Propranolol reduces risk of knee or hip replacement due to osteoarthritis: A propensity score matched cohort study-using data from the Clinical Practice Research Datalink

Introduction

Osteoarthritis (OA) is the commonest form of arthritis and affects approximately one in four adults older than 45 years of age¹. There is a paucity of effective structure-modifying drug for OA, and analgesics only have a modest effect size (ES) and may cause troublesome and potentially serious side effects^2,3. Consequently, many people undergo total joint replacement (TJR), most commonly at the knee or the hip. An estimated 1.9 million knee or hip TJRs are projected to be performed each year in the USA alone by the year 2030⁴.

Our recent research demonstrated that β-adrenoreceptor blocking drugs (β-blockers) atenolol and propranolol have anti-nociceptive effects on knee and/or hip pain, with the largest ES for propranolol⁵. Prior to this, we reported lower opioid consumption and less severe joint pain in people with large-joint lower limb OA prescribed β-blockers⁶, and β-blocker prescription associated with lower opioid use at day 30 in another study on patients undergoing knee TJR⁷. However, this observation was not confirmed in a study using Osteoarthritis Initiative (OAI) data⁸. Whether β-blockers reduce incidence of TJR in people with OA is not known.

Thus, the objective of this study was to examine whether β-blocker prescription associates with a lower risk of lower limb arthroplasty in a primary-care population with knee or hip OA.

Methods

Study population

Patients aged ≥40 years, newly diagnosed with knee or hip OA between 1st January 1990 and 31st December 2013, with at-least 2-year prior registration in the CPRD before OA diagnosis or β-blocker prescription, and contributing acceptable research quality data in up-to-standard GP practices were included in this study (Figure 1).

Figure 1. Selection of the study population.

Results

Data for 13,620 participants exposed to β-blockers and up to five age, sex and OA location matched unexposed participants (n=48,636) were ascertained during the study period. Of these, data for 6,970 PS-matched β-blocker exposed (n=3,485), and unexposed (n=3,485) participants contributing 42,066 person-years of follow-up were analysed (Figure 1). The majority of participants had knee OA (81.12%), more than half our participants were women (57.89%) and the mean (SD) age at OA diagnosis was 65 (11) years. There was covariate balance between exposed and unexposed after PS-matching on all covariates except for hypertension (SMD=0.115) for which there was a minor imbalance (Table 5). Hypertension was included in the model as a covariate to account for the imbalance. After PS matching, unexposed participants had a similar number of consultations with their GP in the preceding 12-months as the exposed, with median (Inter Quartile Range) 11 (6 to 18) and 11 (7 to 18) GP visits, respectively.

Overall β-blocker prescription was not associated with hip or knee TJR (aHR 1.11; 95 % CI 0.98 – 1.25), knee TJR (aHR 1.14; 95 % CI 0.98 –1.34) and hip TJR (aHR 1.23; 95 % CI 0.96 – 1.57) (Table 6). Similar results were observed on the assessment of β -blocker classes except for β-blocker with MSE which showed a reduction in the risk of knee or hip TJR (aHR 0.69; 95% CI 0.52 – 0.93). The NNT (95% CI) to prevent joint replacement at two years follow-up was 32 (23–52). When data were stratified according to individual drugs, there was a protective effect for propranolol but an increase in the risk of knee or hip TJR for atenolol (Table 7; Figure 2).

Figure 2. The association between propranolol and knee or hip replacement: Kaplan-Meier survival estimates.

Discussion

In this study, we found no association between β-blocker prescription and TJR when all β-blockers were considered together. However, when β-blockers possessing different properties were considered, this study found that propranolol, a non-selective β-blocker, reduces the risk of TJR at the knee and the hip. This is consistent with our previous findings that propranolol reduces the risk of primary-care consultations for knee OA and knee pain by 22% and 20% respectively⁵.

There are several mechanisms by which propranolol may cause analgesia. These include blocking the β2 adrenoreceptors on the peripheral nociceptors, dorsal root ganglia, and superficial dorsal horn^17–19, regulation of periaqueductal grey neurons firing, interference with sensitization in the rostral ventromedial medulla and locus coeruleus^20,21, and increased analgesic effect of opioids²². Propranolol also induces infiltrative cutaneous analgesia and is more potent than lidocaine²³. It acts by blocking the voltage sensitive Na+ and Ca2+ channels, reducing Na+ and Ca2+ influxes, and decreasing intracellular cyclic adenosine monophosphate (AMP) via reduction of the adenyl-cyclase activity²³.

