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AN UNHAPPY OUTLOOK FOR DRUG THERAPY
863
Letters
to
the Editor
AN UNHAPPY OUTLOOK FOR DRUG THERAPY
SIR,-Drug manufacturers, doctors, and the Committee on Safety of Medicines (CSM), for share responsibility for ensuring that drugs are effective and safe. Concern over the integrity and credibility of these controlling bodies has arisen from doubt seeded by various interested parties and events. The CSM seems to be in a quandary and has reacted to medical and lay press opinions destructively rather than constructively. The resulting confusion is depriving patients of useful drugs. Rheumatology has been affected more than any other specialty and communication with the regulatory authority is to be discussed in a seminar on drug toxicity at the forthcoming meeting of the British Society for Rheumatology. The trend has resulted from misconceptions that must be corrected before any further useful treatments are lost through overzealous reaction. The CSM seems to consider safety to the exclusion of efficacy. CSM action implies that doctors are careless, that they require legislative control rather than training in the use of drugs. The CSM’s decisions are inconsistent; it allows potentially harmful drugs to be available without prescriptionl and at the same time bans apparently similar drugs without consideration of relative efficacy. Benoxaprofen2and fenclofenac3may have provided more than symptomatic relief, and their premature withdrawal has left their long-term value in rheumatoid arthritis unresolved. The CSM seems not to know that many years of careful evaluation are needed to establish any effect of an anti-rheumatic drug on the progression of the disease. Patent law and the NHS pricing system do not cater for pre-marketing evaluation of drugs with limited indications. The result is massive promotion once a drug has been introduced, exposing large numbers of patients (many of whom do not need a disease-modifying drug) to the agent. Side-effects and specific effects then emerge-and the survival of the drug will depend on which effects appear first and arouse most public interest. The
alter native-detailed,
prolonged
pre-marketing
evaluation,
preferably in hospital-would have permitted long-term comparisons of efficacy and safety of agents such as benoxaprofen and fenclofenac with established drugs such as gold.and penicillamine. The CSM seems to be swayed by presumptious and uninformed views in both the medical and lay press.4 a few weeks before benoxaprofen was withdrawn the CSM endorsed a circular from the company warning on its use in the elderly. A similar churlish response occurred with phenylbutazone-any restrictions should have been imposed 10 years earlier since no significant new information has recently been revealed. Dr Herxheimer’s philosophy (June 30, p 1460) that old drugs should be withdrawn when new agents become available is correct only when the superiority of the new agent is clearly established, and, as Dr Selhon has noted (July 14, p 103), specific effects and disadvantages may not emerge for years. The monitoring of adverse reactions by the CSM’s yellow card system is uncontrolled, retrospective, and can be misconstrued-and it is open to pressure from the media. The more scientific prescription event monitoring, used by the drug surveillance research unit at Southampton University, suggested that benoxaprofen was safe.5 The relation between doctors and the pharmaceutical industry has also received attention lately. Professor Rawlins’ article (Aug 4, p 276) was extreme. Dogmatic restrictions on the interface between doctors and the drug makers can only harm patients. Bribery and corruption must, of course, be punished but this is distinct from the necessary working relationship. Companies need clinical input to learn what types of agent doctors require and to discuss the results of clinical trials. When a drug is licensed, information must be publicised-a secret panacea is useless. Medical journals and advertisements achieve this in part but a forum permitting discussion of the advantages and disadvantages of a new agent is also desirable. Such meetings require sponsorship-the NHS is not going to pay-and they may be held outside the UK to permit international contact or to remove the participants from the distractions of day-to-day work. Patients, prompted by the media, are encouraged to question our motives in attending such meetings.
Only
.
