Ann Rheum Dis: first published as 10.1136/ard.26.2.127 on 1 March 1967. Downloaded from Ann. rheum. Dis. (1967), 26, 127 SIDE-EFFECTS OF INDOMETHACIN BY P. L. BOARDMAN and F. DUDLEY HART Westminster Hfotpital, London This paper reports side-effects on indomethacin on indomethacin over a 4-month period and finally in patients with rheumatic disorders, with particular had a severe melaena. Robinson (1965) reported reference to factors which may affect their frequency anaemia in 4 per cent. of 193 patients. In one and severity. patient seen by the authors, occult gastro-intestinal Side-effects occur in three major groups; referable blood loss exceeded 25 ml. per day. The finding of to the central nervous system, the gastrointestinal occult blood in the stools has varied from 2 per cent. system, and the skin. Percy, Stephenson, and (Ballabio, Cirla, Girardi, Caruso, and Colombo, Thompson (1964) emphasized the psychic side- 1963) to 45 per cent. (Datey and Pandya, 1964). effects, including depression and hallucinations; Raised blood urea levels have been reported epilepsy and coma have occurred (Thompson and occasionally in patients on indomethacin (Michotte copyright. Percy, 1966), and Robinson (1965) reported narco- and Wauters, 1964; Ballabio and others, 1963; lepsy and suicide. Thompson, 1964); in general the rise did not reach Rashes related to the administration of indo- the upper limit of normal. The development of methacin include urticaria and purpura. Activation proteinuria with granular casts was noted in one of latent infection was reported by Solomon (1966). patient by Bruckner and Randle (1965). In contrast, Robinson, Fitzpatrick, and Graessle Rubens-Duval and Villiaumey (1964) recorded (1965) reported increased resistance of mice and rats one instance of transient neutropenia and one of to bacterial infection when treated with indo- transient thrombocytopenia. An occasional de- http://ard.bmj.com/ methacin. crease in circulating eosinophils was noted by Acute gastrointestinal emergencies are well recog- Miehlke (1964). No abnormality has been detected nized (Dixon, Jones, Wanka, and Wood, 1963; in the bone marrow (Rothermich, 1964, 1966; Lovgren and Allander, 1964). Fluid retention is Berman, 1965) and no irreversible changes in the rare (Ballabio and Caruso, 1964). peripheral blood count have so far been reported. Abnormal liver function tests have been recorded Sicuteri, Michelacci, and Anselmi (1964) demon- occasionally. Katz, Pearson, and Kennedy (1965), strated a vasoconstrictor effect, exerted preferentially on September 26, 2021 by guest. Protected in a series of 97 patients, found two with raised on the cerebral circulation; in a patient with essential serum alkaline phosphatase and SGOT (serum hypertension, a considerable prolonged rise in aspartate transaminase) levels, but pointed out that pressure was recorded. neither had control determinations. Bruckner and Occasional deterioration in diabetic control has Randle (1965) noted raised serum alkaline phos- been reported as a result of indomethacin (Katz and phatase levels in three out of fourteen patients with others, 1965; Ballabio and others, 1963), but generally rheumatoid arthritis; a transient rise in SGOT there is little effect on glucose tolerance. One of us occurred in one. No controls were available. (FDH) found no effect on diabetic balance when Wanka, Jones, Wood, and Dixon (1964) estimated administering the drug to five diabetic patients, gastrointestinal bleeding during indomethacin though one of these first developed diabetes mellitus therapy by means of erythrocytes labelled with radio- while on indomethacin. Patients occasionally find active chromium. The mean daily loss on aspirin was difficulty in differentiating between hypoglycaemic 5 9 ml. compared with 1I2 ml. on indomethacin. attacks and the cerebral side-effects of indomethacin. One of their patients developed progressive anaemia The administration ofindomethacin by suppository 127 C Ann Rheum Dis: first published as 10.1136/ard.26.2.127 on 1 March 1967. Downloaded from 128 ANNALS OF THE RHEUMATIC DISEASES has certain therapeutic advantages, as in the relief of giddiness, was also noted. A record was kept of the early morning stiffness. Systemic reactions, such as interval between the start of treatment and the develop- headache and giddiness, are less prominent and local ment of side-effects. Indomethacin-induced dyspepsia rectal irritation is only an occasional, relatively was compared with that caused by the pyrazoles (phenyl- unimportant problem (Holt and Hawkins, 1965; butazone and oxyphenbutazone). Woolf, 1965; Whitehouse and Hart, 1965). Results Side-effects occurred in 113 patients (49 - 5 per Material cent.), 181 spontaneous symptoms being recorded This analysis is based on results in 228 patients; 118 (Table I) in 71 (61 -7 per cent.) of the 115 on high with rheumatoid arthritis, 32 with ankylosing spondylitis, dosage and in 42 (37 - 1 per cent.) of the 113 on low 52 with osteo-arthrosis, and 26 with gout, details of whom dosage. This is a significant difference(x2 = 13-6; have been reported previously (Hart and Boardman, n = 1;P< 0-01). 