Title: Can treatment with beta adrenoreceptor blocking drugs reduce the risk of developing symptomatic osteoarthritis and requiring total joint replacement in the general population: a prospective cohort study using data from the UK Clinical Practice Research Datalink
Funder: Department of Health and Social Care

Abstract: Background: Osteoarthritis (OA) is the commonest form of arthritis and affects 15% of the general population. No specific therapy exists for OA and medical management focuses on analgesia. However, currently used analgesics have modest efficacy in OA pain, and their use associates with troublesome and potentially serious side-effects including cardiovascular and renal diseases. This is particularly problematic in people with OA as they have a high prevalence of cardiovascular comorbidities. Thus, there is an unmet need to develop analgesics for OA pain which can be used safely in people with cardiovascular diseases. Findings from several human, animal and in vitro studies suggest that &beta;-adrenoreceptor blocking drugs (&beta;-blockers) may provide analgesia in OA. Recently, we discovered an association between &beta;-blocker prescription and lower pain severity (adjusted Odds Ratio (aOR) 0.68; 95%C.I. 0.51-0.91) and less use of opioids (aOR 0.73; 95%CI 0.54-0.98) in adults with lower-limb large-joint OA. Additionally, each year of treatment with &beta;-blockers reduced the risk of joint pain (aOR 0.96 (95%CI 0.93, 0.99), and the results remained unchanged when data from individuals on &beta;1-selective drugs only were included (aOR 0.71; 95%C.I. 0.53-0.96)), suggesting that the analgesic effect of &beta;-blockers in OA may be mediated by &beta;1-adrenoreceptor blockade. As this was a cross-sectional study carried out in older individuals it needs confirmation in other primary-care based cohorts before proceeding to randomized controlled trial (RCT). Such a study will also permit identification of the specific &beta;-blocker that is most likely to have an analgesic effect for evaluation in a RCT. Objectives: To find out if &beta;-blockers reduce the risk of developing symptomatic knee or hip OA, and requiring total joint replacement in those with knee or hip OA. Methods: Data from Clinical Practice Research Datalink (CPRD) will be used. CPRD contains anonymised healthcare records from 14 million individuals and represents 8% of the UK population at any time. All diagnoses, reasons for consultation, results, and referrals are recorded electronically, anonymised and stored. Study design: Cohort study &beta;-blockers and incident knee or hip OA Participants &ge;40 years in age without previous consultation for arthritis, or analgesic prescriptions, who received &ge;2 continous &beta;- blocker prescription will be compared to four controls matched on GP surgery and propensity score for &beta;-blocker prescription for risk of incident knee OA (primary outcome); and hip OA, knee and hip pain (secondary outcomes). Participants with contra-indications to &beta;-blockers will be excluded. &beta;-blockers and total joint replacement Participants &ge;40 years in age with incident knee or hip OA, without any joint replacement, OA at other joints, other forms of arthritis, other disease (see above) will be identified. The risk of total knee replacement (primary outcome); and total hip replacement, new analgesic prescription (secondary outcomes) will be compared between those receiving &ge;2 continous prescriptions of &beta;-blockers and four matched unexposed controls as described above. Duration of treatment, cumulative dose, and mean daily dose will be secondary exposures, and sensitivity analysis will be performed selecting the patients based on first consultation for knee or hip pain. Statistical analysis: Kaplan Meier curves will be plotted and Cox proportional hazard ratios (HRs) and 95% CIs will be calculated to assess the associations described above. The HRs will be adjusted for a propensity score for &beta;-blocker prescription and other covariates. Dose response analysis will be performed for treatment duration and cumulative dose. Stratified analysis will be performed by: [1] class of &beta;-blocker: &beta;1-selective e.g. Atenolol versus non-selective e.g. Propranolol [2] intrinsic sympathomimetic effect: present e.g. Acebutalol versus absent e.g. Bisoprolol [3] individual &beta;-blockers. Stratified analysis will be performed according to indication(s) for &beta;-blocker prescription e.g. hypertension, coronary heart disease, atrial fibrillation etc.

Lay abstract: Osteoarthritis is the commonest form of arthritis and affects 15% of the general population. It is the leading cause of pain and disability. No specific therapy exists for osteoarthritis and its treatment focuses on painkillers which can cause troublesome and life threatening side-effects. Findings from several laboratory studies suggest that beta-adrenoreceptor blocking medicines (beta-blockers) used in the treatment of angina, hypertension, and irregular heart beat can reduce osteoarthritis pain. We recently demonstrated for the first time that people with osteoarthritis prescribed beta-blockers for these conditions have milder joint pain and are less likely to be prescribed strong and potentially toxic morphine-like painkillers. As participants in this study were elderly and recruited from hospitals, we want to confirm these findings in community based studies before conducting cumbersome and expensive clinical trials. We will use data from the Clinical Practice Research Datalink (CPRD) for this study. CPRD contains detailed anonymised medical information for 14 million people registered with a GP in the UK. Their data is collected at the GP surgery during consultations and stored after reomving identifiable information. We will investigate if people prescribed beta-blockers are less likely to develop knee or hip osteoarthritis, require strong painkillers and joint replacement surgery. We will identify people who have been commenced on beta-blockers without any form of arthirtis diagnosed and never seen their GP for joint pain or received a prescription for pain-killers (group-A), or have osteoarthritis and have been commenced on beta-blockers (group-B). Their risk for developing knee or hip osteoarthritis (group-A participants), being started on strong painkillers and requiring joint replacement surgery (group-B participants) will be compared to similar people not on this medication. This study was developed with involvement of the ARUK Pain Centre PPI group, and its results will be published in scientific journals, newsletters, and Nottingham University website.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MUSCULOSKELETAL