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Ethics, clinical research, and clinical practice in obstetric anaesthesia
498
Return to Pakistan of
pipenzolate plus phenobarbitone
SIR,-Some time ago a 19-day-old baby was brought to this hospital seriously ill with abdominal distension and constipation. She had been irritable and had been taken to a local doctor who prescribed ’Piptal’ drops, after which she fell asleep. A few hours later abdominal distension developed. Her parents continued giving the drops but she became worse, at which point she was brought to us. The baby died. In those days I was working with Prof Tariq Iqbal Bhutta, and we were running a campaign against antimotility drugs, especially ’Imodium’ (loperamide). We also approached the manufacturers of piptal and the Pakistan Ministry of Health, seeking restrictions on the promotion of piptal drops. Our argument was that piptal overdosage in babies results in abdominal distension, drowsiness, and respiratory depression. The drops are not manufactured in any developed country. Ferozesons (the manufacturers in Pakistan) claim to have a licence from Lakeside Laboratories, USA, but that company does not produce the medicine for use in the United States. There is no published evidence available on the efficacy of this preparation. The dosage schedule is potentially dangerous-namely, 05 ml 15 min after every feed, irrespective of body weight and number of feeds. Piptal contains phenobarbitone and has a long duration of action: this may cause cumulative effects. We asked Ferozesons to stop production but had no response. Only when our observations were publicised outside Pakistan did the machinery begin to move. The Ministry of Health called a meeting of all manufacturers of antimotility drugs and the antispasmodic agent piptal on June 10, 1990, and the drugs were banned. A year later the Ministry of Health reissued a licence for the manufacturer of piptal drops (containing pipenzolate and phenobarbitone) and this product is freely available once again. Last year six babies were brought to this hospital with abdominal distension and a history of intake of piptal drops. One baby died and another was taken away against medical advice. Phenobarbitone has been added for its sedative properties. The other ingredient, pipenzolate, can cause distension of the intestines and abdomen, the consequences of which may be serious. Piptal at a dose of 6-5 ml contains 39 mg phenobarbitone and 26 mg pipenzolate. There are many reasons for a baby crying but true colic is rare. No textbook mentions pipenzolate for infantile colic, which should be managed by improved feeding techniques, winding, and
avoiding underfeeding or overfeeding. Subsequent inquiries revealed that Ferozesons appealed against the decision of Pakistan’s drug registration authority on the grounds that the drops were not antidiarrhoeal but anticholinergic, and that appeal had been accepted. I pointed out that we had never said that piptal was an antidiarrhoeal preparation. Every doctor knows full well that it is an anticholinergic drug, and this ground of appeal is spurious. At the 1990 meeting, in the presence of manufacturers, all hazards of these drugs were discussed. Anyway if piptal is being promoted as an anticholinergic drug why add phenobarbitone? Department of Paediatric Medicine, Hospital,
Nishtar
Multan, Pakistan
KHALID
IQBAL TAHIR
Ethics, clinical research, and clinical practice in obstetric anaesthesia SIR,-In obstetric anaesthesia it is not only clinical investigators but also practitioners who need to face up to the responsibilities outlined in your Feb 8 editorial. I was recently invited by Dr Felicity Reynolds, editor of the International Journal of Obstetric Anesthesia, to prepare a review article for the first volume of this new specialist publication, to encourage properly controlled trials in obstetric anaesthesia. Because the growth of the subspecialty of obstetric anaesthesia has been mirrored by an increased use of epidural block for pain relief in labour, Dr Howell and I’ reviewed what was known about the effects of this widely used form of pain relief. Analyses of observational data suggest that, compared with other methods of pain relief in labour, epidural block may increase the risks of maternal pyrexia,2 instrumental delivery,3,4 caesarean section for
