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ARE THERE SAFER HYPNOTICS THAN BARBITURATES ?
57
Special Article ARE THERE SAFER HYPNOTICS THAN
BARBITURATES ? B. M. BARRACLOUGH Medical Research Council Clinical
Psychiatry Unit, Graylingwell Hospital, Chichester, Sussex
The mortality associated with prescribing barbiturates, barbiturate containing ipecacuanha, and nitrazepam has been assessed. Over the six years 1965-70, the numbers of deaths in which these drugs were implicated and the death rate per million prescriptions for each drug were 12,354 and 133 for barbiturates, 1 and 9 for barbiturate containing ipecacuanha, and 90 and 13 for nitrazepam. The evidence suggests that nitrazepam is a safer drug than barbiturate. No definite conclusions can be reached about the safety of barbiturate
Summary
rates, barbemets, and nitrazepam was found in these mortality tables. When two, three, four, or five drugs together are given as the cause of death, which is so in about 10% of deaths, then if one of the three drugs was in the list the death was attributed to it. Twelve deaths associated with both barbiturate and nitrazepam were therefore counted twice. The estimated number of prescriptions dispensed by chemist contractors under the N.H.S. (E.C. 10) for the years 1965-70 for barbiturates, barbemets, and nitrazepam were provided by the Department of Health and Social Security, from the 0’5% sampling of all prescriptions, maintained for the efficient management of the health service. This estimate does not include private practice and hospital prescriptions, and is subject to sampling error.
RESULTS
The differences between the death-rates for barbiturates and barbemets, and barbiturates and nitraDEATH-RATES PER MILLION PRESCRIPTIONS
1965-70
containing ipecacuanha. INTRODUCTION
POISONING with barbiturates accounted for about 2000 deaths in 1970-two-thirds of all poisoning deaths in that year. 1300 were suicides, 300 were accidents, and 400 were " undetermined " deaths.l Prescribing safer hypnotics and sedatives than bar-
biturates, more especially by general practitioners, might influence this mortality by making overdoses less likely to be fatal. Two preparations, barbiturate tablets containing an emetic (amylobarbitone, butobarbitone, phenobarbitone, or cyclobarbitone and ipecacuanha), and nitrazepam, may be less likely than barbiturates to cause death by overdose. Tablets containing an emetic (" barbemets ") are thought to cause vomiting when 60-70% of the minilethal dose of barbiturate has been swallowed and thus prevent barbiturate poisoning. The evidence for the efficacy of this approach to the prevention of barbiturate poisoning is equivocal.2 Although barbemets have been marketed in England since 1953, they have not been freely prescribed, and only comprised 0-08% of the 13-1million barbiturate prescriptions dispensed by chemist contractors under the N.H.S. in 1970. Nitrazepam is a non-barbiturate hypnotic belonging to the benzodiazepine group. Clinical trials have shown it to be an effective hypnotic.3,4 There were 2-7 million nitrazepam prescriptions in 1970, and its use has increased rapidly since 1965. It is thought to be as effective as barbiturate and safer. mum
,
METHOD
The average death-rates, for the
population of England prescriptions issued for each drug, were calculated for the six-year period 1965-70, and the rates were compared. Deaths from poisoning are published annually by the General Register Office under the heading of the four external.causes of death, suicide (E950), accident (E850-869), undetermined deaths (E980), and homicide (E962).The number of deaths associated with barbituand
,
"
’
Wales, aged
over
fifteen,
per million
both very large (P<0.001) (see accompanying table). Since there was only one observed death for barbemets, in which methylpentynol was also implicated, results about it must be interpreted with caution. zepam
are
DISCUSSION
The large differences in death-rates suggest that both barbemets and nitrazepam are less lethal than barbiturates in clinical practice. However, this assumes that patients who were prescribed barbemets and nitrazepam had an equal, or a greater, risk of overdose as the population prescribed barbiturates. A reduced suicide risk would account for the difference in death-rates. Barbemets are specifically recommended for the patient at increased risk of attempted suicide, and it is difficult to imagine their prescription for any other reason. So for barbemets the assumption is probably justified. Nothing can be said with confidence about the suicide risk in patients prescribed nitrazepam, arguments can be presented favouring both a higher and a lower risk. The suggestion that both barbemets and nitrazepam are less likely to be fatal assumes that, although size of prescription is not such an important factor as suicide risk (since patients may hoard drugs and most single prescriptions contain lethal amounts), variation in prescription size is unimportant in accounting for the difference in death-rates. There is no reliable evidence on this point. Finally, it must also be assumed that the mortality
