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Three Part Question

In [adult patients with acute gouty arthritis] are [oral corticosteroids safe and effective] at [reducing pain]?

Clinical Scenario

You are working in the Emergency Department and it is 0200h on Sunday morning. You review a 65 year old gentleman with severe atraumatic foot pain, particularly over the 1st metatarsophalangeal joint. He is overweight, with a history of hypertension and ischaemic heart disease, and you diagnose gout.

Medical school knowledge tells you he needs colchicine, although a quick look at the British National Formulary suggests it can be toxic in higher doses (plus how will he get hold of this before Monday?). You review international guidelines which recommend non-steroidal anti-inflammatory drugs (NSAIDs) as first line treatment, but his co-morbidities may preclude their use.
You see that systemic steroids are also recommended, but you wonder if they will work…

Search Strategy

MEDLINE 1946 – November 2016 via BMA library interface.
(exp Gout/ OR exp Arthritis, Gouty/ OR podagra.mp OR crystal arthropathy.mp OR gout.mp OR gout$.mp) AND (exp steroids/ OR steroid$.mp./ OR corticosteroid$.mp. OR prednisolone.mp. OR dexamethasone.mp. OR hydrocortisone.mp) LIMIT to English AND Human

Also EMBASE, Cochrane library, UK trials gateway, www.clinicaltrials.com, http://ethos.bl.uk/Home.do , bibliography search.

Search Outcome

982 papers found.
Abstracts reviewed for relevance, of which 48 were obtained and reviewed.
5 papers were relevant and of sufficient quality, and are included in this BET (including one Cochrane Review).

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Man, Cheung et al. 2007 Hong Kong, China	90 adult patients attending a single ED with <3/7 joint pain & clinical diagnosis of gout.   Randomised to prednisolone 30mg + PRN paracetamol 1g 5/7 or IM diclofenac 75mg stat + indomethacin 50mg TDS 2/7 then 25mg TDS 3/7 + PRN paracetamol.	Randomised controlled trial.	Primary outcome: Decrease in pain (with activity) per day (VAS 0 - 100mm).   Secondary outcome: adverse events.	Statistically significant difference in pain reduction with activity for steroid group:   Mean rate of decrease in pain score for NSAID group was 1.7mm (+/- 0.7mm) per day, for the steroid group 2.9mm (+/- 2.0mm). Mean difference between groups was 1.2mm (95%CI 0.4-2.0mm/day, p= 0.0026).   More adverse events in NSAID group (63% v. 27%). 11% in NSAID group had GI bleed.	Not designed as equivalence trial.   Convenience sampling in selection process
Janssenns, Lucassen et al 2008 Netherlands	Cochrane review of 3 RCTs comparing steroids with NSAIDs for acute gout. 148 patients in total.	Cochrane systematic review	Outcomes varied between studies.	Inconclusive evidence for the efficacy of corticosteroids for treatment of acute gout.	Statistical pooling of data not possible.   Very low to moderate quality studies only.
Janssens, Janssen et al. 2008 Netherlands	120 patients (any age) referred to study centre from primary care with confirmed acute gout (crystals identified on joint aspiration).   Randomised to Prednisolone 35mg OD 5/7 or Naproxen 500mg BD 5/7.	Randomised controlled trial	Primary outcome: Decrease in pain (VAS 0 - 100mm) up to day 4.   Secondary outcome: adverse events.	Mean decrease in pain at day 4 was 44·7 mm for prednisolone and 46·0 mm for naproxen (mean difference 1·3 mm; 95% CI –9·8 to 7·1)   No significant difference in adverse events (p= 0.42).   No major adverse effects reported	Possibility of selection bias due to referral process.   Limited applicability to ED practice as all cases proven gout.
Xu, Liu et al. 2016 China	132 adults with acute gouty arthritis (referred to Endocrinology department of single hospital).   Randomised to: Prednisolone 35mg OD Indomethacin 50mg TDS Etoricoxib 120mg OD 5/7	Open label randomised controlled trial.	Primary outcome: Reduction in pain (assessed with 5 point Likert scale) at days 2 and 4   Secondary outcomes: adverse events.	Decrease in pain scores significant for each drug group.   No significant difference in reduction in pain between pairing.   Mean difference pain reduction between pairs: Prednisolone vs. etoricoxib: 0.12 (95% CI -0.15 to 0.38) Prednisolone vs. indomethacin: 0.11 (95% CI -0.16 to 0.39 Etoricoxib vs. indomethacin: 0.00 (95% CI -0.26 to 0.25)   Significantly greater adverse events in indomethacin group (p=0.03).	No documentation of power calculations or selection process.   Open label trial so chance of introduction of bias.   Only 4 day follow up.   Large numbers of drop outs (more in indomethacin and steroid arms.
Rainer, Cheng et al. 2016 Hong Kong, China	416 dults with acute gout presenting to 4 emergency departments.   Randomised to Prednisolone 30mg OD or Indomethacin 50mg TDS for 2 days, 25mg TDS for 3 days.   All participants given paracetamol PRN.	Randomised controlled trial	Primary outcome: Reduction in pain at rest and with activity, assessed with VAS (0 -100mm).   Secondary outcomes: Adverse effects (study powered to assess this outcome).	No clinically or statistically significant difference in reduction in pain at rest (p=0.8) or with activity (p=0.2).   Mean reduction in pain at rest- Prednisolone group: 1.68mm/d (95% CI 1.39 to 1.97mm/d) Indomethacin group: 1.80mm/d (95% CI 1.46 to 2.13mm/d).   With activity- Prednisolone group: 3.19mm/d (95 %CI 2.85 to 3.52mm/d) Indomethacin group 2.96mm/d (95% CI 2.62 to 3.30mm/d).   Significantly greater occurrence minor adverse events for indomethacin in first 2 hours (p=>0.01). No difference over subsequent days (p=1.00).   No serious adverse events in either group.	Convenience sample.