dystocia,5 chronic backache,6 and chronic headacheSome analyses have also raised the possibility of adverse effects of epidural block on the baby. 8,9 Because selection biases may have accounted for the associations between these adverse outcomes and epidural block, Howell and I analysed the results of controlled trials comparing epidural block with alternative methods of pain relief in labour. Obstetric anaesthetists have done only nine reasonably well controlled trials and studied a total of fewer than 600 women in the 20 years or so since this form of pain relief was introduced for labour. Unfortunately, these trials tell us little about the effects of epidurals (apart from confirming the greatly increased likelihood that instruments will be used for delivery if epidural block is used during the second stage of labour). We suggested that, in view of the combination of very widespread use of epidural block during labour and the observational evidence suggesting that it might have serious maternal side-effects, there was a need for obstetric anaesthetists to do randomised trials to address these important uncertainties about the effects of their practice.’ Howell and I were surprised that, without waiting for reactions from their readers, Reynolds and her editorial colleagues felt it necessary to dissociate themselves from these conclusions. In an editorial published in the same issue of the journal they wrote that "the views expressed are those of the authors, the editors being only too aware that most mothers would not take kindly to receiving epidural analgesia on a random basis". Your editorial notes that "clinical investigators have an absolute responsibility to ensure that the protocol for their study fulfils scientific criteria, that a specific and appropriate question be posed, and that an answer is possible as a result of the proposed measurements". The statement made by the editors of the International Journal of Obstetric Anesthesia implies either that they encourage researchers to abrogate these responsibilities in respect of research to assess the effects of epidural block during labour, or that there is no longer any possibility of learning about the effects of a technique on which the growth of their subspecialty has depended so heavily. Perhaps the reason that they are so confident that women would not agree to take part in properly controlled trials is that they and other anaesthetists are less forthcoming than they should be about disclosing evidence that epidurals may have important adverse effects. Obstetric anaesthetists give the impression that they are not living up to their responsibilities, either as researchers or as clinicians. National Perinatal Epidemiology Unit, Radcliffe Infirmary, Oxford OX2 6HE, UK
IAIN CHALMERS
CJ, Chalmers I. A review of prospectively controlled comparisons of epidural with non-epidural forms of pain relief during labour. Int J Obstet Anesth 1992; 1: 93-110. 2. Fusi L, Steer PJ, Maresh MJA, Beard RW. Maternal pyrexia associated with theuse of epidural analgesia in labour. Lancet 1989; i: 1250-52. 3. Kaminski H, Stafl A, Aiman J. The effects of epidural analgesia on the frequency of instrumental obstetric delivery. Obstet Gynecol 1987; 69: 770-73. 4. Paterson C, Banfield P. Epidural analgesia and maternal satisfaction. Br Med J 1991; 302: 1079. 5. Thorp JA, Parisi VM, Boylan PC, Johnston DA. The effect of continuous epidural analgesia on caesarean section for dystocia in nulliparous women. Am J Obstet Gynecol 1989; 161: 670-75. 6. MacArthur C, Lewis M, Knox EG, Crawford JS. Epidural anaesthesia and long term backache after childbirth. Br Med J 1990; 301: 9-12. 7. MacArthur C, Lewis M, Knox EG. Health after childbirth. London: HMSO, 1991. 8. Scanlon JW. Effects of obstetric anesthesia and analgesia on the newborn: a select, annotated bibliography for the clinician. Clin Obstet Gynecol 1981; 24: 649-70. 9. Avard DM, Nimrod CM. Risks and benefits of obstetric epidural analgesia: a review. Birth 1985; 12: 215-25. 1. Howell
Patient referral and NHS reforms SjR,—Professor Benjamin (Jan 4, p 60) and Dr White (Jan 25, p 250) refer to delays and prolonged negotiations with purchasers over extracontractual referrals. Fortunately, those referrals went ahead eventually, but this is not always so in the new NHS. A patient, referred to me specifically because she was dissatisfied with the quality of the local services she had received for the same complaint, has recently been refused referral by her purchasing authority, on the grounds of cost.