58
data is correct and that under-reporting of barbemets and nitrazepam as causes of death has not led to spuriously low death-rates for these drugs. Barbemets deaths may be under-reported, because barbemets are unfamiliar and may be included under the nonspecific heading of "barbiturate" to which 14 % of barbiturate deaths are allocated by coroners’ inquests. This possibility was checked by calculating the deathrates per million prescriptions for three barbiturate preparations which are prescribed with a similar low frequency to barbemets and which may be unfamiliar also. They were phenylmethylbarbituric acid, nealbarbitone, and heptabarbitone. Each of their death-rates and their combined rate was significantly less than that for all barbiturates, but similar to the barbemet rate (see table). This suggests that under-reporting is reponsible for the low death-rate associated with barbemet, there being no reason to suppose that these three preparations are less lethal than the more widely used barbiturates. Under-reporting seems unlikely to have influenced the numbers of deaths reported to be associated with nitrazepam. For nitrazepam, no definite conclusions are possible about the influence of risk of suicide and size of prescription in causing the difference in deathrate, and under-reporting is probably not important. The evidence about barbemets is inconclusive but does indicate that they are worth assessing in an experimental clinical setting. The manufacturers have received some reports of vomiting after overdoses.s Although prescriptions for barbiturates decreased by a quarter (from 17-2 million prescriptions in 1965 to 13-1 prescriptions in 1970), over the same period deaths associated with barbiturates only fell from 2037 to 2010. The death-rate per million barbiturate prescriptions is actually increasing. Thus safer barbiturate preparations should be investigated. For nitrazepam the evidence suggests that there is a real difference in safety compared with barbiturate, a conclusion which accords with reports of recovery after very large overdoses. Nitrazepam may be safer than the table indicates, since in 53 (60%) deaths, other drugs (barbiturates, antidepressants, and phenothiazines) were implicated, and nitrazepam was recorded as the sole cause of death in only 37 cases. A feature of nitrazepam which may contribute to its safety is the bulky tablet of the commonly prescribed ’Mogadon’, which makes the swallowing of overdoses hard work. Fifty tabets of mogadon 5 mg. weighed 27-5 g., four times more than fifty tablets of ’Amytal’ 100 mg., which weighed 7-7 g. Perhaps barbiturate would be safer as big tablets? The Department of Health and Social Security kindly provided the numbers of prescriptions for the drugs discussed. Mr Peter Fayers gave statistical advice and Dr D. Pallis suggested the test for under-reporting. REFERENCES
Pharm. J. 1968, 200, 387; 1969, 202, 177; 1969, 203, 74; 1970, 204, 703; 1971, 206, 422-426; 1972, 208, 530. 2. Mathew, H., Lawson, A. A. H. Treatment of Common Acute Poisonings; p. 153. Edinburgh, 1970. 3. Mathew, H., Proudfoot, A. T., Aitken, R. C. B., Raeburn, J. A., Wright, N. Br. med. J. 1969, iii, 23. 4. Haider, I. Br. J. Psychiat. 1968, 114, 337. 1.
5. G. O. Woodward and Co. Personal communication.
Occasional
Survey
IMMUNITY DEFICIENCY IN PATHOGENESIS OF GLOMERULONEPHRITIS D. K. PETERS
P. J. LACHMANN
Department of Medicine and Immunology, Royal Postgraduate Medical School, London W12
Evidence is presented indicating that the development of immune-complex glomerulonephritis can be related to defective clearance of antigen by antibody. Some of the factors which might be responsible for this failure are failure of antibody to confer immunity to infection, general and specific failure of T-cell responses, and deficiency of complement. The validity of treating immunecomplex glomerulonephritis by measures aimed at suppressing immune responses is questioned.