Our findings are broadly consistent with the results of previous observational studies reporting less severe pain and lower analgesic requirements in people prescribed β-blockers^6,7. In intervention studies, propranolol has shown analgesic benefits on musculoskeletal pain due to fibromyalgia, temporomandibular joint dysfunction and reduced post-operative analgesic requirement in people undergoing surgery^24–26.

However, the findings of our current study do not agree with those of a study using data from the Osteoarthritis Initiative which reported no difference in pain severity between people prescribed and not prescribed β-blockers. This may be due to a lack of power to detect differences in that study, with a modest sample size of 1,168 and only 15% of participants being exposed to β-blockers²⁷.

Propranolol may be particularly suitable as an analgesic for people with OA who have comorbid anxiety²⁸. Similarly, it may be useful in treatment of neuropathic-like OA pain that is non-responsive to NSAIDs and driven by β₂ adrenoreceptor stimulation¹⁹. Additionally, people with low COMT gene activity may benefit more from propranolol as an analgesic²⁹. This is of particular mechanistic relevance as >70% Caucasians have COMT (158Met) polymorphisms that confer low activity of the COMT gene³⁰.

In the present study, atenolol prescription associated with an increased risk of TJR; this was an unexpected finding given the results of our previous study in which atenolol reduced the risk of incident knee pain. This discordance may be due to the fact that β₁-adrenoreceptor blockade reduces bone resorption and increases bone mineral density³¹, and increased bone mineral density associates with an increased risk of TJR³². Additionally, increased bone mineral density is also causally associated with end-stage OA according to a mendelian randomisation study using data from the UK Biobank³³. Unlike β₁-adrenoreceptor blockade, β₂-adrenoreceptor blockade with propranolol does not affect bone resorption or increase bone mineral density³¹.

The findings of this study should be validated in independent datasets and confirmed in a randomised controlled trial before propranolol is adopted as an analgesic for people with OA.

The strengths of our study are its power derived from a large population sample size, confounder control by achieving covariate balance between PS-matched β-blocker exposed and unexposed groups, and adjustment for other factors such as health-seeking behaviour and comorbidities. We are confident that the majority of people with OA were included in this study as it is unlikely that someone with OA will be seen in a secondary care hospital service, including private settings, without consulting their GP first given GPs are the first port of call for people with chronic conditions in the UK. This increases generalisability of the study findings. People with less than two years of registration in their current GP practice were excluded to minimise the chance of including prevalent cases of OA as incident OA. Additionally, we excluded participants with chronic painful conditions and contra-indications to β-blockers to minimise confounding by indication that may not be addressed by PS matching.

To define the start of the follow-up period, we used a validated definition of primary care diagnosis of knee or hip OA^34,35 and did not define our population just on consultation for knee or hip joint pain. Similarly, we used a GP entry of joint replacement surgery to define our outcomes. This has been validated against Hospital Episode Statistics (HES) and UK joint registry data and shown to have excellent validity^36,37. Only 60% of CPRD practices are linked to HES and restricting the dataset to such practices would result in loss of sample size.

There are limitations to this study. First, we used primary care consultation for knee or hip OA which is likely to be later than the onset of OA symptoms. However, it is unlikely that this delay will be different according to the exposure status. Second, the exposure was dichotomised as present or absent and we did not analyse cumulative dose response. Third, our controls were not individuals initiating another drug (i.e., active comparator). This is because there is a hierarchy in the use of different drugs for the treatment of cardiovascular diseases in the UK driven by NICE guidelines. For example, the NICE guidelines recommend beta-blockers to treat resistant hypertension that has failed to respond to most other anti-hypertensive agents including ACE inhibitors, diuretics, angiotensin-II receptor blockers and calcium channel blockers. In contrast, they recommend β-blockers as first-line drugs for treatment of angina, atrial fibrillation, and heart failure. Therefore, using an active comparator study design would introduce biased selection of unexposed participants. Primary-care prescriptions in the UK are typically issued for four weeks at a time. In this study, exposed participants were required to receive two prescriptions in a 60-day period in order to enrich the sample with participants likely to continue with β-blocker treatment. This introduces immortal time bias as follow-up started at first prescription (index date). However, as both exposed and unexposed participants were required to have at-least 90 days of follow-up from their index date without undergoing TJR, immortal time bias between the first and second prescription is cancelled out.

In summary, we report that the non-selective β-blocker propranolol reduces the risk of knee or hip TJR. A randomised controlled trial is required to further evaluate the analgesic potential of propranolol in OA.