Br. J. clin. Pharmac. (1979), 7
LETTERSTOTHE EDITORS
529
SALICYLATES AND HOMEOPATHY The paper 'Salicylates and homeopathy in rheumatoid arthritis: preliminary observations' by Gibson, Gibson, MacNeill, Gray, Carson Dick & Watson Buchanan (1978) is of interest not only because of the topical nature of the subject and the superficially impressive response to homeopathy, but also because of the defects in the trial design. These defects should be of concern to readers of the British Journal of Clinical Pharmacology as publication of even preliminary observations in a specialist journal devoted to drug research gives a cachet of respectability to those observations in the eyes of nonspecialists. The question initially posed by the investigators was presumably 'how does homeopathy compare with conventional therapy or placebo in the treatment of rheumatoid arthritis?'. The trial, however, compared one preparation of aspirin (Nu-seals, Lilly) with the entire discipline of homeopathy using 200 remedies, and specifically excluded the disease modifying drugs, gold and penicillamine from the regimens of the
rheumatologists (Empire Rheumatism Council, 1961; Multicentre Trial Group, 1973). A comparison of disciplines might have been expected to have left rheumatologists as well as homeopathists free to prescribe remedies appropriate to the patient's clinical circumstances. A comparison of treatments should have defined a group of patients appropriate for treatment with a predetermined number of homeopathic remedies and compared their progress with that of patients treated with a limited group of conventional remedies. It will be recalled that 195 patients entered the trial, 100 consecutive new rheumatoid arthritis patients were treated with placebo, 41 patients with aspirin, and 54 with homeopathy plus a flexible regimen of their previous treatments. All groups were treated by different physicians, individual physicians and patients coming to a mutual agreement as to when improvement had occurred, at no time was there an independent assessment of response. The placebo group was not comparable with the homeopathy plus conventional therapy or the salicylate treated group, being patients presenting new to the hospital, the latter two groups being allocated from patients who had been attending the Centre for Rheumatic Diseases from 4 months to 10 years. Attitudes and expectations in the new and experienced patients may have been very different. The placebo group was administered sucrose powder, not a difficult substance to recognize, and once recognised by an individual, the clustering of all placebo patients in one clinic is likely to have
facilitated transfer of information on the nature of the treatment, leading to a rapid loss of group confidence in their physician's therapy. This being an open trial the general physician was aware that he was administering sucrose powder to patients in pain and was unlikely to have generated much enthusiasm in this treatment, it is therefore perhaps surprising that some patients continued for as long as 6 weeks in this fashion. Salicylate levels were monitored in the salicylate treated group. However, no details of these are presented despite the fact that these are essential to distinguish between simple overprescription or idiosyncratic response to salicylates. In view of the fact that the homeopathy treated group were allowed to continue treatment with their previous therapy, it is impossible to infer anything about the therapeutic response to homeopathy from this study. Even the group of 23 (42.6%) who finished the year on homeopathy alone may have simply entered remission having endured an exacerbation supported by their previous therapy and the attentions of the homeopathic specialists. It seems likely that these specialists felt a greater commitment to the success of their discipline in this trial than the rheumatologists felt towards enteric coated aspirin or the general physician to sucrose power. These variations in commitment are very likely to have affected the mutual physician and patient assessments of improvement (Bagley, Greer & Ramsay, 1973). The only conclusion that can be firmly drawn from this trial is that homeopathic treatment carries a low incidence of side-effects. No inference of its efficacy in treating rheumatoid arthritis can be made. The fact that this full paper contains only 'preliminary observations' may allow for some of the deficiencies in the trial design; however, even in a preliminary study the plotting of observations of response on the same ordinate and abscisse implies that the groups of data on the resultant graph are comparable. This is not the case for the 'comparison of the drop out rate' of the different groups in Figure 1 of the paper Gibson et al. (1978). These workers have in fact performed three entirely separate trials, each trial involving only one treatment regimen. There is no common factor between any of these trials, neither treatment, patients, assessor or physician being common to any two of the groups. There is thus no basis for inferred comparisons between treatment effects. It will be of great interest to review the results of the proposed balanced study; such a study should compare discipline with discipline or treatment with treat-
530
LETTERSTOTHE EDITORS
ment using patients drawn from similar populations. Treatments should be administered double-blind, patients seeing the same physicians or being assessed by an independent observer. Although randomization for homeopathic or conventional therapies might at first appear difficult, it could conveniently be performed at the level of dispensing a double placebo technique being used. In view of the investment of medical finance and manpower based on studies such as this, and the hopes that may be raised in rheumatoid arthritis
Br. J. clin. Pharmac. (1979), 7
sufferers, it is important that published preliminary studies should be of a design that is at least balanced and unbiased.
G. HUSTON Guy's Arthritis Research Unit, Guy's Hospital Medical School, London Bridge SE) 9RT Received December 29, 1978
References BAGLEY, C., GREER, S. & RAMSAY, I. (1973). Human relations: the uncontrolled variable in double-blind clinical trials. Res. Comm. Chem. Path. Pharmac., 5, 529-537. EMPIRE RHEUMATISM COUNCIL (1961). Gold therapy in rheumatoid arthritis: final report of a multicentre con-
troliedtrial.AnnRheum.Dis.,20, 315-333.
