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Fatigue is a common symptom of rheumatic diseases and frequently persists even when patients are in a near-remission state. In seeking options to manage troublesome symptoms such as fatigue, complementary and alternative medicines (CAM) are often used by patients despite a lack of evidence base behind such treatment strategies. CAM use is further promoted by social media and ‘influencer’ marketing without rigorous process to ensure scientific accuracy. One mechanism of recent interest in the CAM market is enhancing cellular pathways of nicotinamide adenine dinucleotide (NAD+), purported to restore mitochondrial function. However, clinical trials of NAD+ pathway supplements lack rigorous trial design, many declare conflicts of interest, and safety data is limited. Ultimately, CAM use by our patients is unavoidable. To adequately inform patients about CAM, we need to keep updated on both the latest scientific literature and social media trends. In so doing, we can then propose to patients how standard-of-care therapies, evidence-based lifestyle modifications and CAM might safely and effectively integrate to form a treatment plan.

Objectives Fibromyalgia is frequently treated with opioids due to limited therapeutic options. Long-term opioid use is associated with several adverse outcomes. Identifying factors associated with long-term opioid use is the first step in developing targeted interventions. The aim of this study was to evaluate risk factors in fibromyalgia patients newly initiated on opioids using machine learning.Methods A retrospective cohort study was conducted using a nationally representative primary care dataset from the UK, from the Clinical Research Practice Datalink. Fibromyalgia patients without prior cancer who were new opioid users were included. Logistic regression, a random forest model and Boruta feature selection were used to identify risk factors related to long-term opioid use. Adjusted ORs (aORs) and feature importance scores were calculated to gauge the strength of these associations.Results In this study, 28 552 fibromyalgia patients initiating opioids were identified of which 7369 patients (26%) had long-term opioid use. High initial opioid dose (aOR: 31.96, mean decrease accuracy (MDA) 135), history of self-harm (aOR: 2.01, MDA 44), obesity (aOR: 2.43, MDA 36), high deprivation (aOR: 2.00, MDA 31) and substance use disorder (aOR: 2.08, MDA 25) were the factors most strongly associated with long-term use.Conclusions High dose of initial opioid prescription, a history of self-harm, obesity, high deprivation, substance use disorder and age were associated with long-term opioid use. This study underscores the importance of recognising these individual risk factors in fibromyalgia patients to better navigate the complexities of opioid use and facilitate patient-centred care.

BackgroundOpioids administered in hospital during the immediate postoperative period are likely to influence post-surgical outcomes, but inpatient prescribing during the admission is challenging to access. Modified-release(MR) preparations have been especially associated with harm, whilst certain populations such as the elderly or those with renal impairment may be vulnerable to complications. This study aimed to assess postoperative opioid utilisation patterns during hospital stay for people admitted for major/orthopaedic surgery.MethodsPatients admitted to a teaching hospital in the North-West of England between 2010-2021 for major/orthopaedic surgery with an admission for ≥1 day were included. We examined opioid administrations in the first seven days post-surgery in hospital, and "first 48 hours" were defined as the initial period. Proportions of MR opioids, initial immediate-release(IR) oxycodone and initial morphine milligram equivalents (MME)/day were calculated and summarised by calendar year. We also assessed the proportion of patients prescribed an opioid at discharge.ResultsAmong patients admitted for major/orthopaedic surgery, 71.1% of patients administered opioids during their hospitalisation. In total 50,496 patients with 60,167 hospital admissions were evaluated. Between 2010-2017 MR opioids increased from 8.7% to 16.1% and dropped to 11.6% in 2021. Initial use of oxycodone IR among younger patients (≤70 years) rose from 8.3% to 25.5% (2010-2017) and dropped to 17.2% in 2021. The proportion of patients on ≥50MME/day ranged from 13% (2021) to 22.9% (2010). Of the patients administered an opioid in hospital, 26,920 (53.3%) patients were discharged on an opioid.ConclusionsIn patients hospitalised with major/orthopaedic surgery, 4 in 6 patients were administered an opioid. We observed a high frequency of administered MR opioids in adult patients and initial oxycodone IR in the ≤70 age group. Patients prescribed with ≥50MME/day ranged between 13-22.9%. This is the first published study evaluating UK inpatient opioid use, which highlights opportunities for improving safer prescribing in line with latest recommendations.

