1630 BRITISH MEDICAL JOURNAL VOLUME 284 29 MAY 1982 cluding medical care and research in their for aspirin. Discontinuations for lack of efficacy for reporting in detail the side effects en- own countries. were equivalent for benoxaprofen and aspirin but countered while treating various arthritides D HADDOCK twice as high for ibuprofen. with benoxaprofen (8 May, p 1365). We have all The experimental work reported by Dr Colin Liverpool School of Tropical Medicine, met similar problems to a greater or lesser L3 Hindson and others (p 1368) confirms the findings Liverpool 5QA of Kligmant and Griest2 in the USA and Ferguson extent. et a13 in the UK. They conclude that phototoxicity When this drug was released on the market due to benoxaprofen is a predictable side effect exactly two years ago great publicity was given and is related to exposure to both the drug and to in the general press, and claims were made Side effects of benoxaprofen ultraviolet A radiation. With appropriate measures, as if a "cure" for arthritis had been found. The exposure to UVA can be minimised. result has been that we have been overwhelmed SIR,-The BMJ of 8 May contains three The report by Drs Hugh McA Taggart and by our patients (with paper cuttings in their articles concerning side effects ofbenoxaprofen. Joan M Alderdice (p 1372) of fatalities in elderly taking benoxaprofen is remarkable for the hands) for prescription of this drug. Drs J P Halsey and N Cardoe (p 1365) report patients I hope this article will be a side effects encountered in a study of 300 striking concentration of six deaths in one practice. lesson to the No jaundice and no deaths due to hepatic failure general press when a new drug appears, not to patients treated with benoxaprofen. The side raise false hopes in the describe are qualitatively similar were reported in approximately 2200 carefully minds of the sufferers effects they followed patients who participated in clinical of this terrible disease. to those previously reported for the drug, but trials in the USA. The Inman report did not their incidence is considerably higher than mention the occurrence of jaundice. It is now M A WAJED has been noted in other studies. For example, estimated that approximately 500 000 patients Hemel Hempstead General they reported that 65-3% of patients had at have received benoxaprofen in the UK. Exclusive Hospital, least one side effect, 28-6% had photo- of the experience of Dr Taggart/Alderdice and of Hemel Hempstead, Herts HP2 4AD sensitivity, 8% onycholysis, and 18% gastro- Goudie et al' (see below), Dista UK has received intestinal side effects. The drug was with- 11 reports of jaundice. Three of these patients drawn in 34-6% of patients because of side died; other drugs and complicating underlying conditions are involved in these deaths, and further SIR,-We would like to clarify one point which effects. They noted that side effects were more investigation is being carried out to define the role in patients over 70 years of age. may be misleading in our article (8 May, frequent of benoxaprofen. p 1368). We demonstrated phototoxicity in all Recently Dr William Inman (personal com- Several clinical and pathological features of patients whom we phototested. To date, we munication) at the Drug Surveillance Unit at the Drs Taggart and Alderdice's patients are note- have investigated 14 Caucasian who University of Southampton circulated to general worthy. All of the patients were over 80 years of patients practitioners the results of a postmarketing age, and all were women. One patient had an were receiving benoxaprofen for rheumatoid surveillance study of benoxaprofen involving 5000 enlarged liver six months before benoxaprofen was conditions and who presented with no evidence patients. In those trials "events" were recorded in prescribed. All were on other medications, including of skin disease. In all 14 subjects we observed 46% of patients: 13% had cutaneous events (4% paracetamol in three. A confusing observation was immediate responses of erythema and flaring, photosensitivity); 1-5% had onycholysis; and 11% that at necropsy the major finding was intrahepatic together with subjective sensations of itching gastrointestinal events. cholestasis, a condition which is very rarely fatal. and burning. Clinical trial data accumulated in North America Decreased renal function was present in some of Although the study of Dr Halsey and Dr in over 2200 patients studied for up to three years the patients prior to therapy, and renal failure was a Cardoe (8 p showed that drug-related side effects occurred in a prominent feature of the clinical course. May, 1365) reported photo- total of 29% of patients (events of uncertain B M Goudie et a14 recently reported the sensitivity side effects in 28-6% of patients causality occurred in a further 27%' of patients): occurrence of jaundice in three patients on taking benoxaprofen, we believe there is the phototoxicity, onycholysis, or both in about 15%; benoxaprofen. All