GIBSON, R.G., GIBSON, S.L.M., MacNEILL, A.D., GRAY, G.H., CARSON DICK, W. & WATSON BUCHANAN, W.
(1978). Salicylates and homeopathy in rheumatoid arthritis: preliminary observations. Br. J. clin. Pharmac., 6, 391-395. MULTICENTRE TRIAL GROUP(1973). Controlled trial of Dpenicillamine in severe rheumatoid arthritis. Lancet, i, 275-280.
SALICYLATES AND HOMEOPATHY Thank you for the opportunity to reply to Dr Huston, (1979). We fully accept the general criticism that the trial design in this preliminary study was imperfect. The protocol written prior to the commencement of the study would have met these criticisms but as we pointed out ourselves 'the best laid plans o' mice and men gang aft agley'. The following points should be underlined (although most are covered in the original paper). 1. We treat patients with rheumatoid arthritis pharmacologically in terms of 'first-line' and 'second-line' patients (Dick, 1978). All patients in the study were selected from a pool of patients in the former class. The entry characteristics of the different groups disclose a considerable degree of similarity in terms of the clinical characteristics of disease, duration and severity. 2. All patients were assessed throughout the study by an entirely independent, non-involved assessor in addition to assessments by patient and physician. 3. The independent assessor and the source and similarity of clinical material are common factors. 4. Any restriction or predetermination of the homeopathic pharmacopoeia invalidates the basis of homeopathic prescribing. 5. Salicylate therapy was monitored individually by clinical efficacy or toxicity on the one hand and by serum salicylate concentrations on the other for precisely those reasons that Dr Huston cites.
6. We have conducted a series of cohort studies over the past 6 years using drop out rate or 'compliance' as an imp43rtant arbiter of drug performance in the individual patient (Rooney, Capell, Paterson, Buchanan & Dick, 1978). This study was conducted during that programme. 7. Our null hypothesis was 'that homeopathy is ineffective and detrimental to the patient'. We feel that the data in this preliminary paper allows us to refute this null hypothesis.
W. CARSON DICK Centre for Rheumatic Diseases, Baird Street, Glasgow R. GIBSON Consultant Physician, Homeopathic Hospital, Great Western Road, Glasgow G.I.L. GRAY Department of Community Medicine, Ruchill Hospital, Bilsland Drive, Glasgow W.W. BUCHANAN Centre for Rheumatic Diseases, Baird Street,
Glasgow Received January 29, 1979
LETTERSTOTHE EDITORS
529
SALICYLATES AND HOMEOPATHY The paper 'Salicylates and homeopathy in rheumatoid arthritis: preliminary observations' by Gibson, Gibson, MacNeill, Gray, Carson Dick & Watson Buchanan (1978) is of interest not only because of the topical nature of the subject and the superficially impressive response to homeopathy, but also because of the defects in the trial design. These defects should be of concern to readers of the British Journal of Clinical Pharmacology as publication of even preliminary observations in a specialist journal devoted to drug research gives a cachet of respectability to those observations in the eyes of nonspecialists. The question initially posed by the investigators was presumably 'how does homeopathy compare with conventional therapy or placebo in the treatment of rheumatoid arthritis?'. The trial, however, compared one preparation of aspirin (Nu-seals, Lilly) with the entire discipline of homeopathy using 200 remedies, and specifically excluded the disease modifying drugs, gold and penicillamine from the regimens of the
rheumatologists (Empire Rheumatism Council, 1961; Multicentre Trial Group, 1973). A comparison of disciplines might have been expected to have left rheumatologists as well as homeopathists free to prescribe remedies appropriate to the patient's clinical circumstances. A comparison of treatments should have defined a group of patients appropriate for treatment with a predetermined number of homeopathic remedies and compared their progress with that of patients treated with a limited group of conventional remedies. It will be recalled that 195 patients entered the trial, 100 consecutive new rheumatoid arthritis patients were treated with placebo, 41 patients with aspirin, and 54 with homeopathy plus a flexible regimen of their previous treatments. All groups were treated by different physicians, individual physicians and patients coming to a mutual agreement as to when improvement had occurred, at no time was there an independent assessment of response. The placebo group was not comparable with the homeopathy plus conventional therapy or the salicylate treated group, being patients presenting new to the hospital, the latter two groups being allocated from patients who had been attending the Centre for Rheumatic Diseases from 4 months to 10 years. Attitudes and expectations in the new and experienced patients may have been very different. The placebo group was administered sucrose powder, not a difficult substance to recognize, and once recognised by an individual, the clustering of all placebo patients in one clinic is likely to have
