for the characterization of the inclusion complex. Male Swiss mice were used for experimental procedures where mechanical hyperalgesia, thermal hyperalgesia, muscular strength, Fos immunofluorescence was studied after induction of hyperalgesia. Mechanism of action was also investigated through tail flick test and capsaicin-induced nociception. Endothermic events and morphological changes showed that the slurry complex method was the best method for the complexation. After induction of hyperalgesia, the oral administration of LIM-βCD (50mg/kg) significantly increased the paw withdrawal threshold compared to uncomplexed limonene. Fos immunofluorescence showed that both compounds significantly decreased the number of Fos-positive cells in the dorsal horn. In nociceptive tests, FLU was able to reverse the antinociceptive effect of LIM-βCD. After intraplantar administration of capsaicin, LIM was able to significantly decrease time to lick. LIM-βCD has antihyperalgesic action superior to its uncomplexed form, with possible action in the dorsal horn of the spinal cord. These results suggest the possible applicability of LIM, uncomplexed or complexed with βCD, in conditions such as FM and neuropathic pain, for which there are currently only limited pharmacological options., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: Febrile neutropenia (FN) is an oncological emergency that may reduce patient survival due to chemotherapy dose delays or reductions. It is recommended that patients at risk for FN receive prophylaxis with granulocyte-colony stimulating factor (G-CSF). Bone pain is a common side effect through a mechanism not fully understood. It is thought to be due to histamine release from an inflammatory response., Methods: This was a retrospective cohort from January to November 2015. Oncology patients receiving an initial dose of G-CSFs rated their bone pain on a 0-10 scale prior to starting each cycle of chemotherapy and at least 1 day after G-CSF had been given. Those who developed bone pain received prophylaxis at their next G-CSF dose with a combination of famotidine and loratadine. The primary endpoint was to determine the analgesic effects of double histamine blockade for G-CSF induced bone pain. The secondary endpoint was to determine potential risk factors for the development of bone pain., Results: Thirty percent of patients developed bone pain within this cohort, and 17 patients were included in the final analysis. Bone pain scores were lower by a mean of 1.21[(0.20-2.23), p = 0.019] in patients who were prophylaxed with the double histamine blockade. Type of cancer, treatment, age, and BMI were not significant predictors of bone pain., Conclusion: The use of a double histamine blockade is an inexpensive, safe, and effective way to alleviate bone pain symptoms secondary to G-CSF agents. Further investigation is warranted for prospective larger studies to confirm these results.

Introduction: Musculoskeletal pain associated to statin use, is the most common adverse event, leading to cessation of treatment. Several studies proposed Vitamin D deficiency to increase the risk of pain associated to statin intake., Objectives: To evaluate whether vitamin D status is linked to musculoskeletal pain associated to statin use., Methods: We performed a systematic review based on electronic searches through MEDLINE, Cochrane Central and EMBASE to identify studies that 1) included patients on statin therapy 2) with vitamin D serum levels assessment, 3) in relation to musculoskeletal pain., Results: The electronic search identified 127 potentially eligible studies, of which three were included and analysed in the present study. The heterogeneity of studies did not allow metanalysis. A systematic review and two cohort studies not included in the previous systematic review, revealed a statistically significant association of vitamin D deficit in patients with musculoskeletal pain on statin therapy., Conclusion: The displayed evidence suggests a significant association between 25OHD serum levels<30ng/ml and the presence of musculoskeletal pain in patients on statin therapy., (Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Purpose: Chemotherapy-induced neutropenia is a serious and potentially life-threatening consequence of cancer treatment. Prophylactic treatment with granulocyte-colony stimulating factor (G-CSF) decreases the incidence of febrile neutropenia, the rate of hospitalization, and the use of antibiotics in patients at risk. The aim of this study was to assess efficacy, safety, and use of Zarzio(®)-biosimilar of Neupogen(®) (G-CSF; filgrastim)-in prophylaxis of chemotherapy-induced neutropenia in current practice in cancer patients., Methods: We conducted an observational, prospective, longitudinal, and multicentric study in France. The incidence of neutropenia was evaluated at each cycle of chemotherapy., Results: One hundred eighty-four patients (women, 64.7 %; mean age, 61.7 years) with solid tumor (89.7 %; breast cancer, 50.5 %) or non-Hodgkin lymphoma (10.3 %) were included. The risk of febrile neutropenia based on chemotherapy regimen was >20 % for 32.1 % of patients. No case of febrile neutropenia was reported. Neutropenia was the cause of hospitalization and/or antibiotic therapy in 10 patients. The most frequent adverse events related to Zarzio(®) were pain, in particular bone pain. No serious adverse event related to Zarzio(®) was reported., Conclusion: The results obtained in real-life conditions confirm that Zarzio(®) is efficient and well tolerated in cancer patients.