were women and over 70 years potential for photosensitivity reactions in a and gastrointestinal complaints in 15%. of age. Two recovered when benoxaprofen was much higher proportion of patients. These numbers illustrate the problems en- discontinued; one died of bronchopneumonia. countered in attempting to compare the incidence Jaundice has been reported with most of the other BRIAN DIFFEY in available non-steroidal anti-inflammatory drugs. of side effects reported various trials. The Regional Medical Physics Department, differences noted may be related to population More detailed information will be required to Dryburn Hospital, differences, but probably the most important assess the significance of the cluster of fatal cases Durham DH1 5TW factors are the method by which side effects are reported by Drs Taggart and Alderdice, but it is COLIN HINDSON sought and the manner in which they are evaluated. clear that jaundice associated with benoxaprofen Dermatology Department, Drs Halsey and Cardoe alluded to this problem is a rare event. Royal Infirmary, in interpretation when they noted that in their The increased incidence of minor side Sunderland SR2 7JE study the incidence of side effects may have been artificially high owing to coincidental non-drug effects in elderly people reported by Drs related medical conditions. They also pointed out Halsey and Cardoe, the jaundice in elderly that side effects have been reported in 150" of patients reported by Drs Taggart and Alder- dice and by Goudie et al, and the pharmaco- SIR,-At first sight, the BMJ of 8 May might patients with rheumatoid arthritis taking placebo, make any rheumatologist cringe with shame. suggesting the difficulty of assigning a causal kinetic data showing a prolonged half life of azapropazone relationship between administration of a drug and benoxaprofen in elderly patients with impaired Drug-induced lupus (p 1358), a possible side effect. of interactions (p 1373), and polyarthritis due to renal function emphasises the importance (pl373) are all mentioned. But it is To gain a true picture of the incidence of side using a reduced dose in such patients. Pre- quinidine effects with different drugs it is necessary to the three papers on benoxaprofen toxicity conduct a study taking all necessary steps to scribing information supplied by Lilly (Dista) That Dr J P attention to this which demand attention. by control bias-for example, random entry and specifically calls important Halsey and Dr N Cardoe (p 1365) is a straight- double-blind design. Such studies were done in consideration. Elderly patients should be is observed forward record of events: drug toxicity in the clinical trials of benoxaprofen sponsored by followed carefully, and if jaundice The total incidence of toxic reactions Eli Lilly and Company. In those trials photo- benoxaprofen should be promptly dis- practice. sensitivity and onycholysis were identified as side continued. was very high, but we need to see the same effects of benoxaprofen but not of aspirin or reporting system used for other drugs-that is, ibuprofen. The incidence of gastrointestinal side W IAN H SHEDDEN a control group. What was the incidence of Vice President, Lilly Research effects was similar to that of ibuprofen but about Laboratories toxicity due to other drugs taken singly or in half that observed with aspirin. Unlike the Eli Lilly and Company, combinations under the same conditions ? gastrointestinal side effects, photosensitivity is Indianapolis, Indiana The phototoxic reaction described and dis- generally preventable and can be minimised by cussed in Dr Colin Hindson and colleagues' of to the use of Kligman AM, Kaidbey KH. Eturopean Joutrnal of avoidance exposure sun, protective Rheumnatology and Inflammrnation. 1982 ,5 :127-37. paper (p 1368) can be most uncomfortable clothing, and the use of sunscreen lotions. 2Griest MC, Oxols II, Ridolfo AS, Muus JC. Eu4ropean Drs Halsey and Cardoe comment on the 7ournal of Rheumatology and Inflammation 1982; for patients. We have known about this now with which were withdrawn 5:138-47. for over two years, and the company concerned frequency patients Ferguson J, Addo HA, McG PE, Woodcock KR, from benoxaprofen because of the occurence of Johnson BE, Frain-Bell W. Br J Derm (in press). have issued cards for patients warning them side effects. This gives an incomplete picture. A 4 Goudie BM, Birnie GF, Watkinson G, MacSween how to reduce its frequency. Were any of a is the RNM, Kissen LH, Cunningham NE. Lancet better measure of drug's acceptability 1982 ;i :959. Dr Hindson and colleagues' patients so frequency of drug discontinuance due both to side warned ? effects and to lack of efficacy. In the six-month For the past three or four years it has been controlled trials drug was withdrawn for both reasons in 17`o of benoxaprofen patients, 230' of my practice to ask of pharmaceutical represen- those on ibuprofen, and 25°" of those on aspirin. SIR,-May I through your columns extend