facilitated transfer of information on the nature of the treatment, leading to a rapid loss of group confidence in their physician's therapy. This being an open trial the general physician was aware that he was administering sucrose powder to patients in pain and was unlikely to have generated much enthusiasm in this treatment, it is therefore perhaps surprising that some patients continued for as long as 6 weeks in this fashion. Salicylate levels were monitored in the salicylate treated group. However, no details of these are presented despite the fact that these are essential to distinguish between simple overprescription or idiosyncratic response to salicylates. In view of the fact that the homeopathy treated group were allowed to continue treatment with their previous therapy, it is impossible to infer anything about the therapeutic response to homeopathy from this study. Even the group of 23 (42.6%) who finished the year on homeopathy alone may have simply entered remission having endured an exacerbation supported by their previous therapy and the attentions of the homeopathic specialists. It seems likely that these specialists felt a greater commitment to the success of their discipline in this trial than the rheumatologists felt towards enteric coated aspirin or the general physician to sucrose power. These variations in commitment are very likely to have affected the mutual physician and patient assessments of improvement (Bagley, Greer & Ramsay, 1973). The only conclusion that can be firmly drawn from this trial is that homeopathic treatment carries a low incidence of side-effects. No inference of its efficacy in treating rheumatoid arthritis can be made. The fact that this full paper contains only 'preliminary observations' may allow for some of the deficiencies in the trial design; however, even in a preliminary study the plotting of observations of response on the same ordinate and abscisse implies that the groups of data on the resultant graph are comparable. This is not the case for the 'comparison of the drop out rate' of the different groups in Figure 1 of the paper Gibson et al. (1978). These workers have in fact performed three entirely separate trials, each trial involving only one treatment regimen. There is no common factor between any of these trials, neither treatment, patients, assessor or physician being common to any two of the groups. There is thus no basis for inferred comparisons between treatment effects. It will be of great interest to review the results of the proposed balanced study; such a study should compare discipline with discipline or treatment with treat-
530
LETTERSTOTHE EDITORS
ment using patients drawn from similar populations. Treatments should be administered double-blind, patients seeing the same physicians or being assessed by an independent observer. Although randomization for homeopathic or conventional therapies might at first appear difficult, it could conveniently be performed at the level of dispensing a double placebo technique being used. In view of the investment of medical finance and manpower based on studies such as this, and the hopes that may be raised in rheumatoid arthritis
Br. J. clin. Pharmac. (1979), 7
sufferers, it is important that published preliminary studies should be of a design that is at least balanced and unbiased.
G. HUSTON Guy's Arthritis Research Unit, Guy's Hospital Medical School, London Bridge SE) 9RT Received December 29, 1978
References BAGLEY, C., GREER, S. & RAMSAY, I. (1973). Human relations: the uncontrolled variable in double-blind clinical trials. Res. Comm. Chem. Path. Pharmac., 5, 529-537. EMPIRE RHEUMATISM COUNCIL (1961). Gold therapy in rheumatoid arthritis: final report of a multicentre con-
troliedtrial.AnnRheum.Dis.,20, 315-333.
GIBSON, R.G., GIBSON, S.L.M., MacNEILL, A.D., GRAY, G.H., CARSON DICK, W. & WATSON BUCHANAN, W.
(1978). Salicylates and homeopathy in rheumatoid arthritis: preliminary observations. Br. J. clin. Pharmac., 6, 391-395. MULTICENTRE TRIAL GROUP(1973). Controlled trial of Dpenicillamine in severe rheumatoid arthritis. Lancet, i, 275-280.
SALICYLATES AND HOMEOPATHY Thank you for the opportunity to reply to Dr Huston, (1979). We fully accept the general criticism that the trial design in this preliminary study was imperfect. The protocol written prior to the commencement of the study would have met these criticisms but as we pointed out ourselves 'the best laid plans o' mice and men gang aft agley'. The following points should be underlined (although most are covered in the original paper). 1. We treat patients with rheumatoid arthritis pharmacologically in terms of 'first-line' and 'second-line' patients (Dick, 1978). All patients in the study were selected from a pool of patients in the former class. The entry characteristics of the different groups disclose a considerable degree of similarity in terms of the clinical characteristics of disease, duration and severity. 2. All patients were assessed throughout the study by an entirely independent, non-involved assessor in addition to assessments by patient and physician. 3. The independent assessor and the source and similarity of clinical material are common factors. 4. Any restriction or predetermination of the homeopathic pharmacopoeia invalidates the basis of homeopathic prescribing. 5. Salicylate therapy was monitored individually by clinical efficacy or toxicity on the one hand and by serum salicylate concentrations on the other for precisely those reasons that Dr Huston cites.
6. We have conducted a series of cohort studies over the past 6 years using drop out rate or 'compliance' as an imp43rtant arbiter of drug performance in the individual patient (Rooney, Capell, Paterson, Buchanan & Dick, 1978). This study was conducted during that programme. 7. Our null hypothesis was 'that homeopathy is ineffective and detrimental to the patient'. We feel that the data in this preliminary paper allows us to refute this null hypothesis.
W. CARSON DICK Centre for Rheumatic Diseases, Baird Street, Glasgow R. GIBSON Consultant Physician, Homeopathic Hospital, Great Western Road, Glasgow G.I.L. GRAY Department of Community Medicine, Ruchill Hospital, Bilsland Drive, Glasgow W.W. BUCHANAN Centre for Rheumatic Diseases, Baird Street,
Glasgow Received January 29, 1979
