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Should we tell trial patients that they might receive placebo?
1041
It is my understanding from discussions with Dr Mukesh Kapila of ODA that this change in approach reflects a new health sector support strategy that should be more in tune with the needs of the Caribbean. ODA also provides considerable development support in this part of the world in other ways-to the British dependent territories, bilaterally with selected countries, through UK nongovernmental organisations, and via contributions to multilateral agencies (such as the European Community and WHO, and other UN agencies). When CAREC came into being, as a PAHO/WHO centre, in 1975, it had a staff of 35 and served fourteen Caribbean countries. The centre today employs about 100 people and has a modern scientific and managerial structure that should allow us to compete effectively for ODA funding in the coming years. We now serve nineteen states, including six British territories (who have a favourable track record of direct quota payments to CAREC). Rather than viewing the change in ODA funding procedures as a form of "abandonment", we would prefer to see the relationship as one more analogous to scientific and managerial maturity. CAREC, PO Box 164,
FRANKLIN WHITE,
Port of
Director
Spain, Trinidad
Should
we
tell trial patients that receive placebo?
they might
SIR,-Patients must give informed consent before taking part in a clinical trial and the guidelines for good clinical trial practice in the European Community and Scandinavia lay down that patients be informed if they might be allocated to placebo. In two clinical trials!,2 in the maternity ward of a Norwegian hospital, treatment for postpartum pain was evaluated in two groups of patients. A trial of paracetamol versus placebo was followed by a comparison of paracetamol and naproxen, the second trial being initiated immediately after the first one had finished. The trial protocols were identical and the same hospital staff took care of the patients. The patients in the first trial were told that they might receive a placebo; the patients participating in the second study knew that they would receive one of two active drugs. Experience in these two trials may throw light on the effect of telling patients that a placebo may be
given. The intensity of postpartum uterine cramping was recorded on a cm visual analogue scale (VAS) by women asking for analgesic treatment. Pain intensity was recorded when treatment was initiated, and 2 and 4 h after medication. Statistical analysis was
primarily based on the difference between pain intensities at 0 and 2 h. The figure shows the median responses, high values representing large reductions in pain. The trials were sequential in design so the number of patients can be regarded as part of the results. Both studies ended with small numbers of patients; the paracetamol groups had 40 and 34 patients, respectively. Before the two trials a pilot study with 5 patients on naproxen and 5 patients on paracetamol had been done, following the protocol of the second trial, and these 5 patients on paracetamol have been included in the group knowing they would receive active treatment, raising that number to 39. The median pain reduction in the paracetamol groups after 2 h was 21 mm in the first trial and 40 mm in the second, and after 4 h reductions were 175 mm and 38-0 mm, respectively (one-sided p, 0-079 at 2 h and 0-084 at 4 h; Wilcoxon rank-sum test). An explanation for the observed difference between pain reduction in the two trials may be that the patients in the second trial expected and experienced a considerable effect of the given drug because they knew that they would receive an active drug, whereas those in the first trial were more sceptical since they knew they might receive a placebo ("a drug that did not work"). As a result of this scepticism, the effect of the active drug in the first trial was reduced. There are no differences between the two studies that could explain the different responses while on paracetamol, other than information about possible placebo treatment. When patients participating in a clinical trial are informed that they may receive placebo, the effect of the active drug in the trial may be reduced, and the trial will tend to underestimate the effect of the same drug in ordinary clinical practice. Perhaps we should think again about whether we need to tell patients that a placebo may be
given. I thank Gunnar Fyllingen, Heidi Landre, and Britt-Ingjerd Nesheim for help with the study and Lars Walloe for comments.
Department of Informatics, University of Oslo, 0316 Oslo 3, Norway
EVA SKOVLUND
1. Skovlund
E, Fyllingen G, Landre H, Nesheim B-I. Comparison of postpartum pain using a sequential trial design I: paracetamol versus placebo. Eur J Clin Pharmacol (in press). 2. Skovlund E, Fyllingen G, Landre H, Nesheim B-I. Comparison of postpartum pain treatments using a sequential trial design II: naproxen versus paracetamol. Eur J Clin Pharmacol (m press). treatments
10
Time after medication
(h)
Median pain intensity difference 2 and 4 h after medication. t = paracetamol, trial 2 (including pilot study patients). -
paracetamol, trial 1.