Pain management has been a challenging issue for people living with rheumatic and musculoskeletal diseases (RMDs) and health professionals for decades. Pharmacological treatments remain a core element of pain management of inflammatory arthritis and osteoarthritis. Yet balancing the benefits/harms in pain management within RMDs can be difficult to navigate due to limited effective options, and emerging adverse events in a population where individual risk is important to consider due to patient multimorbidity, immunosuppression and polypharmacy. Paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) analgesics are widely used among RMD patients, however both classes of drugs have been associated with new safety concerns in the last two decades. Perhaps as a result in combination with multifactorial influences, opioid prescribing has increased from the 2000s–2010s in the majority of RMD focussed studies, accompanied with a rising trend of long-term opioid use, despite limited evidence on efficacy. Gabapentinoids have also shown increasing trends more recently, despite an unclear role in chronic pain management for RMDs within current guidelines. Antidepressants are recommended as the first line of pharmacological treatment of chronic primary pain (e.g., fibromyalgia) by the latest National Institute for Health and Care Excellence (NICE) guideline released in April 2021. This concise narrative review will discuss pharmacological options for pain management, based on the latest evidence that includes the main analgesic drug classes: paracetamol, NSAIDs, opioids, antidepressants, and gabapentinoids. We will discuss the efficacy of these analgesics in RMDs and emerging safety concerns to enable more informed shared decisions with patients commencing such medications.

Background The opioid epidemic in North America has been driven by an increase in the use and potency of prescription opioids, with ensuing excessive opioid-related deaths. Internationally, there are lower rates of opioid-related mortality, possibly because of differences in prescribing and health system policies. Our aim was to compare opioid prescribing rates in patients without cancer, across 5 centers in 4 countries. In addition, we evaluated differences in the type, strength, and starting dose of medication and whether these characteristics changed over time. Methods and findings We conducted a retrospective multicenter cohort study of adults who are new users of opioids without prior cancer. Electronic health records and administrative health records from Boston (United States), Quebec and Alberta (Canada), United Kingdom, and Taiwan were used to identify patients between 2006 and 2015. Standard dosages in morphine milligram equivalents (MMEs) were calculated according to The Centers for Disease Control and Prevention. Age- and sex-standardized opioid prescribing rates were calculated for each jurisdiction. Of the 2,542,890 patients included, 44,690 were from Boston (US), 1,420,136 Alberta, 26,871 Quebec (Canada), 1,012,939 UK, and 38,254 Taiwan. The highest standardized opioid prescribing rates in 2014 were observed in Alberta at 66/1,000 persons compared to 52, 51, and 18/1,000 in the UK, US, and Quebec, respectively. The median MME/day (IQR) at initiation was highest in Boston at 38 (20 to 45); followed by Quebec, 27 (18 to 43); Alberta, 23 (9 to 38); UK, 12 (7 to 20); and Taiwan, 8 (4 to 11). Oxycodone was the first prescribed opioid in 65% of patients in the US cohort compared to 14% in Quebec, 4% in Alberta, 0.1% in the UK, and none in Taiwan. One of the limitations was that data were not available from all centers for the entirety of the 10-year period. Conclusions In this study, we observed substantial differences in opioid prescribing practices for non-cancer pain between jurisdictions. The preference to start patients on higher MME/day and more potent opioids in North America may be a contributing cause to the opioid epidemic. Using population-based cohorts in North America, UK and Taiwan, Dr. Meghna Jani and colleagues describe opioid prescribing rates in patients with non-cancer pain who are using opioids for the first time. Author summary Why was this study done? An opioid crisis has affected several high-income countries, especially in North America, followed by sharp increase in opioid-related deaths in recent years. There is little evidence on how opioid prescribing rates compare internationally and the differences between countries in the type, strength, starting dose of opioids, and whether these characteristics change over time. What did the researchers do and find? We analyzed data from 2,542,890 adults who were prescribed opioids for the first time between 2006 to 2016 in 4 countries and 5 jurisdictions (United States, Boston; Canada, Quebec and Alberta; United Kingdom; Taiwan). The highest opioid prescribing rates in 2014 were observed in Alberta at 66/1,000 persons compared to 52, 51, and 18/1,000 in the UK, US, and Quebec, respectively, after standardizing for age and sex. Median morphine milligram equivalents (MMEs)/day at first use was highest in Boston at 38 MME/day and in contrast were less than half of the US in the UK (12 MME/day) and Taiwan (8 MME/day). Oxycodone was the first prescribed opioid in 65% of patients of the US cohort compared to 14%, Quebec 4%, Alberta; 0.1%, UK; and none in Taiwan. At initiation of an opioid, 20% of US patients, 13% of Quebec patients, and 10% of Albertans exceeded the US CDC–recommended threshold of 50 MME/day compared to 0.6% in the UK and 0.2% in Taiwan. What do these findings mean? In one of the first international comparisons to our knowledge, the preference to initiate patients on higher MME/day and more potent opioids in North America may be a contributing factor to the opioid epidemic.