Background: Cancer survival rates are improving, but this increased survivorship is offset by persistent treatment-related symptoms. Taxane-induced musculoskeletal pain (TIMP) is 1 treatment-related symptom likely undermining cancer survivors' health-related quality of life., Objective: The specific aims of this review were to evaluate (1) the conceptual clarity of TIMP, (2) descriptions of the TIMP symptom experience, (3) contextual variables influencing TIMP, and (4) the impact of TIMP on selected outcomes., Methods: A systematic approach conducted in PubMed yielded 688 articles, and 12 articles included evaluable data related to TIMP., Results: On average, 2 to 4 terms signifying TIMP were used; among the terms arthralgia, myalgia, and bone pain, the range of TIMP prevalence estimates varied from 1.3% to 94%. Intensity was measured in all studies, most commonly (50% of studies) using the National Cancer Institute Common Toxicity Criteria. Contextual variables and the impact of TIMP on outcomes were addressed in only 17% and 42% of studies, respectively., Conclusions: Research to date has involved inconsistent use of terms signifying TIMP. Assessment of TIMP has been largely limited to intensity, with few studies evaluating contextual variables influencing TIMP or the impact of TIMP on outcomes. More comprehensive TIMP assessment is necessary in future research., Implications for Practice: In order to improve patient-reported outcomes in cancer care, control of treatment-related symptoms is essential. Further research about TIMP will address national priorities for generating new knowledge to advance symptom science and will be directly relevant to the care of cancer survivors undergoing taxane-based chemotherapy.

Introduction: Large databases of clinician reported (e.g., allergy repositories) and patient reported (e.g., social media) adverse drug reactions (ADRs) exist; however, whether patients and clinicians report the same concerns is not clear., Objectives: Our objective was to compare electronic health record data and social media data to better understand differences and similarities between clinician-reported ADRs and patients' concerns regarding aspirin and atorvastatin., Methods: This pilot study explored a large repository of electronic health record data and social media data for clinician-reported ADRs and patients concerns for two common medications: aspirin (n = 31,817 ADRs accessible in clinical data; n = 19,186 potential ADRs accessible in social media data) and atorvastatin (n = 15,047 ADRs accessible in clinical data; n = 23,408 potential ADRs accessible in social media data)., Results: We found that the most frequently reported ADRs matched the most frequent patients' concerns. However, several less frequently reported reactions were more prevalent on social media (i.e., aspirin-induced hypoglycemia was discussed only on social media). Overall, we found a relatively strong positive and statistically significant correlation between the frequency ranking of reactions and patients' concerns for atorvastatin (Pearson's r = 0.61, p < 0.001) but not for aspirin (Pearson's r = 0.1, p = 0.69)., Conclusion: Future studies should develop further natural language methods for a more detailed data analysis (i.e., identifying causality and temporal aspects in the social media data).

Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase, and voriconazole concentration did not predict for fluoride excess and associated pain. Periostitis due to fluoride excess is a common adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible after drug discontinuation. Alternative antifungal agents with a lower risk for fluoride excess should be considered in patients receiving voriconazole who develop fluoride excess and pain., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Aromatase inhibitor (AI) therapy is associated with musculoskeletal (MS) toxicity, which adversely affects quality of life and therapy adherence. Our objective was to evaluate whether genetic variants may predict endocrine therapy-related MS pain and hot flashes in a prospective observational cohort study., Patients & Methods: 254 early breast cancer patients starting AI (n = 159) or tamoxifen therapy (n = 95) were included in this genetic biomarker study. MS and vasomotor symptoms were assessed at baseline and after 3, 6 and 12 months of therapy. AI-induced MS pain was defined as an increase in arthralgia or myalgia relative to baseline. Single nucleotide polymorphisms (SNP) in candidate genes involved in oestrogen signalling or previously associated with AI-related MS pain or oestrogen levels were selected., Results: Overall, 13 SNPs in CYP19, CYP17, osteoprotegerin (OPG) and oestrogen receptor 1 exhibited an allele frequency >0.05 and were included in the analysis. Patients carrying the G allele of rs2073618 in OPG experienced significantly more AI-induced MS toxicity compared to the wildtype allele, after correction for multiple testing (P = 0.046). Furthermore, this SNP was associated with severity of pain (P = 0.018). No association was found with regard to the other SNPs, both in AI and tamoxifen-treated patients. Neither could an association with vasomotor symptoms be demonstrated., Conclusion: The SNP rs2073618 in OPG is associated with an increased risk of MS symptoms and pain with AI therapy, which has not been reported previously. Validation of this finding in larger cohorts and further functional studies are required., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Lipegfilgrastim is a once-per-cycle, fixed-dose, glycoPEGylated recombinant granulocyte colony-stimulating factor (G-CSF) recently approved in Europe to reduce the duration of chemotherapy-induced neutropenia and incidence of febrile neutropenia in patients with cancer receiving chemotherapy. Bone pain-related (BPR) adverse events are commonly associated with G-CSF therapy. This post hoc analysis examined BPR treatment-emergent adverse events (TEAEs) in two comparative studies of lipegfilgrastim or pegfilgrastim in patients receiving chemotherapy., Methods: A post hoc analysis was conducted using integrated data from two double-blind randomized studies in patients with breast cancer receiving docetaxel and doxorubicin and treated prophylactically with subcutaneous lipegfilgrastim 6 mg or pegfilgrastim 6 mg once per cycle. BPR TEAEs were defined as arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, myalgia, neck pain, noncardiac chest pain, and pain in extremity. Relationship of BPR TEAEs to study treatment or chemotherapy was also reported by the investigators., Results: The analysis included 306 patients (lipegfilgrastim: n = 151; pegfilgrastim: n = 155). The proportion of patients experiencing BPR TEAEs was similar with lipegfilgrastim and pegfilgrastim (25.2 vs 21.9%, respectively), as was the proportion of patients experiencing BPR treatment-emergent adverse drug reactions (TEADRs) (18.5 vs 16.8%, respectively). No BPR TEADRs were serious, and none led to discontinuation., Conclusions: Nonsevere BPR TEAEs and TEADRs were observed in patients with breast cancer receiving chemotherapy and G-CSF; rates of BPR events were similar between lipegfilgrastim and pegfilgrastim. The similar BPR safety profile of lipegfilgrastim and pegfilgrastim provides support for use in patients with breast cancer receiving chemotherapy.

Purpose: Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Omega-3 fatty acids (O3-FAs) can be effective in decreasing arthralgia resulting from rheumatologic conditions and reducing serum triglycerides., Patients and Methods: Women with early-stage breast cancer receiving an AI who had a worst joint pain/stiffness score ≥ 5 of 10 using the Brief Pain Inventory-Short Form (BPI-SF) were randomly assigned to receive either O3-FAs 3.3 g or placebo (soybean/corn oil) daily for 24 weeks. Clinically significant change was defined as ≥ 2-point drop from baseline. Patients also completed quality-of-life (Functional Assessment of Cancer Therapy-Endocrine Symptoms) and additional pain/stiffness assessments at baseline and weeks 6, 12, and 24. Serial fasting blood was collected for lipid analysis., Results: Among 262 patients registered, 249 were evaluable, with 122 women in the O3-FA arm and 127 in the placebo arm. Compared with baseline, the mean observed BPI-SF score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo. In a linear regression adjusting for the baseline score, osteoarthritis, and taxane use, adjusted 12-week BPI-SF scores did not differ by arm (P = .58). Triglyceride levels decreased in patients receiving O3-FA treatment and remained the same for those receiving placebo (P = .01). No between-group differences were seen for HDL, LDL, or C-reactive protein., Conclusion: We found a substantial (> 50%) and sustained improvement in AI arthralgia for both O3-FAs and placebo but found no meaningful difference between the groups., (© 2015 by American Society of Clinical Oncology.)