The correct response is to foster responsible attitudes in all concerned not to abandon meetings with a high educational content. Rheumatologists discussing the long-term treatment of rheumatoid arthritis (Aug 4, p 278) accept that there are two major categories of drug therapy-simple analgesics or non-steroidal antiinflammatory agents (NSAID) for symptomatic relief and diseasemodifying agents that may alter the prognosis. Disease-modifying agents do seem to have a limited useful lifespan, hence the need for new agents. Benoxaprofen and fenclofenac might have had an important role. The precipitous withdrawal of anti-rheumatic drugs has been influenced by criticisms of the doctor/pharmaceutical industry relationship, to the detriment of patients. The removal of benoxaprofen and fenclofenac, in the belief their side-effects were inappropriate for simple NSAIDs, was wrong; the yellow-card system should be replaced; and a constructive approach to drug evaluation, allowing for commercial incentive, is required. If the present trend continues rheumatologists will have to console themselves by evaluating ice, splints and green-lipped mussel extract.
P. T. DAWES P. D. FOWLER M. F. SHADFORTH T. E. HOTHERSALL
Staffordshire
Rheumatology Centre, Haywood Hospital,
Burslem, Stoke on Trent, Staffs ST6 7AG 1. Dawes
PT, Fowler PD, Shadforth MF, Hothersall
anti-imflammatory drugs
over
the
counter:
TE. Availability of non-steroidal Information needed. Br Med J 1984;
289: 413-14.
MF, Crook PR, Fowler PD. The effects of benoxaprofen on clinical and serological features of rheumatoid arthritis: Comparison with similar effects from chloroquine and dapsone. Arthritis Rheum 1982; 4 (suppl): 121. Bedi SS, Eberi R, Million R, Silas AM. Fenclofenac and diclofenac in the treatment of rheumatoid arthritis. Br J Rheumatol 1984; 3: 214-19. Struthers G, Smith D, Scott DGI, Farr M, Symmons DPM, Coppock J, Bacon PA. The rattled CSM should think again. Br Med J 1984; 289: 318. Inman WHW. PEM News 1984, no 2.
2. Shadforth
3. 4.
5.
INTENSIVE CARE SEDATION NOW
SIR,-The withdrawal of ’Althesin’ and doubts about etomidate given by continuous infusion for sedation in the intensive
when
unit (ITU) has prompted many units to reconsider their regimens for providing sedation in ventilated patients, and the
therapy
whole issue has been reviewed in a Lancet editorial (June 23, p 1388). In 1981, Merriman reported on the sedative techniques in thirty-four ITUs in the UK. The commonest first-line drugs were benzodiazepines or opioids alone or in combination. The most frequently used opioids were phenoperidine (62% of units), papaveretum (32%), and morphine (26%). Diazepam was used in 64% of the units, compared with lorazepam in 32%. In 26% of the ITUs questioned, nitrous oxide was used to provide short-term sedation. We have reviewed the practice of twenty-four ITUs in the postalthesin/etomidate era. Twelve of the units questioned were in teaching hospitals, the others were in district general hospitals. 75% had a definite sedation programme compared with only 53% in the earlier study. Opioids were used in the first-line regimens in 81 % of units and benzodiazepines in only 29%. Although there has been no real change in the choice of opioid the water-soluble benzodiazepine midazolam is now widely used and is the most frequently used of the pure hypnotic agents. The main reasons for midazolam use are that it does not accumulate on repeat administration or continuous infusion, that it causes amnesia, that its respiratory depressive action permits easy control of ventilation, and that its duration of action is predictable. From our experience we would question the predictability of duration and no studies on the disposition and metabolism of midazolam are available to support the claim for nonaccumulation. The withdrawal of althesin has resulted in a significant change in drug regimens in eleven of the ITUs questioned; most now use a mixture of benzodiazepine and opioid. Two units still use althesin as their first-line drug for the control of ventilation in the patient with a head injury. Current practice seems to be against relaxants; their use as a firstline drug was reported in only 16% of patients compared with 91 % in Merriman’s study.Even so caution must be emphasised when discussing the use of neuromuscular blocking drugs in the context of sedation.