Comment(s)

This search revealed one Cochrane review, two moderate quality studies, one high quality study and one of low quality. These studies allow one to draw the following conclusions: Corticosteroids and NSAIDs are both effective at treating the pain of flares of gouty arthritis in adults, and are equivalent in their efficacy and that corticosteroids have a similar adverse effects profile to NSAIDs. Certain factors should be highlighted. All studies excluded patients with significant renal disease or any history of bleeding disorder or gastrointestinal bleeding, as they could not be safely randomised to receive NSAIDs. As such the studies demonstrated equivalence in treatment for a somewhat atypical, fairly healthy group of patients with AGA. However it reasonable to extrapolate that, if analgesic effects are equivalent in a population for whom a choice of agents is available, then for patients with significant co-morbidities where steroids are the only choice of anti-inflammatory agent both the clinician and the patient can be reasonably confident of good symptom control. Three of the four RCTs reviewed used indomethacin (one with a stat dose of IM diclofenac) as the NSAID comparator for their studies. Indomethacin is not a drug typically utilised in the UK, where naproxen is the common stronger NSAID available. Naproxen has a similar (or slightly reduced) analgesic effect when compared to indomethacin, with a better tolerability. As such although the NSAID in most trials reviewed was not one likely to be prescribed in UK EDs, the results when compared to prednisolone still apply. With respect to safety, only one study demonstrated a significantly increased occurrence of serious adverse effects when NSAIDs were administered (in this study with a combination of intramuscular diclofenac then indomethacin. While this study was not powered to assess this secondary outcome, 11% of patients in this group developed gastrointestinal bleeding (with peptic ulceration proven on endoscopy). However this finding was not reproduced by the other studies where oral NSAIDs only were administered, and in particular Rainer, Cheng et al did not find evidence of increased risk of harm in their larger trial which was powered to assess for adverse events. Overall, therefore, it is arguable that the safety profile of both drugs may be described as equivalent, and that in the UK, where naproxen will be more commonly prescribed by emergency physicians, this finding will hold true, if appropriate caution in prescription of NSAIDs is followed. Three of the studies (including the highest quality study) took a pragmatic approach to recruitment, foregoing joint aspiration and microscopic confirmation of the diagnosis of gout as the inclusion criterion for enrolment. As mentioned above, this reflects the likely investigative course for a patient attending an ED with an acutely painful, swollen joint, although this means there may have been some misdiagnosis of the underlying condition (which should have been shared equally between study arms by randomisation). This demonstrates that steroids are as effective as NSAIDs for the patient for whom a definitive diagnosis will not be possible before commencing acute treatment, and makes these results more applicable to our practice.

Editor Comment

BAF using for Aug

Clinical Bottom Line

Oral steroids are as effective as oral NSAIDs for pain relief for acute gouty arthritis, and may be prescribed with confidence of efficacy and safety for patients attending the ED with clinically diagnosed acute gout.

References

1. Man CY, Cheung ITF, Cameron PA and Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med 2007; 49: 670–677
2. Janssens HJEM, Lucassen PLBJ, van de Laar FA, Janssen M and van de Lisdonk EH. Systemic corticosteroids for acute gout Cochrane Database Syst Rev 2008: CD005521.
3. Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL and van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: A double-blind, randomised equivalence trial Lancet 2008; 371: 1854–1860
4. Xu L, Liu S, Guan M and Xue Y. Comparison of Prednisolone, Etoricoxib, and Indomethacin in Treatment of Acute Gouty Arthritis: An Open-Label, Randomized, Controlled Trial. Med Sci Monit 2016; 22: 810–817.
5. Rainer TH, Cheng CH, Janssens Hein. JEM, Man CY, Tam LS, Choi YF, Yau WH, Lee WH, Lee KH, Graham CA. Oral Prednisolone in the Treatment of Acute Gout: A Pragmatic, Multicenter, Double- Blind Randomized Trial. Ann Intern Med 2016; 164: 464–471.