Return to Pakistan of
pipenzolate plus phenobarbitone
SIR,-Some time ago a 19-day-old baby was brought to this hospital seriously ill with abdominal distension and constipation. She had been irritable and had been taken to a local doctor who prescribed ’Piptal’ drops, after which she fell asleep. A few hours later abdominal distension developed. Her parents continued giving the drops but she became worse, at which point she was brought to us. The baby died. In those days I was working with Prof Tariq Iqbal Bhutta, and we were running a campaign against antimotility drugs, especially ’Imodium’ (loperamide). We also approached the manufacturers of piptal and the Pakistan Ministry of Health, seeking restrictions on the promotion of piptal drops. Our argument was that piptal overdosage in babies results in abdominal distension, drowsiness, and respiratory depression. The drops are not manufactured in any developed country. Ferozesons (the manufacturers in Pakistan) claim to have a licence from Lakeside Laboratories, USA, but that company does not produce the medicine for use in the United States. There is no published evidence available on the efficacy of this preparation. The dosage schedule is potentially dangerous-namely, 05 ml 15 min after every feed, irrespective of body weight and number of feeds. Piptal contains phenobarbitone and has a long duration of action: this may cause cumulative effects. We asked Ferozesons to stop production but had no response. Only when our observations were publicised outside Pakistan did the machinery begin to move. The Ministry of Health called a meeting of all manufacturers of antimotility drugs and the antispasmodic agent piptal on June 10, 1990, and the drugs were banned. A year later the Ministry of Health reissued a licence for the manufacturer of piptal drops (containing pipenzolate and phenobarbitone) and this product is freely available once again. Last year six babies were brought to this hospital with abdominal distension and a history of intake of piptal drops. One baby died and another was taken away against medical advice. Phenobarbitone has been added for its sedative properties. The other ingredient, pipenzolate, can cause distension of the intestines and abdomen, the consequences of which may be serious. Piptal at a dose of 6-5 ml contains 39 mg phenobarbitone and 26 mg pipenzolate. There are many reasons for a baby crying but true colic is rare. No textbook mentions pipenzolate for infantile colic, which should be managed by improved feeding techniques, winding, and
avoiding underfeeding or overfeeding. Subsequent inquiries revealed that Ferozesons appealed against the decision of Pakistan’s drug registration authority on the grounds that the drops were not antidiarrhoeal but anticholinergic, and that appeal had been accepted. I pointed out that we had never said that piptal was an antidiarrhoeal preparation. Every doctor knows full well that it is an anticholinergic drug, and this ground of appeal is spurious. At the 1990 meeting, in the presence of manufacturers, all hazards of these drugs were discussed. Anyway if piptal is being promoted as an anticholinergic drug why add phenobarbitone? Department of Paediatric Medicine, Hospital,
Nishtar
Multan, Pakistan
KHALID
IQBAL TAHIR
Ethics, clinical research, and clinical practice in obstetric anaesthesia SIR,-In obstetric anaesthesia it is not only clinical investigators but also practitioners who need to face up to the responsibilities outlined in your Feb 8 editorial. I was recently invited by Dr Felicity Reynolds, editor of the International Journal of Obstetric Anesthesia, to prepare a review article for the first volume of this new specialist publication, to encourage properly controlled trials in obstetric anaesthesia. Because the growth of the subspecialty of obstetric anaesthesia has been mirrored by an increased use of epidural block for pain relief in labour, Dr Howell and I’ reviewed what was known about the effects of this widely used form of pain relief. Analyses of observational data suggest that, compared with other methods of pain relief in labour, epidural block may increase the risks of maternal pyrexia,2 instrumental delivery,3,4 caesarean section for