my tatives two questions about their drug, parti- Discontinuations for side effects were equivalent appreciation to Dr J P Halsey and Dr N cularly if it happens to be a long-acting inflam- for benoxaprofen and ibuprofen but twice as high Cardoe from Norfolk and Norwich Hospital matory agent. What differences in metabolism BRITISH MEDICAL JOURNAL VOLUME 284 29 MAY 1982 1631 and effects are there in the elderly, and what is and have also demonstrated an increased rate be payable in respect of death or personal in- the excretion in breast milk ? The answers are of nail growth in patients within one month jury (including antenatal injury) suffered few because the data are lacking. Pharmaco- of starting benoxaprofen and a return to by any person: (a) in the course of employ- dynamics are done usually in volunteer staff normal growth rates after stopping the drug. ment; (b) through the use of a motor vehicle of the company concerned, and they are by One such patient is a 68-year-old man with an or other means of transport; (c) through the definition going to be under 65. So the popula- average fingernail growth rate of 0-5 mm/ manufacture, supply or use of goods and ser- tion who will perhaps predominantly be ex- week; within one month of commencing vices; (d) otherwise through the act or omission posed in the case of anti-inflammatory agents benoxaprofen 600 mg daily the average finger- of another where compensation under the pre- is not usually studied before general release. nail growth rate had increased to 0-9 mm/week, sent law is recoverable only on proof of fault, This must be remedied. and this is maintained while on the drug. or under the rules of strict liability, having The lesson of phenylbutazone and its great Although onycholysis with benoxaprofen may regard to the cost and other implications of the increase in half life in the elderly is there for us in part be related to exposure to ultraviolet arrangements for the recovery ofcompensation, all. All long-acting anti-inflammatory agents light, this is unlikely to be the sole factor, whether by way of compulsory insurance or should be regarded with suspicion in the and there are many features in which it differs otherwise." elderly, and a lower dose used. The Belfast from the onycholysis associated with tetra- Unfortunately there were 188 recommenda- series is extraordinary: all six patients treated cyclines. tions including, I believe, some very important with benoxaprofen by Dr Hugh McA Taggart D FENTON ones which are not mentioned-for example, and Dr Joan Alderdice (p 1372) died of Department of Dermatology, compensating the parents or guardians of all cholestatic jaundice or renal failure. The first Wycombe General Hospital, handicapped children; defining medical injury patient presumably had pre-existing liver High Wycombe, Bucks HPl1 2TT into medical accident, which should be disease before taking benoxaprofen. The I Rook A, Wilkinson DS, Ebling FJG. Textbook of promptly and properly compensated, and medi- highest alkaline phosphatase in case 5 was dermatology. Oxford: Blackwell, 1979:1127. cal negligence which requires prolonged litiga- 2 Fenton DA, Wilkinson JD. J Roy Soc Med 1982 (in only just at the top of the normal range and press). tion; extension of our already efficient work lower than it was in case 4 before the start of injuries scheme to include the self-employed; benoxaprofen treatment. cover for commuters; and expansion of the I hold no particular brief for Dista Ltd, SIR,-We were interested in the reports of occupational disease schedule, etc. Each and have been involved in none -of the trials of facial milia occurring as a side effect of benoxa- every recommendation was costed in 1978, benoxaprofen, and am not complacent over profen therapy (8 May, p 1365 and 1368) as we and it is of interest that the recommended no- drug toxicity. I note that all three papers were have recently seen five cases, four with rheuma- fault scheme for road injuries would have cost accepted five to six weeks before publication toid arthritis and one with osteoarthrosis, with the equivalent of one penny on a gallon of compared with the more usual 12 to 13, and this side effect. Although the temporal petrol. it is, of course, right to alert doctors and the relation to benoxaprofen therapy in our In the article "The world's best system of public to toxicity. I just hope, however, that patients was very similar to that of the patients compensating injury ?" Dr Richard Smith this urge does not distort usual standards of reported, they differed in that all also had (24 April, p 1243) commented that the visit impartial assessment. onycholysis. This has led us to speculate of the Royal Commission to New Zealand M L SNAITH about a common aetiology for the two con- in 1975 was too early, but obviously the New University College Hospital, ditions. It has been suggested that onycholysis Zealand system was studied over the next three London WC1E 6AU is associated with abnormal cell