Prescribing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Inflammatory Arthritis and Osteoarthritis in Adults

Failure of response to non-pharmacological management and regular dosing of paracetamol (1g four times a day)

Inflammatory Osteoarthritis (OA) arthritis

Consider addition of topical NSAID for hand or knee arthritis eg Ibuprofen 5% gel, Piroxicam 0.5% gel or Movelat gel. Then consider adding moderate opioid analgesia, then consider addition of Capsaicin 0.025% cream for hand or knee arthritis-please follow Scriptswitch recommendations in primary care

NSAID INDICATED (refer to guidance note 1) Consider contra-indications and cautions (see below) Risk assess for gastrointestinal (GI) and cardiovascular (CV) risk Avoid NSAIDs if possible in renal and hepatic impairment

Avoid long term use where possible and always aim to use lowest effective dose for shortest possible duration

Contra-indications • A history of hypersensitivity/severe allergic reaction to an NSAID (including aspirin) • Severe heart failure-NSAIDs may impair renal function • Current treatment for gastrointestinal bleeding, symptomatic peptic ulcer, or gastrointestinal perforation/obstruction • Severe hepatic impairment • COX-2s and diclofenac are also contraindicated in people with ischaemic heart disease, cerebrovascular disease, peripheral arterial disease, mild to severe heart failure. Cautions § The elderly-increased risk of serious adverse effects such as gastrointestinal bleeding and perforation § People with a history of peptic ulceration § People with inflammatory bowel disease -NSAIDs may increase the risk of developing or cause exacerbations of ulcerative colitis or Crohn's disease. § Renal impairment (avoid if possible)-sodium and water retention may occur leading to a deterioration in renal function and possibly renal failure

Assess GI and CV risk Consider if benefit of NSAID treatment outweighs risk

No GI or CV GI risk factors CV risk factors Both GI & CV risk factors risk factors No NSAID without risk - refer to No NSAID without risk - refer guidance note 3 to guidance note 2 Ibuprofen or Naproxen Naproxen (guidance note 4) (guidance note 4) Ibuprofen + low or Celecoxib or or cost PPI Etoricoxib + low Celecoxib (guidance note 2) For gout use: (guidance note 4) cost PPI or Naproxen or Etoricoxib-consider CV risks Etoricoxib For gout use: For gout use: Naproxen Naproxen + Etoricoxib + or or low cost PPI low cost PPI Etoricoxib –consider CV risks When duration of use becomes long No NSAID term or repeated When duration of use without risk - add in low cost becomes long term or refer to guidance PPI repeated add in low cost PPI note 2 & 3

Avoid long term use where possible and always aim to use lowest effective dose for shortest possible duration May need to use on an intermittent basis Guidance Notes

1. NSAID Selectivity 1. NSAIDs vary in their selectivity for inhibiting different types of cyclo-oxygenase. The term NSAID includes non- selective NSAIDs and selective NSAIDs (COX 2 inhibitors). 2. Always use the lowest effective dose for the shortest duration possible. All patients must have a gastrointestinal, cardiovascular and renal risk assessment done and the appropriate anti-inflammatory agent selected following a risk versus benefit discussion with the patient. Consider documenting in patient’s clinical notes. 2. Cardiovascular Disease (CV) Risk Factors and Renal Impairment • Ischaemic heart disease • Cerebrovascular disease • Peripheral artery disease • Moderate to severe congestive heart failure • Hypertension • Hyperlipidaemia • Diabetes • Smoking Patients with cardiovascular risks: (i) COX-2 selective inhibitors. The European Medicines Agency (EMEA) concluded COX-2 inhibitors must not be used in patients with established ischaemic heart disease, cerebrovascular disease, congestive heart failure (NYHA II-IV) or peripheral arterial disease. When prescribed in accordance with their cautions, the benefits versus risks remain positive for COX-2 inhibitors when used in their target populations1. Blood pressure monitoring is required prior to and periodically during treatment. Note: Etoricoxib is contraindicated in patients with hypertension whose BP is persistently above 140/90mmHg and has not been adequately controlled. (ii) Non-selective NSAIDS. The EMEA concluded that the benefit-risk balance for non-selective NSAID’s remains favourable when prescribed in accordance with patients risk factors (see page 2). It cannot be excluded that non- selective NSAIDs may be associated with a small increase in the absolute risk for thrombotic events (such as heart attack or stroke), especially when used at high doses for long term treatment3. Concomitant aspirin and/or clopidogrel-see advice under gastro-intestinal risk factors –guidance note 3

Renal Effects of NSAIDs: Patients at risk of renal impairment or renal failure (particularly elderly people) should avoid NSAIDs if possible. If NSAID treatment is absolutely necessary, then the lowest effective dose for the shortest possible duration should be used to control symptoms. The renal function of such patients should be carefully monitored during NSAID treatment.