dystocia,5 chronic backache,6 and chronic headacheSome analyses have also raised the possibility of adverse effects of epidural block on the baby. 8,9 Because selection biases may have accounted for the associations between these adverse outcomes and epidural block, Howell and I analysed the results of controlled trials comparing epidural block with alternative methods of pain relief in labour. Obstetric anaesthetists have done only nine reasonably well controlled trials and studied a total of fewer than 600 women in the 20 years or so since this form of pain relief was introduced for labour. Unfortunately, these trials tell us little about the effects of epidurals (apart from confirming the greatly increased likelihood that instruments will be used for delivery if epidural block is used during the second stage of labour). We suggested that, in view of the combination of very widespread use of epidural block during labour and the observational evidence suggesting that it might have serious maternal side-effects, there was a need for obstetric anaesthetists to do randomised trials to address these important uncertainties about the effects of their practice.’ Howell and I were surprised that, without waiting for reactions from their readers, Reynolds and her editorial colleagues felt it necessary to dissociate themselves from these conclusions. In an editorial published in the same issue of the journal they wrote that "the views expressed are those of the authors, the editors being only too aware that most mothers would not take kindly to receiving epidural analgesia on a random basis". Your editorial notes that "clinical investigators have an absolute responsibility to ensure that the protocol for their study fulfils scientific criteria, that a specific and appropriate question be posed, and that an answer is possible as a result of the proposed measurements". The statement made by the editors of the International Journal of Obstetric Anesthesia implies either that they encourage researchers to abrogate these responsibilities in respect of research to assess the effects of epidural block during labour, or that there is no longer any possibility of learning about the effects of a technique on which the growth of their subspecialty has depended so heavily. Perhaps the reason that they are so confident that women would not agree to take part in properly controlled trials is that they and other anaesthetists are less forthcoming than they should be about disclosing evidence that epidurals may have important adverse effects. Obstetric anaesthetists give the impression that they are not living up to their responsibilities, either as researchers or as clinicians. National Perinatal Epidemiology Unit, Radcliffe Infirmary, Oxford OX2 6HE, UK
IAIN CHALMERS
CJ, Chalmers I. A review of prospectively controlled comparisons of epidural with non-epidural forms of pain relief during labour. Int J Obstet Anesth 1992; 1: 93-110. 2. Fusi L, Steer PJ, Maresh MJA, Beard RW. Maternal pyrexia associated with theuse of epidural analgesia in labour. Lancet 1989; i: 1250-52. 3. Kaminski H, Stafl A, Aiman J. The effects of epidural analgesia on the frequency of instrumental obstetric delivery. Obstet Gynecol 1987; 69: 770-73. 4. Paterson C, Banfield P. Epidural analgesia and maternal satisfaction. Br Med J 1991; 302: 1079. 5. Thorp JA, Parisi VM, Boylan PC, Johnston DA. The effect of continuous epidural analgesia on caesarean section for dystocia in nulliparous women. Am J Obstet Gynecol 1989; 161: 670-75. 6. MacArthur C, Lewis M, Knox EG, Crawford JS. Epidural anaesthesia and long term backache after childbirth. Br Med J 1990; 301: 9-12. 7. MacArthur C, Lewis M, Knox EG. Health after childbirth. London: HMSO, 1991. 8. Scanlon JW. Effects of obstetric anesthesia and analgesia on the newborn: a select, annotated bibliography for the clinician. Clin Obstet Gynecol 1981; 24: 649-70. 9. Avard DM, Nimrod CM. Risks and benefits of obstetric epidural analgesia: a review. Birth 1985; 12: 215-25. 1. Howell
Patient referral and NHS reforms SjR,—Professor Benjamin (Jan 4, p 60) and Dr White (Jan 25, p 250) refer to delays and prolonged negotiations with purchasers over extracontractual referrals. Fortunately, those referrals went ahead eventually, but this is not always so in the new NHS. A patient, referred to me specifically because she was dissatisfied with the quality of the local services she had received for the same complaint, has recently been refused referral by her purchasing authority, on the grounds of cost.