Sum ary
INTRODUCTION
LATELY, evidence has accumulated that most human and animal glomerulonephritides are caused by the
glomerular deposition of antigen-antibody complexes.1 The concept of immune-complex glomerulonephritis arose from essentially simple experiments, in which antigen (usually a foreign serum-protein such as bovine serum-albumin, B.S.A.) was administered to an animal: a single large dose of antigen resulted in an acute, self-limiting disease, one shot serum sickness 2,3; repeated smaller doses could cause chronic glomerulonephritis, provided the animal responded by making just sufficient antibody to generate nephritogenic immune complexes.’,’ For chronic immune-complex nephritis to develop there must be a persistent source of antigen and an antibody response to it. The early experiments using B.S.A. as antigen showed-that it was difficult to induce chronic nephritis in animals with a strong antibody response 4,5; the immune response must therefore provide sufficient antibody to generate immune complexes, but not result in over-rapid elimination of antigen. Thus, as argued by Soothill,6 the development of nephritis can be regarded as a consequence of failure of the immune response-i.e., a failure of antibody to clear the responsible antigen. Persistence of antigen in the face of an antibody response can occur when the antigen is repeatedly administered, as in penicillamine nephropathy,’ or where an autoantigen is released from cells as a result of allergic tissue damage, as is presumably the case with the D.N.A. nucleoprotein antigens in systemic lupus erythematosus. However, in many instances the antigen seems to be of infectious origin.l Chronic viral infection has been found to be a major source of antigen in spontaneous nephritis in animals 8; and, although the antigens responsible for most of the human chronic glomerulonephritides have not been identified, chronic infections-parasitic, bacterial, rickettsial, and viral-can all give rise to immune"
"
Special Article ARE THERE SAFER HYPNOTICS THAN
BARBITURATES ? B. M. BARRACLOUGH Medical Research Council Clinical
Psychiatry Unit, Graylingwell Hospital, Chichester, Sussex
The mortality associated with prescribing barbiturates, barbiturate containing ipecacuanha, and nitrazepam has been assessed. Over the six years 1965-70, the numbers of deaths in which these drugs were implicated and the death rate per million prescriptions for each drug were 12,354 and 133 for barbiturates, 1 and 9 for barbiturate containing ipecacuanha, and 90 and 13 for nitrazepam. The evidence suggests that nitrazepam is a safer drug than barbiturate. No definite conclusions can be reached about the safety of barbiturate
Summary
rates, barbemets, and nitrazepam was found in these mortality tables. When two, three, four, or five drugs together are given as the cause of death, which is so in about 10% of deaths, then if one of the three drugs was in the list the death was attributed to it. Twelve deaths associated with both barbiturate and nitrazepam were therefore counted twice. The estimated number of prescriptions dispensed by chemist contractors under the N.H.S. (E.C. 10) for the years 1965-70 for barbiturates, barbemets, and nitrazepam were provided by the Department of Health and Social Security, from the 0’5% sampling of all prescriptions, maintained for the efficient management of the health service. This estimate does not include private practice and hospital prescriptions, and is subject to sampling error.