Letters
to
the Editor
AN UNHAPPY OUTLOOK FOR DRUG THERAPY
SIR,-Drug manufacturers, doctors, and the Committee on Safety of Medicines (CSM), for share responsibility for ensuring that drugs are effective and safe. Concern over the integrity and credibility of these controlling bodies has arisen from doubt seeded by various interested parties and events. The CSM seems to be in a quandary and has reacted to medical and lay press opinions destructively rather than constructively. The resulting confusion is depriving patients of useful drugs. Rheumatology has been affected more than any other specialty and communication with the regulatory authority is to be discussed in a seminar on drug toxicity at the forthcoming meeting of the British Society for Rheumatology. The trend has resulted from misconceptions that must be corrected before any further useful treatments are lost through overzealous reaction. The CSM seems to consider safety to the exclusion of efficacy. CSM action implies that doctors are careless, that they require legislative control rather than training in the use of drugs. The CSM’s decisions are inconsistent; it allows potentially harmful drugs to be available without prescriptionl and at the same time bans apparently similar drugs without consideration of relative efficacy. Benoxaprofen2and fenclofenac3may have provided more than symptomatic relief, and their premature withdrawal has left their long-term value in rheumatoid arthritis unresolved. The CSM seems not to know that many years of careful evaluation are needed to establish any effect of an anti-rheumatic drug on the progression of the disease. Patent law and the NHS pricing system do not cater for pre-marketing evaluation of drugs with limited indications. The result is massive promotion once a drug has been introduced, exposing large numbers of patients (many of whom do not need a disease-modifying drug) to the agent. Side-effects and specific effects then emerge-and the survival of the drug will depend on which effects appear first and arouse most public interest. The
alter native-detailed,
prolonged
pre-marketing
evaluation,
preferably in hospital-would have permitted long-term comparisons of efficacy and safety of agents such as benoxaprofen and fenclofenac with established drugs such as gold.and penicillamine. The CSM seems to be swayed by presumptious and uninformed views in both the medical and lay press.4 a few weeks before benoxaprofen was withdrawn the CSM endorsed a circular from the company warning on its use in the elderly. A similar churlish response occurred with phenylbutazone-any restrictions should have been imposed 10 years earlier since no significant new information has recently been revealed. Dr Herxheimer’s philosophy (June 30, p 1460) that old drugs should be withdrawn when new agents become available is correct only when the superiority of the new agent is clearly established, and, as Dr Selhon has noted (July 14, p 103), specific effects and disadvantages may not emerge for years. The monitoring of adverse reactions by the CSM’s yellow card system is uncontrolled, retrospective, and can be misconstrued-and it is open to pressure from the media. The more scientific prescription event monitoring, used by the drug surveillance research unit at Southampton University, suggested that benoxaprofen was safe.5 The relation between doctors and the pharmaceutical industry has also received attention lately. Professor Rawlins’ article (Aug 4, p 276) was extreme. Dogmatic restrictions on the interface between doctors and the drug makers can only harm patients. Bribery and corruption must, of course, be punished but this is distinct from the necessary working relationship. Companies need clinical input to learn what types of agent doctors require and to discuss the results of clinical trials. When a drug is licensed, information must be publicised-a secret panacea is useless. Medical journals and advertisements achieve this in part but a forum permitting discussion of the advantages and disadvantages of a new agent is also desirable. Such meetings require sponsorship-the NHS is not going to pay-and they may be held outside the UK to permit international contact or to remove the participants from the distractions of day-to-day work. Patients, prompted by the media, are encouraged to question our motives in attending such meetings.
Only
.