MHRA update June 2013: Diclofenac: Available data indicate that the CV risk with diclofenac is similar to that of the selective COX-2 inhibitors. Consistent with COX-2 inhibitors, diclofenac is now contraindicated in those with: ischaemic heart disease; peripheral arterial disease; cerebrovascular disease; or established congestive heart failure (New York Heart Association [NYHA] classification II–IV). The new treatment advice applies to systemic formulations (i.e., tablets, capsules, suppositories, and injection available both on prescription and OTC from pharmacy); does not apply to topical (i.e. gel or cream) 3. Gastrointestinal (GI) Risk Factors • Past history of gastrointestinal disease - peptic ulcer disease (PUD), GI bleed, GORD • Patients > 75 years with no additional risk factors • Patients > 65 years with one of the following additional risk factors: -concomitant corticosteroids -long term NSAID treatment/maximal dose -concomitant anticoagulant -concomitant aspirin and/or clopidogrel (see guidance note below) -concomitant serotonin re-uptake inhibitor -Inflammatory bowel disease (all NSAIDs including COX 2 inhibitors)

• Concomitant Aspirin There is no consensus in the literature regarding the co-prescribing of low dose aspirin and NSAIDs. Opioid analgesics should be considered before NSAID or COX-2. If NSAID or COX-2 is deemed necessary, this combination can increase the risk of gastro-intestinal side effects therefore, add low cost PPI

Note: ibuprofen may reduce the cardioprotective effects of aspirin 4

• Concomitant Clopidogrel The co-prescribing of NSAIDs and clopidogrel increases the risk of gastro-intestinal side effects. Consider PPIs other than omeprazole or esomeprazole in patients who are taking clopidogrel. Other gastrointestinal therapy such as H2 blockers (except cimetidine) or antacids may be more suitable in some patients 5 2 • Proton Pump Inhibitors (PPIs) NICE Guidance (Management of osteoathritis 2008) suggests the use of low cost PPI’s with COX-2 selective inhibitors or non-selective NSAIDs should be considered in all patients with GI risk factors. This combination offers the lowest potential risk of GI adverse events 6,7,8 PPI cover should only be used for the duration of NSAID use. 4. Formulary NSAIDs Patients not responding to one NSAID may well respond if changed to another NSAID.

Please follow Scriptswitch recommendations in primary care

Non-selective NSAIDs

Naproxen: 250mg to 500mg orally twice a day Note: there is no evidence for using EC naproxen preparations which are higher cost

Ibuprofen: 400mg orally three times daily (No significant arterial thrombotic risk has been identified for doses up to 1200mg daily. Dose can be increased to 2.4g daily in 3 to 4 divided doses if necessary. There are limited data on the risk with ibuprofen at doses between 1.2g and 2.4g . Doses ≥ 2.4g daily are associated with higher risk of arterial thrombotic events)

COX-2 selective inhibitor (see guidance note 2)

Celecoxib: 200mg orally daily in one to two divided doses (maximum 200mg twice daily) Etoricoxib: 30mg orally daily in osteoarthritis 60mg orally daily in rheumatoid arthritis and ankylosing spondylitis. If ineffective, dose may be increased to 90mg orally daily. Once patient clinically stabilised, consider down-titration to 60mg orally daily. 120mg orally daily in acute gout

5. Common Drug Interactions with NSAIDs9

This is not a comprehensive list. For further information please see BNF appendix 1, Stockley’s Drug Interactions, contact your ward/practice pharmacist or local medicines information service

• SSRIs, Venlafaxine – increased risk of bleeding • Ciclosporin – increased risk of nephrotoxicity • Diuretics – increased risk of nephrotoxicity • Lithium – NSAIDs probably reduce excretion of lithium (increased risk of toxicity). NSAIDS should be avoided if possible • Methotrexate – NSAIDs reduce excretion of methotrexate (increased risk of toxicity), however many patients are taking this combination safely through regular monitoring of their renal function and FBC • Tacrolimus – increased risk of nephrotoxicity • Warfarin – increased risk of GI haemorrhage with all NSAIDs. Avoid concurrent use where possible. When concurrent use is necessary extra caution is needed as all NSAIDs can increase INR-increased monitoring recommended after initiating or changing the dose • DOACs – increased risk of bleeding • Quinolones – possible increased risk of convulsions

References

1. European Medicines Agency Concludes Action on COX-2 Inhibitors, June 2005 2. European Medicines Agency recommends strengthening warnings and contraindications for etoricoxib-containing medicines used in the treatment of rheumatoid arthritis and ankylosing spondylitis, June 2008 3. European Medicines Agency review concludes positive benefit-risk balance for non-selective NSAIDs, October 2006 4. MacDonald TM & Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. The Lancet 2003; 361: 573-4. 5. MHRA Drug safety update April 2010. Clopidogrel and proton pump inhibitors: interaction-updated advice 6. Cannon CP et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2006: DOI:10.1016/S0140-6736(06)69666-9. 7. NICE Clinical Guideline No 59 Feb 2008: Osteoarthritis: The care and management of osteoarthritis in adults. www.nice.org.uk 8. NICE Clinical Guideline No 70 Feb 2009: Rheumatoid arthritis: The management of rheumatoid arthritis in adults. www.nice.org.uk 9. Stockley, Drug Interactions, accessed online via www.medicinescomplete.com 10. MHRA Drug safety update June 2013. Diclofenac new contraindications and warnings after a Europe wide review of cardiovascular safety 11. MHRA Drug Safety Update, Vol 10, Issue 3, October 2016:1. Etoricoxib (Arcoxia): revised dose recommendation for rheumatoid arthritis and ankylosing spondylitis 12. MHRA Drug Safety Update, Vol 8, Issue 11, June 2015:2. High-dose ibuprofen (≥2499mg/day): small increase in cardiovascular risk Non-steroidal anti-inflammatory drugs (NSAIDs)-prescribing in inflammatory arthritis and osteoarthritis (adults) V5 Approved by MCGT February 2017 (Published 15/02/17) Review date: February 2020