RESULTS
The differences between the death-rates for barbiturates and barbemets, and barbiturates and nitraDEATH-RATES PER MILLION PRESCRIPTIONS
1965-70
containing ipecacuanha. INTRODUCTION
POISONING with barbiturates accounted for about 2000 deaths in 1970-two-thirds of all poisoning deaths in that year. 1300 were suicides, 300 were accidents, and 400 were " undetermined " deaths.l Prescribing safer hypnotics and sedatives than bar-
biturates, more especially by general practitioners, might influence this mortality by making overdoses less likely to be fatal. Two preparations, barbiturate tablets containing an emetic (amylobarbitone, butobarbitone, phenobarbitone, or cyclobarbitone and ipecacuanha), and nitrazepam, may be less likely than barbiturates to cause death by overdose. Tablets containing an emetic (" barbemets ") are thought to cause vomiting when 60-70% of the minilethal dose of barbiturate has been swallowed and thus prevent barbiturate poisoning. The evidence for the efficacy of this approach to the prevention of barbiturate poisoning is equivocal.2 Although barbemets have been marketed in England since 1953, they have not been freely prescribed, and only comprised 0-08% of the 13-1million barbiturate prescriptions dispensed by chemist contractors under the N.H.S. in 1970. Nitrazepam is a non-barbiturate hypnotic belonging to the benzodiazepine group. Clinical trials have shown it to be an effective hypnotic.3,4 There were 2-7 million nitrazepam prescriptions in 1970, and its use has increased rapidly since 1965. It is thought to be as effective as barbiturate and safer. mum
,
METHOD
The average death-rates, for the
population of England prescriptions issued for each drug, were calculated for the six-year period 1965-70, and the rates were compared. Deaths from poisoning are published annually by the General Register Office under the heading of the four external.causes of death, suicide (E950), accident (E850-869), undetermined deaths (E980), and homicide (E962).The number of deaths associated with barbituand
,
"
’
Wales, aged
over
fifteen,
per million
both very large (P<0.001) (see accompanying table). Since there was only one observed death for barbemets, in which methylpentynol was also implicated, results about it must be interpreted with caution. zepam
are
DISCUSSION
The large differences in death-rates suggest that both barbemets and nitrazepam are less lethal than barbiturates in clinical practice. However, this assumes that patients who were prescribed barbemets and nitrazepam had an equal, or a greater, risk of overdose as the population prescribed barbiturates. A reduced suicide risk would account for the difference in death-rates. Barbemets are specifically recommended for the patient at increased risk of attempted suicide, and it is difficult to imagine their prescription for any other reason. So for barbemets the assumption is probably justified. Nothing can be said with confidence about the suicide risk in patients prescribed nitrazepam, arguments can be presented favouring both a higher and a lower risk. The suggestion that both barbemets and nitrazepam are less likely to be fatal assumes that, although size of prescription is not such an important factor as suicide risk (since patients may hoard drugs and most single prescriptions contain lethal amounts), variation in prescription size is unimportant in accounting for the difference in death-rates. There is no reliable evidence on this point. Finally, it must also be assumed that the mortality
58
data is correct and that under-reporting of barbemets and nitrazepam as causes of death has not led to spuriously low death-rates for these drugs. Barbemets deaths may be under-reported, because barbemets are unfamiliar and may be included under the nonspecific heading of "barbiturate" to which 14 % of barbiturate deaths are allocated by coroners’ inquests. This possibility was checked by calculating the deathrates per million prescriptions for three barbiturate preparations which are prescribed with a similar low frequency to barbemets and which may be unfamiliar also. They were phenylmethylbarbituric acid, nealbarbitone, and heptabarbitone. Each of their death-rates and their combined rate was significantly less than that for all barbiturates, but similar to the barbemet rate (see table). This suggests that under-reporting is reponsible for the low death-rate associated with barbemet, there being no reason to suppose that these three preparations are less lethal than the more widely used barbiturates. Under-reporting seems unlikely to have influenced the numbers of deaths reported to be associated with nitrazepam. For nitrazepam, no definite conclusions are possible about the influence of