turnover at years. Indeed, Justice Woodhouse appeared ***The two papers on the side effects of the nail base, and it might be suggested before the Royal Commission at one of its benoxaprofen were published seven weeks that altered dermal turnover may lead to the closing sessions to give his opinion on his after acceptance, which is not appreciably formation of these lesions. This would be scheme after four years of its operation. In his different from the average of eight weeks (our consistent with the association of milia with review to the New Zealand Law Society in current average) between acceptance and corticosteroid-induced skin atrophy noted in 1978 he stated that there were several serious publication of the three papers in this issue. the previous papers, and two of our most problems but warned that these were not to be Publication of the short report was brought florid cases occurred in patients taking taken out of context from the general overall forward since the subject matter was the same. prednisolone. One patient was also taking success of the scheme, reassuring that "it is -ED, BM7. D-penicillamine, which is known to affect here to stay." In making the following points collagen metabolism, and developed a large he also pointed out how remarkable it is that ulcerated milium which was clinically similar such a wide-ranging reform has operated so SIR,-I was interested to read Dr J P Halsey to a basal cell carcinoma and was therefore well: and Dr N Cardoe's excellent review of biopsied. (1) That lump-sum payments for non- cutaneous and other side effects ofbenoxaprofen Although the development of milia might be economic losses such as pain, loss of amenities, (8 May, p 1365). They state that the onycholysis considered a trivial event to a patient with and impairment of body function did not fit in patients taking benoxaprofen is "similar to arthritis, this is not so in patients with deform- into a social welfare system especially with the that induced by demeclocycline." The similarity ing diseases in whom the "normal" appearance difficulty in assessing real losses. These settle- is only superficial since there are several of their face might be of extreme importance. ments had an adverse effect on rehabilitation, important differences between the onycholysis Certainly four of our five patients discontinued and inhibitory effects on personal incentives produced by the two drugs. therapy because of the cosmetic effect of the and enterprise and the prompt return to work. With demethylchlortetracycline the photo- milia, and we have observed slow improvement There was difficulty in determining the loss of onycholysis is usually painful and rarely affects in this condition since discontinuing therapy. earning capacity among many types of worker. the thumbs since they are less exposed to (2) That there was unfair discrimination sunlight than the fingers.' Toenails are affected P T DAWES against housewives, non-earners, and self- only if exposed. There is no alteration in nail D RAMAN employed, who are seriously disadvantaged growth rate with tetracyclines. The onycholysis IAN HASLOCK by the inability to calculate specific earning occurring with benoxaprofen, however, is Department of Rheumatology, losses. Middlesbrough General Hospital, the of usually painless and frequently affects the Middlesbrough, (3) That statutory requirement thumbs,' and we have seen also onycholysis Cleveland TS5 5AZ employers for first-week incapacities leads affecting the toenails with absolutely no sun to increased but hidden costs added on to pro- exposure. As Dr Halsey and Dr Cardoe go on duction costs as a kind of disguised sales tax. to state: "If benoxaprofen onycholysis is due Compensation: who cares? (4) That there were administrative complica- solely to photosensitivity it should be prevent- tions and waste because of the need to employ able by the application of an opaque nail SIR,-In response to your leading article an insurer as an agent-that is, the State In- varnish." We have found that in fact this does "Compensation: who cares ?" (15 May, surance Agent. not prevent the development of onycholysis or p 1428) as the only clinical member of the (5) That the allocation of present income for significantly alter its progression. Pearson Commission I would like to point out future losses was similar to a funded scheme in The authors further say that: "It has yet that its remit was not limited,and, indeed, many the insurance sense. to be determined whether benoxaprofen can of us who worked at it for five years believed (6) That there was still neglect of rehabilita- increase the rate of nail growth." We have it was far too broad. Its terms ofreference were: tion. reported an increased nail growth in several "To consider to what extent, in what circum- (7) That there was failure to extend the sys- patients on benoxaprofen (24 April, p 1228) stances and bywhat means compensation should tem to such groups as the congenitally disabled,