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Indomethacin and other NSAIDs for gout

 

Clinical bottom line

Oral indomethacin and some other NSAIDS appeared equally efficacious in treating acute gout, based on small randomised trials. One large randomised trial comparing indomethacin with etoricoxib showed that etoricoxib had fewer adverse events.


Since indomethacin has for many years been one of the mainstay treatments for acute gout, Bandolier sought to review studies on its efficacy. This is not easy, since there appear to be no systematic reviews, and few clinical trials, and those that do exist are old and difficult to obtain. Most of the studies identified are now included in Table 1. Other articles examine other NSAIDs where indomethacin was not a comparator.

Studies

The randomised trials found are described in Table 1. They were generally small (as few as five patient per group), and indomethacin was compared with other NSAIDs, Chinese medicines, or with glucocorticoids.

Table 1: randomised trials of indomethacin in acute gout

Reference Design Included patients Outcomes Results

Ruotsi & Vainio, 1978

Quality score 4/5

Randomised, double-blind, parallel-group with proquazone 900 mg (9) and indomethacin 150 mg (9) daily for up to 10 days. Earlier diagnosis of gout, with synovial fluid analysis and X-ray. Primary or secondary gout. Pain, swelling, redness, uric acid etc Rapid and sustained improvement in both groups, with some GI problems with proquazone.

Polderman & Colon, 1979

Quality score undetermined

This multicentre study was randomised by physician, and was open. It compared 200 mg oxamethacin (264) with 100 mg indomethacin (261) daily for up to two weeks. Only 6 of the patients had gout    

Eberl & Dunky, 1983

Quality score 2/5

Randomised, double-blind, parallel-group with 300 mg meclofenamate sodium a day (10) or indomethacin 150 mg a day (10) for six days. Acute attack in a single joint of less than 48 hours duration, and joint was sensitive to touch, red and hot. Median age 48 years Spontaneous pain, swelling, tenderness and limitation of function using categorical scales Patients matched at baseline. Identical results, with symptoms subsiding over 2-7 days. Probably more adverse events with indomethacin, including GI symptoms.

Dörfler 1985

Quality score 2/5

Randomised and double blind in 10 patients with acemethacin (5) or indomethacin (5) variable dosing over 7 days With acute gout Pain relief 4/5 complete relief with each treatment

Lomen et al, 1986

Quality score 3/5

Randomised, double-blind, parallel-group with 400 mg flurbiprofen (14) and 200 mg indomethacin (15) for two days, then half that dose for up to five days (seven days total). Acute attack of monoarticular gouty arthritis of less than 48 hours duration. Diagnosis confirmed by clinical findings and synovial fluid analysis Pain on motion and at rest, and a variety of other measurements, plus global assessment At least 50% of patients in both groups showed improvement within 24 hours. Three withdrawals with flurbiprofen, none with indomethacin. Similar efficacy

Fraser et al, 1987

Quality score 4/5

Randomised, double-blind, parallel-group with azapropazone (days 1-225) or indomethacin (1-28) followed by allopurinol (29-225). Sizes were 47 and 46 patients respectively.Double blind only to day 85. Acute attack of gouty arthritis Uric acid, gouty attacks 12 patients on azapropazone had attacks of gout compared with 21 on indomethacin/allopurinol. Uric acid levels the same after first 28 days.
Altman et al, 1988 Randomised double blind comparison of 50 mg ketoprofen (29)and 25 mg indomethacin (30) in capsules. On day 1 3 capsules initially followed by 2 capsules three hours apart. Two capsules three times a day on days 2-7. Age 35-88 years with acute gout established by urate crystals in synovial fluid, or on clinical criteria. Inflammation for no longer than 48 hours before entry, with pain and tenderness of at least moderate severity.

Clinical global improvement on days 1, 2, 5, and 8, as well as pain, tenderness, restriction of motion, swelling and total score.

Adverse events.

There was no difference between the treatments, with rapid improvement on days 2 through 5.

Patient withdrawal before completion was high (11 ketoprofen and 15 indomethacin, 3 each to adverse reactions. Digestive system adverse events were common (11/9).