* naproxen, trial 2. - = placebo, trial 1.
Non-parametric
95% confidence intervals given for two paracetamol
groups being compared.
Milk, butter, and heart disease SiR,—Findings from the MRC’s Epidemiology Unit (South Wales) on dairy produce consumption and coronary heart disease, the subject of a note in your March 9 issue (p 607), will not help the sense of confusion felt by nutritionists who teach prevention. The possibility that milk and butter-hitherto presented as dietary villains-may be protective has sent shock waves through the ranks of officialdom. The advice of a hastily convened Medical Research Council panel to the effect that we should ignore the Cardiff findings serves only to increase our confusion. Is not the attempt of the MRC panel to discredit the findings of the Cardiff unit a good example of what Solzhenitsyn has called "the censorship of fashion"? The fashionable teaching about dietary fats and heart disease could never have survived without widespread censorship of evidence against a theory, made popular by the evangelism of specialists and the interests of commerce. In the 1950s Norway launched a cholesterol-lowering regimen in which soya margarine replaced butter and soya oil was used extensively. In the next twenty years the increase in the use of soya-oil products was accompanied by a steep and continuing rise in deaths from coronary thrombosisWhen Dr Jens Dedichen, a member of the Norwegian Council for Diseases of the Heart and Arteries, drew attention to the failure of the programme he was surprised at the hostile reaction of his colleagues:-"I was quite simply accused of being ignorant, worse, I was censored".2 A 1988 publication from the WHO Regional Office for Europe3 advises a 30% reduction in saturated fat consumption and an increase in polyunsaturated fats. The monograph ignores European epidemiological data which do not support this advice, and the list of 200 references makes no mention of papers by dissidents such as
It is my understanding from discussions with Dr Mukesh Kapila of ODA that this change in approach reflects a new health sector support strategy that should be more in tune with the needs of the Caribbean. ODA also provides considerable development support in this part of the world in other ways-to the British dependent territories, bilaterally with selected countries, through UK nongovernmental organisations, and via contributions to multilateral agencies (such as the European Community and WHO, and other UN agencies). When CAREC came into being, as a PAHO/WHO centre, in 1975, it had a staff of 35 and served fourteen Caribbean countries. The centre today employs about 100 people and has a modern scientific and managerial structure that should allow us to compete effectively for ODA funding in the coming years. We now serve nineteen states, including six British territories (who have a favourable track record of direct quota payments to CAREC). Rather than viewing the change in ODA funding procedures as a form of "abandonment", we would prefer to see the relationship as one more analogous to scientific and managerial maturity. CAREC, PO Box 164,
FRANKLIN WHITE,
Port of
Director
Spain, Trinidad
Should
we
tell trial patients that receive placebo?