risk of suicide and size of prescription in causing the difference in deathrate, and under-reporting is probably not important. The evidence about barbemets is inconclusive but does indicate that they are worth assessing in an experimental clinical setting. The manufacturers have received some reports of vomiting after overdoses.s Although prescriptions for barbiturates decreased by a quarter (from 17-2 million prescriptions in 1965 to 13-1 prescriptions in 1970), over the same period deaths associated with barbiturates only fell from 2037 to 2010. The death-rate per million barbiturate prescriptions is actually increasing. Thus safer barbiturate preparations should be investigated. For nitrazepam the evidence suggests that there is a real difference in safety compared with barbiturate, a conclusion which accords with reports of recovery after very large overdoses. Nitrazepam may be safer than the table indicates, since in 53 (60%) deaths, other drugs (barbiturates, antidepressants, and phenothiazines) were implicated, and nitrazepam was recorded as the sole cause of death in only 37 cases. A feature of nitrazepam which may contribute to its safety is the bulky tablet of the commonly prescribed ’Mogadon’, which makes the swallowing of overdoses hard work. Fifty tabets of mogadon 5 mg. weighed 27-5 g., four times more than fifty tablets of ’Amytal’ 100 mg., which weighed 7-7 g. Perhaps barbiturate would be safer as big tablets? The Department of Health and Social Security kindly provided the numbers of prescriptions for the drugs discussed. Mr Peter Fayers gave statistical advice and Dr D. Pallis suggested the test for under-reporting. REFERENCES
Pharm. J. 1968, 200, 387; 1969, 202, 177; 1969, 203, 74; 1970, 204, 703; 1971, 206, 422-426; 1972, 208, 530. 2. Mathew, H., Lawson, A. A. H. Treatment of Common Acute Poisonings; p. 153. Edinburgh, 1970. 3. Mathew, H., Proudfoot, A. T., Aitken, R. C. B., Raeburn, J. A., Wright, N. Br. med. J. 1969, iii, 23. 4. Haider, I. Br. J. Psychiat. 1968, 114, 337. 1.
5. G. O. Woodward and Co. Personal communication.
Occasional
Survey
IMMUNITY DEFICIENCY IN PATHOGENESIS OF GLOMERULONEPHRITIS D. K. PETERS
P. J. LACHMANN
Department of Medicine and Immunology, Royal Postgraduate Medical School, London W12
Evidence is presented indicating that the development of immune-complex glomerulonephritis can be related to defective clearance of antigen by antibody. Some of the factors which might be responsible for this failure are failure of antibody to confer immunity to infection, general and specific failure of T-cell responses, and deficiency of complement. The validity of treating immunecomplex glomerulonephritis by measures aimed at suppressing immune responses is questioned.
Sum ary
INTRODUCTION
LATELY, evidence has accumulated that most human and animal glomerulonephritides are caused by the
glomerular deposition of antigen-antibody complexes.1 The concept of immune-complex glomerulonephritis arose from essentially simple experiments, in which antigen (usually a foreign serum-protein such as bovine serum-albumin, B.S.A.) was administered to an animal: a single large dose of antigen resulted in an acute, self-limiting disease, one shot serum sickness 2,3; repeated smaller doses could cause chronic glomerulonephritis, provided the animal responded by making just sufficient antibody to generate nephritogenic immune complexes.’,’ For chronic immune-complex nephritis to develop there must be a persistent source of antigen and an antibody response to it. The early experiments using B.S.A. as antigen showed-that it was difficult to induce chronic nephritis in animals with a strong antibody response 4,5; the immune response must therefore provide sufficient antibody to generate immune complexes, but not result in over-rapid elimination of antigen. Thus, as argued by Soothill,6 the development of nephritis can be regarded as a consequence of failure of the immune response-i.e., a failure of antibody to clear the responsible antigen. Persistence of antigen in the face of an antibody response can occur when the antigen is repeatedly administered, as in penicillamine nephropathy,’ or where an autoantigen is released from cells as a result of allergic tissue damage, as is presumably the case with the D.N.A. nucleoprotein antigens in systemic lupus erythematosus. However, in many instances the antigen seems to be of infectious origin.l Chronic viral infection has been found to be a major source of antigen in spontaneous nephritis in animals 8; and, although the antigens responsible for most of the human chronic glomerulonephritides have not been identified, chronic infections-parasitic, bacterial, rickettsial, and viral-can all give rise to immune"
"