Alloway et al, 1993 Random selection to 50 mg indomethacin oral daily (10), or triamcinolone acetonide 60 mg IM (10). Open study with unblinded observer. Patients with injection took paracetamol, and could have a second injection within two days. Patients with crystalline proven gout and onset of symptoms within five days. Patients seen for up to 30 days for improvement, active joints. More or less than 50% improvement for each joint. Seven lost to follow up, so data on 20 of 27 patients. Significantly higher urea with triamcinalone, otherwise no difference between groups.

Chou & Kuo, 1995

Quality score 1/5

Randomised trial of chinese medicine (20) with indomethacin 125 mg/day (20) (duration not known) Gout diagnosis confirmed by crystals in joint. Treatment within two days of acute onset. Painful, swollen joints, pain Indomethacin was effective, Chinese medicine was not.

Shrestha et al, 1995

Quality score 3/5

Randomised double blind double dummy comparison of IM ketorolac 60 mg (10) or 50 mg oral indomethacin (10). Patients with acute gouty arthritis, with crystals or tophus, and clinical signs and symptoms. Pain scoring using diaries over 24 hours, mainly at home. Mean pain scores were similar in both treatment groups.

Klumb et al, 1996

Quality score 2/5

Randomised, double blind, identical capsules with indomethacin (300 down to 100 mg a day (14) or nimesulide (600 mg down to 200 mg a day (20) for seven days Confirmed diagnosis, within 72 hours of acute attack Pain intensity Identical efficacy

Schumacher et al, 2002


Quality score 5/5

Randomised, double-blind, parallel-group with 120 mg etoricoxib once a day (75) or indomethacin 50 mg three times a day (75) for eight days. Gout defined by ARA criteria and with adequate pain, tenderness and swelling for a sensitive assay. Pain in study joint, plus tenderness, swelling, global assessment to treatment by patient and investigator Patients matched at baseline. Identical results, with symptoms subsiding over four hours to 7 days. Initial pain score of 2.9 (max 4) fell to below 1 by day 4. With etoricoxib, 30% of patients had no or mild pain by 4 hours, over 50% by 2 days, and 80% by 5 days.

More adverse events with indomethacin.

Results

Indomethacin and control treatments were effective in treating pain and inflammation from acute gouty arthritis. Given the short duration of many of the studies, adverse reactions were common.

Comment

These are small trials, though with big effects. The most obvious thing is the small size of these studies, which, together with the different comparators and outcomes, makes any overall comparison difficult. The efficacy of indomethacin accords with clinical experience.

References

  1. A Ruotsi, U Vainio. Treatment of acute gouty arthritis with proquazone and indomethacin. Scandinavian Journal of Rheumatology 1978 Supp 21: 15-17.
  2. J Polderman, M Colon. Oxamethacin: a pilot field study. J Int Med Res 1979 7: 83-89.
  3. E Eberl & A Dunky. Meclofenamate sodium in the treatment of acute gout.Arzneim-Forsch1983 33: 641-643.
  4. H Dörfler. Therapie des akuten Gichtanfalls mit acemetacin. Therapiewock 1985 35: 1161-1166.
  5. PL Lomen et al. Flurbiprofen in the treatment of acute gout. American Journalof Medicine 1986 80 (Suppl 3A): 134-139.
  6. RC Fraser et al. Comparative trial of azapropazone and indomethacin plus allopurinol in acute gout and hyperuricaemia. Journal of the Royal College of General Practitioners 1987 37: 409-411.
  7. RD Altman et al. Ketoprofen versus indomethacin in patients with acute gouty arthritis: a multicenter, double blind comparative study. J Rheumatol 1988 15:1422-1426.
  8. JA Alloway et al. Comparison of triamcinolone acetonide with indomethacin inthe treatment of acute gouty arthritis. J Rheumatol 1993 20: 111-113.
  9. CT Chou, SC Kuo. The anti-inflammatory and hyperuricaemic effects of Chinese herbal formula danggui-nian-tong-tang on acute gouty arthritis: a comparative study with indomethacin and allopurinol. American Journal of Chinese Medicine 1995 ZZIII: 271-271.
  10. M Shrestha et al. Randomized double blind comparison of the analgesic efficacy of intramuscular ketorolac and oral indomethacin in the treatment of acute gouty arthritis. Annals of Emergency Medicine 1995 26: 682-686.
  11. EM Klumb et al. The treatment of acute gout arthritis. Double-blind randomized comparative study between nimesulide and indomethacin. Rev Bras Med 1996 53: 540-546.
  12. HR Schumacher et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ 2002 324: 488-492.