they might
SIR,-Patients must give informed consent before taking part in a clinical trial and the guidelines for good clinical trial practice in the European Community and Scandinavia lay down that patients be informed if they might be allocated to placebo. In two clinical trials!,2 in the maternity ward of a Norwegian hospital, treatment for postpartum pain was evaluated in two groups of patients. A trial of paracetamol versus placebo was followed by a comparison of paracetamol and naproxen, the second trial being initiated immediately after the first one had finished. The trial protocols were identical and the same hospital staff took care of the patients. The patients in the first trial were told that they might receive a placebo; the patients participating in the second study knew that they would receive one of two active drugs. Experience in these two trials may throw light on the effect of telling patients that a placebo may be
given. The intensity of postpartum uterine cramping was recorded on a cm visual analogue scale (VAS) by women asking for analgesic treatment. Pain intensity was recorded when treatment was initiated, and 2 and 4 h after medication. Statistical analysis was
primarily based on the difference between pain intensities at 0 and 2 h. The figure shows the median responses, high values representing large reductions in pain. The trials were sequential in design so the number of patients can be regarded as part of the results. Both studies ended with small numbers of patients; the paracetamol groups had 40 and 34 patients, respectively. Before the two trials a pilot study with 5 patients on naproxen and 5 patients on paracetamol had been done, following the protocol of the second trial, and these 5 patients on paracetamol have been included in the group knowing they would receive active treatment, raising that number to 39. The median pain reduction in the paracetamol groups after 2 h was 21 mm in the first trial and 40 mm in the second, and after 4 h reductions were 175 mm and 38-0 mm, respectively (one-sided p, 0-079 at 2 h and 0-084 at 4 h; Wilcoxon rank-sum test). An explanation for the observed difference between pain reduction in the two trials may be that the patients in the second trial expected and experienced a considerable effect of the given drug because they knew that they would receive an active drug, whereas those in the first trial were more sceptical since they knew they might receive a placebo ("a drug that did not work"). As a result of this scepticism, the effect of the active drug in the first trial was reduced. There are no differences between the two studies that could explain the different responses while on paracetamol, other than information about possible placebo treatment. When patients participating in a clinical trial are informed that they may receive placebo, the effect of the active drug in the trial may be reduced, and the trial will tend to underestimate the effect of the same drug in ordinary clinical practice. Perhaps we should think again about whether we need to tell patients that a placebo may be
given. I thank Gunnar Fyllingen, Heidi Landre, and Britt-Ingjerd Nesheim for help with the study and Lars Walloe for comments.
Department of Informatics, University of Oslo, 0316 Oslo 3, Norway
EVA SKOVLUND
1. Skovlund
E, Fyllingen G, Landre H, Nesheim B-I. Comparison of postpartum pain using a sequential trial design I: paracetamol versus placebo. Eur J Clin Pharmacol (in press). 2. Skovlund E, Fyllingen G, Landre H, Nesheim B-I. Comparison of postpartum pain treatments using a sequential trial design II: naproxen versus paracetamol. Eur J Clin Pharmacol (m press). treatments
10
Time after medication
(h)
Median pain intensity difference 2 and 4 h after medication. t = paracetamol, trial 2 (including pilot study patients). -
paracetamol, trial 1.
* naproxen, trial 2. - = placebo, trial 1.
Non-parametric
95% confidence intervals given for two paracetamol
groups being compared.
Milk, butter, and heart disease SiR,—Findings from the MRC’s Epidemiology Unit (South Wales) on dairy produce consumption and coronary heart disease, the subject of a note in your March 9 issue (p 607), will not help the sense of confusion felt by nutritionists who teach prevention. The possibility that milk and butter-hitherto presented as dietary villains-may be protective has sent shock waves through the ranks of officialdom. The advice of a hastily convened Medical Research Council panel to the effect that we should ignore the Cardiff findings serves only to increase our confusion. Is not the attempt of the MRC panel to discredit the findings of the Cardiff unit a good example of what Solzhenitsyn has called "the censorship of fashion"? The fashionable teaching about dietary fats and heart disease could never have survived without widespread censorship of evidence against a theory, made popular by the evangelism of specialists and the interests of commerce. In the 1950s Norway launched a cholesterol-lowering regimen in which soya margarine replaced butter and soya oil was used extensively. In the next twenty years the increase in the use of soya-oil products was accompanied by a steep and continuing rise in deaths from coronary thrombosisWhen Dr Jens Dedichen, a member of the Norwegian Council for Diseases of the Heart and Arteries, drew attention to the failure of the programme he was surprised at the hostile reaction of his colleagues:-"I was quite simply accused of being ignorant, worse, I was censored".2 A 1988 publication from the WHO Regional Office for Europe3 advises a 30% reduction in saturated fat consumption and an increase in polyunsaturated fats. The monograph ignores European epidemiological data which do not support this advice, and the list of 200 references makes no mention of papers by dissidents such as