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Osteoarthritis is a common condition that is expected to become even more prevalent by the end of the decade.1 Despite its commonness, our understanding of the disease has evolved to acknowledge inflammation as a mediator of degenerative changes and pain.2
Over time, there has been an increased acknowledgement that non-pharmacological interventions, particularly weight loss and exercise can have profound benefits on patient quality of life.1,3 Of the oral pharmacotherapies, paracetamol has been a long-standing first-line treatment. But in light of modified-release (MR) paracetamol being up-scheduled to Pharmacist Only (S3) on 1 June 2020,4 now is a good time to reflect on what the evidence says today and what to consider as we have that conversation with patients tomorrow.5-8
In 2018, the RACGP guidelines scrutinised the percieved clinical benefit of paracetamol for knee and hip osteoarthritis.1
Again in 2019 a Cochrane review found only a 3% benefit over placebo in the management of patient’s pain.6 That meta-analysis found only weak evidence for using paracetamol in the management of osteoarthritis.6
Only minimal improvements in pain and functionality were observed when paracetamol was prescribed for hip or knee osteoarthritis, the Cochrane review reported.6 That review also undertook a subgroup analysis which considered whether dose had a bearing on outcomes.6
According to that analysis there was no difference in management of pain or function when the dose of paracetamol was altered (3.0 g/day or less versus 3.9 g/day or greater).6
Where to from here for oral pain relief for osteoarthritis?
Australian clinical pharmacologist and rheumatologist Professor Ric Day authored a review in Lancet Rheumatology5 that raised issues of ethics, placebo effect and patient education in relation to the management of osteoarthritis pain with paracetamol. The Lancet review discussed how much of the ‘patient recorded benefit’ is actually due to the patient’s belief in the prescriber and the medication.5 Could this be a placebo effect of benefit occurring in some patients who are prescribed paracetamol?5
This leads to the vexed question if the patient is perceiving benefit, which may or may not be mostly placebo in effect, is there harm in prescribing paracetamol? While patients have a belief that paracetamol is a safe medication, as pharmacists, we are aware of the dangers of toxicity levels of paracetamol causing irreversible liver damage and failure that may require a liver transplant.3,7 Paracetamol toxicity can be fatal.3,7
Patients using paracetamol for the management of osteoarthritis tend to use the MR version at a dose of two tablets three times a day.3,7 The recommendation to up schedule the MR version of paracetamol is due mainly to the pharmacokinetic profile of the MR version causing unpredictability in the blood concentration levels of paracetamol.7
In turn, this unpredictability of dissolution can make the management of overdose using acetylcysteine very difficult.7 The forthcoming upscheduling provides pharmacists with opportunity to counsel patients on the appropriate use of MR paracetamol.
Patient confusion between the two different recommended dose timings for regular and MR paracetamol can lead to accidental overdose.7 This is likely largely due to confusion about the dose difference between MR and regular paracetamol with the maximum dose being 6 tablets per day for the MR formulation rather than 8 tablets per day for the regular one.
There is little evidence to suggest that this low-level chronic toxicity is a cause of hepatotoxicity requiring treatment in otherwise well patients but remains best avoided and may be of concern in those with pre-existing hepatic impairment.7
A second consideration is whether it is ethical to prescribe a medication that has little evidence of clinical benefit. According to the Lancet review, the patient may not be informed of the limited evidence of efficacy of paracetamol in the management of osteoarthritis pain and functionality, and may not also be asked to give consent to trial this medication as their treatment.5
The authors of a large BMJ meta-analysis8 asked for a review of clinical practice guidelines to consider the evidence that they had collated and to answer the following questions:
- Is there a clinical benefit of regular paracetamol in the management of pain and disability of function in osteoarthritis?
- Is there significant evidence of altered liver function tests in patients taking paracetamol and why is this so?
As there may be significant inflammatory components to the clinical aspect of osteoarthritis it is necessary to consider whether management of the inflammatory process is warranted for management of pain and functionality.
When considering using an anti-inflammatory e.g. NSAIDs, there does need to be careful screening of the patient to reduce the risk of potential harm.3 Patients with high blood pressure, kidney disease or at risk of bleeds would need to be managed carefully on these medications.3
The prescriber will assess the risk and may prescribe a short term NSAID with additional monitoring in place e.g. regular blood pressure checks, monitor for increased bleeding. Topical NSAIDs may be used in patients at higher risk.1,3
Patients presenting with osteoarthritis need to be advised of the latest evidence to assist them to manage their pain and functionality. The current recommendations include:1,3
- Weight management
- Exercise and movement
- Use of non-steroidal anti-inflammatory agents (while considering risk factors) short term for flare-ups
- Use of duloxetine in some cases where other forms of pain relief are ineffective
- Non-pharmacological treatments.
- The Royal Australian College of General Practitioners. Guideline for the management of knee and hip osteoarthritis. 2nd edn. East Melbourne, Vic: RACGP, 2018.
- Sokolove S, Lepus CM. Ther Adv Musculoskel Dis 2013;5(2):77-94.
- eTG, ‘Osteoarthritis’ accessed 22/03/2020.
- TGA, Changes to the way modified release paracetamol products are supplied: questions and answer. 2019. At: www.tga.gov.au/changes-way-modified-release-paracetamol-products-are-supplied-questions-and-answers
- Day RO, et al. ‘Is it ethical to prescribe paracetamol for acute low back pain and osteoarthritis?’ Lancet Rheumatology, 2019;1(3):e140 – e142.
- Leopoldino AO, et al. ‘Paracetamol versus placebo for knee and hip osteoarthritis (Review) Cochrane library’ Cochrane Database of systematic reviews 2019;2:CD013272.
- Application to Amend the Poisons Standard Modified Release Paracetamol 6-8 November 2018. Australian Government Department of Health.
- Machado G, et al. ‘Efficacy and safety of paracetamol for spinal pain and osteoarthritis systematic review and meta-analysis of randomised placebo-controlled trials.’BMJ 2015;350:h1225.