BackgroundThe opioid epidemic in North America has been driven by an increase in the use and potency of prescription opioids, with ensuing excessive opioid-related deaths. Internationally, there are lower rates of opioid-related mortality, possibly because of differences in prescribing and health system policies. Our aim was to compare opioid prescribing rates in patients without cancer, across 5 centers in 4 countries. In addition, we evaluated differences in the type, strength, and starting dose of medication and whether these characteristics changed over time.Methods and findingsWe conducted a retrospective multicenter cohort study of adults who are new users of opioids without prior cancer. Electronic health records and administrative health records from Boston (United States), Quebec and Alberta (Canada), United Kingdom, and Taiwan were used to identify patients between 2006 and 2015. Standard dosages in morphine milligram equivalents (MMEs) were calculated according to The Centers for Disease Control and Prevention. Age- and sex-standardized opioid prescribing rates were calculated for each jurisdiction. Of the 2,542,890 patients included, 44,690 were from Boston (US), 1,420,136 Alberta, 26,871 Quebec (Canada), 1,012,939 UK, and 38,254 Taiwan. The highest standardized opioid prescribing rates in 2014 were observed in Alberta at 66/1,000 persons compared to 52, 51, and 18/1,000 in the UK, US, and Quebec, respectively. The median MME/day (IQR) at initiation was highest in Boston at 38 (20 to 45); followed by Quebec, 27 (18 to 43); Alberta, 23 (9 to 38); UK, 12 (7 to 20); and Taiwan, 8 (4 to 11). Oxycodone was the first prescribed opioid in 65% of patients in the US cohort compared to 14% in Quebec, 4% in Alberta, 0.1% in the UK, and none in Taiwan. One of the limitations was that data were not available from all centers for the entirety of the 10-year period.ConclusionsIn this study, we observed substantial differences in opioid prescribing practices for non-cancer pain between jurisdictions. The preference to start patients on higher MME/day and more potent opioids in North America may be a contributing cause to the opioid epidemic.

Background: Rheumatoid arthritis is a chronic autoimmune disease that primarily causes inflammation, pain and stiffness in the joints. People with severe disease may be treated with biological disease-modifying anti-rheumatic drugs, including tumour necrosis factor-α inhibitors, but the efficacy of these drugs is hampered by the presence of anti-drug antibodies. Monitoring the response to these treatments typically involves clinical assessment using response criteria, such as Disease Activity Score in 28 joints or European League Against Rheumatism. Enzyme-linked immunosorbent assays can also be used to measure drug and antibody levels in the blood. These tests may inform whether or not adjustments to treatment are required or help clinicians to understand the reasons for treatment non-response or a loss of response. Methods: Systematic reviews were conducted to identify studies reporting on the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assays to measure drug and anti-drug antibody levels to monitor the response to tumour necrosis factor-α inhibitors [adalimumab (Humira®; AbbVie, Inc., North Chicago, IL, USA), etanercept (Enbrel®; Pfizer, Inc., New York, NY, USA), infliximab (Remicade®, Merck Sharp & Dohme Limited, Hoddesdon, UK), certolizumab pegol (Cimzia®; UCB Pharma Limited, Slough, UK) and golimumab (Simponi®; Merck Sharp & Dohme Limited)] in people with rheumatoid arthritis who had either achieved treatment target (remission or low disease activity) or shown primary or secondary non-response to treatment. A range of bibliographic databases, including MEDLINE, EMBASE and CENTRAL (Cochrane Central Register of Controlled Trials), were searched from inception to November 2018. The risk of bias was assessed using the Cochrane ROBINS-1 (Risk Of Bias In Non-randomised Studies – of Interventions) tool for non-randomised studies, with adaptations as appropriate. Threshold and cost–utility analyses that were based on a decision tree model were conducted to estimate the economic outcomes of adding therapeutic drug monitoring to standard care. The costs and resource use were considered from the perspective of the NHS and Personal Social Services. No discounting was applied to the costs and effects owing to the short-term time horizon of 18 months that was adopted in the economic analysis. The impact on the results of variations in testing and treatment strategies was explored in numerous clinically plausible sensitivity analyses. Results: Two studies were identified: (1) a non-randomised controlled trial, INGEBIO, that compared standard care with therapeutic drug monitoring using Promonitor® assays [Progenika Biopharma SA (a Grifols–Progenika company), Derio, Spain] in Spanish patients receiving adalimumab who had achieved remission or low disease activity; and (2) a historical control study. The economic analyses were informed by INGEBIO. Different outcomes from INGEBIO produced inconsistent results in both threshold and cost–utility analyses. The cost-effectiveness of therapeutic drug monitoring varied, from the intervention being dominant to the incremental cost-effectiveness ratio of £164,009 per quality-adjusted life-year gained. However, when the frequency of testing was assumed to be once per year and the cost of phlebotomy appointments was excluded, therapeutic drug monitoring dominated standard care. Limitations: There is limited relevant research evidence and much uncertainty about the clinical effectiveness and cost-effectiveness of using enzyme-linked immunosorbent assay-based testing for therapeutic drug monitoring in rheumatoid arthritis patients. INGEBIO had serious limitations in relation to the National Institute for Health and Care Excellence scope: only one-third of participants had rheumatoid arthritis, the analyses were mostly not by intention to treat and the follow-up was 18 months only. Moreover, the outcomes might not be generalisable to the NHS. Conclusions: Based on the available evidence, no firm conclusions could be made about the cost-effectiveness of therapeutic drug monitoring in England and Wales. Future work: Further controlled trials are required to assess the impact of using enzyme-linked immunosorbent assays for monitoring the anti-tumour necrosis factors in people with rheumatoid arthritis. Study registration: This study is registered as PROSPERO CRD42018105195. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 8. See the NIHR Journals Library website for further project information.

