Preface

NPOJIP editorial

Epidemic of encephalopathy by continuous use of NSAIDs is a drug disaster as large scale as those by thalidomide, SMON and blood-products-induced HIV

　We have been studying and make some comments about the risk of NSAIDs that are probably related with Reye's syndrome (or severe type of influenza-related encephalopathy).
　When Japanese Ministry of health and Welfare (MHW) decided to stop studying Reye's syndrome in December 1998, we thought it a serious problem.
　We collected most of the task force reports of MHW on Reye's syndrome and/or flu-related encephalopathy in which we found many data that indicated close association between Reye's syndrome or severe flu-related encephalopathy and NSAIDs.

Risk is 13-50 times higher for getting RS or severe encephalopathy and 18 times higher for getting it and die.

[1] As for Reye's syndrome (definite or clinically diagnosed Reye's syndrome), one of the results in the report of the studies by the task force of MHW in 1990-1992 (reported in 1994) showed that NSAIDs use is estimated 18 times higher for getting encephalopathy and dying (the probability of mistaking saying so is below one in 1000: i.e. p<0.001 in statistical term).
[2] One of the studies in the report (the study by Medical Association of Osaka Prefecture) showed that NSAIDs use was related with getting Reye's syndrome. As individual case was described in the study report, we recalculated the data and found that only 8.3 % of the patients with encephalopathy other than Reye's syndrome used NSAIDs, while 36.7 % of those with clinically diagnosed Reye's syndrome used NSAIDs and 53.8 % of those with definitely diagnosed Reye's syndrome used NSAIDs.
　It can be expressed that NSAIDs is 13 times more risky than non-user for getting definitely diagnosed Reye's syndrome (statistically p=0.0042) and 6 times more risky for getting clinically diagnosed Reye's syndrome (statistically p=0.017).

The report by the task force shows that investigators were aware of the risk

[3] The report for 1993 (made in 1995) described that mefenamic acid and diclofenac was more frequently used in definite or clinically diagnosed Reye's syndrome: among 32, 9 (28.1 %) used mefenamic acid and 3 (9.4 %) used diclofenac, 12 (37.5 %) took either of the two, while among 19 patients with encephalopathy other than Reye's syndrome used neither of the two. The investigator described this data and commented especially mefenamic acid, "it should be noticed."
[4] They also said "It was noted that the proportion of the users of non-steroidal anti-inflammatory drugs such as mefenamic acid or diclofenac NA among patients with Reye's syndrome seemed increase in 1988 and after than in 1987 and before." Moreover, they pointed out that the survey carried out in the Kinki districts (Osaka and neighbor prefectures) showed the similar results and they said, "These were the remarkable findings".
[5] In the report for 1994 (made in 1996), more remarkable findings were described: among nine patients with definite Reye's syndrome 8 (89 %) used NSAIDs, while among 44 with encephalopathy other than Reye's syndrome 6 (14 %) used them: these data indicate NSAIDs is 51 times risky to induce Reye's syndrome (p=0.0000021).
[6] The report also pointed out that all of the four patients with Reye's syndrome reported from Kinki districts used NSAIDs.
　The report of the task force of MHW in 1996 described that the epidemiological methods of the study comparing Reye's syndrome and encephalopathy other than Reye's syndrome done by the task force of MHW were correct. These studies were not case-control studies in the strict sense of definition, but they were very important as they repeatedly showed NSAIDs as the risk factor inducing Reye's syndrome or severe flu-related encephalopathy.

At least eight individual results showed the close association

　Thus by 1998, at least six individual study showed close association between Reye's syndrome or severe flu-related encephalopathy and NSAIDs. By including two studies done in 1999 and in 2000, the number of the studies that showed the close association between them is at least eight. Thus none should say that NSAIDs use is only the promoting factor of the severity of encephalopathy and not the cause inducing Reye's syndrome or severe encephalopathy. We have to think that NSAIDs is working at the point inducing Reye's syndrome or severe encephalopathy. So it is very important not to use NSAIDs as antipyretics to lower the body temperature in the infection including flu or common cold.

Ignoring the risk of NSAIDs is the matter of responsibility

　The first warnings should be made for the risk of the NSAIDs use in March 1994 at the latest when the report of task force for 1990 to 1992 made. And at the latest the measure "to suspend using NSAIDs" should be taken at March 1995 when almost definite data indicating NSAIDs as the major risk factor inducing Reye's syndrome were collected. If warnings had been issued in 1994, at least a half hundred lives might be saved every year and more than a hundred sufferers of sequelae of severe encephalopathy might be prevented.
　Investigator's conclusions ignoring the risk after discussing these data improperly may be an error. It should be said that the Pharmaceutical and Medical Safety Bureau have been continuing to induce drug disasters as it have never been taking measure after receiving reports containing many data indicating the close association between NSAIDs and Reye's syndrome or severe flu-related encephalopathy.
　We have proposed to stop using NSAIDs for antipyretics and have proposed to carry out a case-control study at least three times since January 1999. We have proposed a protocol of the case-control study as the task force of MHW in February 1999, but it was not accepted. It is a very serious problem that the Pharmaceutical and Medical Safety Bureau in MHW does not accept the true meanings of these data.

A drug disaster as large scale as those by thalidomide, SMON and blood-products-induced HIV

　We would like to point out that misestimating the results of the studies and delay of taking measures by the Pharmaceutical and Medical Safety Bureau in MHW have been producing a new drug disaster as large scale as that by thalidomide, SMON and blood-products-induced HIV.
　MHW (now Ministry of Health, Labor and Welfare: MHLW) should reassess those epidemiological studies done by the task force of MHW, should recognize NSAIDs as risk factor inducing Reye's syndrome or severe flu-related encephalopathy, and should also take a necessary measure (contraindicated for the use as antipyretics in infectious diseases).

Drug industries producing NSAIDs should change labeling by adding the contraindication for the use as antipyretics.

　For patients, we would like to emphasize that antipyretics are in principle unnecessary for fever by infection and if you want to use any on of antipyretics, acetaminophen (paracetamol) is far safer than NSAIDs antipyretics.

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