The correct response is to foster responsible attitudes in all concerned not to abandon meetings with a high educational content. Rheumatologists discussing the long-term treatment of rheumatoid arthritis (Aug 4, p 278) accept that there are two major categories of drug therapy-simple analgesics or non-steroidal antiinflammatory agents (NSAID) for symptomatic relief and diseasemodifying agents that may alter the prognosis. Disease-modifying agents do seem to have a limited useful lifespan, hence the need for new agents. Benoxaprofen and fenclofenac might have had an important role. The precipitous withdrawal of anti-rheumatic drugs has been influenced by criticisms of the doctor/pharmaceutical industry relationship, to the detriment of patients. The removal of benoxaprofen and fenclofenac, in the belief their side-effects were inappropriate for simple NSAIDs, was wrong; the yellow-card system should be replaced; and a constructive approach to drug evaluation, allowing for commercial incentive, is required. If the present trend continues rheumatologists will have to console themselves by evaluating ice, splints and green-lipped mussel extract.
P. T. DAWES P. D. FOWLER M. F. SHADFORTH T. E. HOTHERSALL
Staffordshire
Rheumatology Centre, Haywood Hospital,
Burslem, Stoke on Trent, Staffs ST6 7AG 1. Dawes
PT, Fowler PD, Shadforth MF, Hothersall
anti-imflammatory drugs
over
the
counter:
TE. Availability of non-steroidal Information needed. Br Med J 1984;
289: 413-14.
MF, Crook PR, Fowler PD. The effects of benoxaprofen on clinical and serological features of rheumatoid arthritis: Comparison with similar effects from chloroquine and dapsone. Arthritis Rheum 1982; 4 (suppl): 121. Bedi SS, Eberi R, Million R, Silas AM. Fenclofenac and diclofenac in the treatment of rheumatoid arthritis. Br J Rheumatol 1984; 3: 214-19. Struthers G, Smith D, Scott DGI, Farr M, Symmons DPM, Coppock J, Bacon PA. The rattled CSM should think again. Br Med J 1984; 289: 318. Inman WHW. PEM News 1984, no 2.
2. Shadforth
3. 4.
5.
INTENSIVE CARE SEDATION NOW
SIR,-The withdrawal of ’Althesin’ and doubts about etomidate given by continuous infusion for sedation in the intensive
when
unit (ITU) has prompted many units to reconsider their regimens for providing sedation in ventilated patients, and the
therapy
whole issue has been reviewed in a Lancet editorial (June 23, p 1388). In 1981, Merriman reported on the sedative techniques in thirty-four ITUs in the UK. The commonest first-line drugs were benzodiazepines or opioids alone or in combination. The most frequently used opioids were phenoperidine (62% of units), papaveretum (32%), and morphine (26%). Diazepam was used in 64% of the units, compared with lorazepam in 32%. In 26% of the ITUs questioned, nitrous oxide was used to provide short-term sedation. We have reviewed the practice of twenty-four ITUs in the postalthesin/etomidate era. Twelve of the units questioned were in teaching hospitals, the others were in district general hospitals. 75% had a definite sedation programme compared with only 53% in the earlier study. Opioids were used in the first-line regimens in 81 % of units and benzodiazepines in only 29%. Although there has been no real change in the choice of opioid the water-soluble benzodiazepine midazolam is now widely used and is the most frequently used of the pure hypnotic agents. The main reasons for midazolam use are that it does not accumulate on repeat administration or continuous infusion, that it causes amnesia, that its respiratory depressive action permits easy control of ventilation, and that its duration of action is predictable. From our experience we would question the predictability of duration and no studies on the disposition and metabolism of midazolam are available to support the claim for nonaccumulation. The withdrawal of althesin has resulted in a significant change in drug regimens in eleven of the ITUs questioned; most now use a mixture of benzodiazepine and opioid. Two units still use althesin as their first-line drug for the control of ventilation in the patient with a head injury. Current practice seems to be against relaxants; their use as a firstline drug was reported in only 16% of patients compared with 91 % in Merriman’s study.Even so caution must be emphasised when discussing the use of neuromuscular blocking drugs in the context of sedation.