1965; Boardman and Hart, 1965). For this study, as Of the 185 patients who received both indo- long-term placebo studies were not practicable, thepatients methacin and a pyrazole derivative, 97 developed were divided into two groups for comparative purposes: side-effects on indomethacin, of whom 40 were (1) 115 patients received a relatively high dosage of intolerant of phenylbutazone or oxyphenbutazone indomethacin tablets (mean 2-9 mg./kg./day; S.D. ± (40/97 = 41-2 per cent.). Among the 88 patients 1 .5); who tolerated indomethacin, sixteen were intolerant (2) 113 patients received a low dosage of indomethacin of the pyrazoles (16/88 = 9-9 per cent.). This is a significant difference (X2 = 10-50; n = 1; P< 0-01). capsules (mean 1 - 1 mg./kg./day; S.D. ± 0-37). Although there is some variation in the absorption of TABLE I indomethacin tablets (Hodgkinson, 1963), the main ACTUAL COMPLAINTS AND INCIDENCE difference between the two groups was considered to be IN PATIENTS RECEIVING INDOMETHACIN one of dosage. Side-effect No. of Complaints Method copyright. Headache 50 All patients were seen in the out-patients clinic at Giddiness 30 monthly intervals. They were also seen within 14 days of Dyspepsia 18 any alteration in therapy. They were instructed to return Muzziness 17 at any time if side-effects developed. At each visit they Nausea 15 were asked about untoward reactions generally, leading Vomit 7 questions being avoided, except for a direct inquiry Diarrhoea 6 regarding the occurrence of dyspepsia. Patients received Drowsiness 6 indomethacin and phenylbutazone or oxyphenbutazone Odd 5 http://ard.bmj.com/ at different times, the drugs never being prescribed to- Rash 4 gether. Sensation ofdrunkeness The mean period of administration of indomethacin 4 Faint 2 was 15 weeks (range one dose only to 87 weeks), the total Ill 2 treatment amounting to 3,420 patient weeks. The length Legs odd 2 Costive I of treatment with the pyrazole agents varied from one Drumming in ears dose to 326 weeks (mean 50 weeks), the total treatment Doped I to weeks. The Loss of taste and smell I amounting 9,250 patient average period Swollen tongue 1 on September 26, 2021 by guest. Protected of treatment in the high dosage indomethacin group was Depressed I Lassitude I 12 weeks, and in the low dosage indomethacin group 18 Nightmares I weeks. Shaky I Mouth ulceration The nature, frequency, and severity of side-effects were Neck rigidity I recorded, the last in three grades; mild, moderate, and Throbbing all over I severe. Mild side-effects were noted by, but did not Light-headedness I inconvenience, the patient. Moderately severe side- Total 181 effects made the patient modify his daily activities and usually take a few hours' rest. Severe side-effects were incapacitating for a few hours, rest in bed being im- The incidence of side-effects in relation to perative and symptoms very unpleasant. Patients suffering from side-effects described the reac- diagnosis and dosage is shown in Table II (opposite). tions in their own words. The number of spontaneous It was about equal in cases of rheumatoid arthritis complaints varied from one to four symptoms at one and ankylosing spondylitis in both dosage groups. time, this being taken as an index of severity of the reac- In the low dosage group the incidence of side-effects tion. The dominant complaint, either headache or in cases of gout was about the same as in cases of Ann Rheum Dis: first published as 10.1136/ard.26.2.127 on 1 March 1967. Downloaded from SIDE-EFFECTS OF INDOMETHACIN 129 TABLE II SIDE EFFECTS, CHARACTERISTICS, DOSAGE, AND DIAGNOSIS IN 228 PATIENTS Dosage Higb Low Number of Patients 115 113 Total Patients with Side-effects No. 71 42 Per cent. 61-7 37-1 Rheumatoid Arthritis (118) 70-1 43-1 Side-effects (per cent.) related to Ankylosing Spondylitis (32) 71*4 45 45 Diagnosis in 228 Patients* Osteo-arthrosis (52) 46- 1 25 -6 Gout (26) 21*4 41*6 Severe 7*0 0 Severity of Side-effects (per cent.) Moderate 40*8 26-2 Mild 52-1 73 8 Number of Spontaneous Four 4 2 0 Complaints by Each Patient Three 15 4 7*14 with Side-Effects (per cent.) Two 32 * 3 16*6 One 47-8 76-18 Dominant Complaint Headache No. 41 9 Percentage of Those with Side-effects in the Group 57*6 21 4 Giddiness No. 21 22 Percentage of Those with Side-effects in the Group 29*5 52*4 * No. of patients with each diagnosis given in brackets. arthritis and spondylitis, and was much lower in patients (69 per cent.), between 48 hrs and 28 days those with osteoarthrosis (25-6 per cent.). In the in 28 patients, and after 28 days in seven patients. high dosage group it was also lower in those with In six patients, in whom early, transient side-effects osteo-arthrosis, but very much lower in those with developed, it was possible to continue with indo- gout (21 *4 per cent.).