BackgroundThe US opioid epidemic has led to similar concerns about prescribed opioids in the UK. In new users, initiation of or escalation to more potent and high dose opioids may contribute to long-term use. Additionally, physician prescribing behaviour has been described as a key driver of rising opioid prescriptions and long-term opioid use. No studies to our knowledge have investigated the extent to which regions, practices, and prescribers vary in opioid prescribing whilst accounting for case mix. This study sought to (i) describe prescribing trends between 2006 and 2017, (ii) evaluate the transition of opioid dose and potency in the first 2 years from initial prescription, (iii) quantify and identify risk factors for long-term opioid use, and (iv) quantify the variation of long-term use attributed to region, practice, and prescriber, accounting for case mix and chance variation.Methods and findingsA retrospective cohort study using UK primary care electronic health records from the Clinical Practice Research Datalink was performed. Adult patients without cancer with a new prescription of an opioid were included; 1,968,742 new users of opioids were identified. Mean age was 51 ± 19 years, and 57% were female. Codeine was the most commonly prescribed opioid, with use increasing 5-fold from 2006 to 2017, reaching 2,456 prescriptions/10,000 people/year. Morphine, buprenorphine, and oxycodone prescribing rates continued to rise steadily throughout the study period. Of those who started on high dose (120-199 morphine milligram equivalents [MME]/day) or very high dose opioids (≥200 MME/day), 10.3% and 18.7% remained in the same MME/day category or higher at 2 years, respectively. Following opioid initiation, 14.6% became long-term opioid users in the first year. In the fully adjusted model, the following were associated with the highest adjusted odds ratios (aORs) for long-term use: older age (≥75 years, aOR 4.59, 95% CI 4.48-4.70, p < 0.001; 65-74 years, aOR 3.77, 95% CI 3.68-3.85, p < 0.001, compared to ConclusionsOf patients commencing opioids on very high MME/day (≥200), a high proportion stayed in the same category for a subsequent 2 years. Age, deprivation, prescribing factors, comorbidities such as fibromyalgia, rheumatological conditions, recent major surgery, and history of substance abuse, alcohol abuse, and self-harm/suicide were associated with long-term opioid use. Despite adjustment for case mix, variation across regions and especially practices and prescribers in high-risk prescribing was observed. Our findings support greater calls for action for reduction in practice and prescriber variation by promoting safe practice in opioid prescribing.

Introduction The opioid epidemic in North America has, in part, been attributed to an increase in opiate use for non-cancer pain and the prescription of more potent molecules. In contrast, the United Kingdom appears unaffected by this crisis, possibly because of differences in primary care prescribing, or health system policies. Objective To determine if there are differences in opiate prescribing for new users in primary care in the United Kingdom, United States, and Canada. Approach Electronic health record data from Quebec, Canada (MOXXI), the United States (Partners Health Care, Boston MA), and the United Kingdom (CPRD random sample of 600,000) were used to identify new users of opiates (no prior prescription in 2 years), at least 18 years old between 2006-2016. Cancer patients were excluded after harmonizing equivalent READ and ICD9/10 codes. Generic drug names in each jurisdiction were mapped to the WHO ATC classification, and characterized using morphine milligram equivalents (MME). Results Overall 655,877 new users were identified, of whom 78% of 58,286 (U.S.), 88% of 6,251 (Canada), and 96% of 600,000 (UK) were non-cancer patients. Mean age of new users was 49 (SD 16) in the US, 57 (SD 16) in Canada, and 52 (SD 19) in the UK. 57.6% (UK) to 67.3% (US) of new users were women. In the UK, 86.5% of patients were started on codeine (MME:0.15), compared to 43.9% in Canada and 8.5% in the U.S. In the U.S 65.0\% were started on oxycodone (MME:1.5), and 10.9% on hydrocodone (MME:1). In Canada, tramadol (18.2%; MME: 0.1) followed by oxycodone (13.2%) were the next most commonly prescribed drugs. Conclusion/Implications Substantial differences in opioid prescribing practices for non-cancer pain were observed between the UK and Canadian and United States sites. The predilection to start patients on more potent opiates in North America may be a contributing cause to the opiate epidemic.