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Re: the fentanyl transdermal patch in the dying phase
Vol. 26 No. 1 July 2003
Journal of Pain and Symptom Management
589
Letters
Re: The Fentanyl Transdermal Patch in the Dying Phase To the Editor: In the title of their recent paper,1 Ellershaw and colleagues ask “Is pain control compromised or enhanced by continuation of the fentanyl transdermal patch in the dying phase?” It would perhaps be surprising if they had found that withdrawing an analgesic had improved pain control, particularly bearing in mind that the study itself was funded by the manufacturers of that analgesic. The paper contains no statement of any conflict of interest, but its primary conclusion is that pain control is not compromised if transdermal fentanyl is continued and appropriate guidelines are followed for managing breakthrough pain. Unfortunately, even this apparently simple conclusion cannot be justified from the study. The authors note that ‘two groups of dying patients were identified,’ but give no information as to how either sample was selected. Comparing the two groups is, therefore, meaningless, as we do not know what potential biases were introduced at the time of selection. The first group consisted of patients who had been treated, presumably with good analgesia, with transdermal fentanyl. In the last three days of their life, these patients were given extra doses of opioid as needed, either as oral morphine or as subcutaneous diamorphine. On the day before they died, half of the group required on average 2 extra doses of extra analgesia, and no fewer than 85% of the group had a syringe driver set up to administer a subcutaneous infusion of diamorphine in the dying phase. Clearly, the transdermal fentanyl patch was not providing them with adequate analgesia. No patient had the transdermal fentanyl patch
쑖 2003 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
removed, so we cannot say whether it was better to remove the patch or to continue it. For the same reason, there also was no evidence to support the paper’s second conclusion, that when the patch is removed and an alternative strong opioid substituted, there is the possibility of suboptimal pain control. The second group of patients had been treated with oral morphine, and was switched to a subcutaneous infusion of diamorphine in the dying phase. The authors do not say for how long the syringe driver was used, nor what potency ratio was used in the switch. However, the median dose of diamorphine in the syringe driver over the last three days of life in this group remained unchanged at 30 mg. It would seem, therefore, that the proportion of patients needing an increase in their regular analgesia was substantially lower than 85%. The authors found that patients in the fentanyl group were significantly more likely to have been noted as having good pain control 20 hours before death (P ⫽ 0.041) and 8 hours before death (P ⫽ 0.002). However, within the paper they made 23 statistical comparisons, making it inappropriate to adopt a P value of 0.05 (the observed difference will arise by chance alone in one out of 20 observations) as signifying statistical significance. It is thus only at 8 hours before death that there was a statistically significant difference. Bearing in mind that we do not know for how long the patients had had syringe drivers at this stage, it is possible that the potency ratio being used for converting to injected diamorphine from oral morphine was too low. In that case, rather than demonstrating that patients treated with transdermal fentanyl had adequate analgesia, this observation may be showing us that this particular group of patients treated with a syringe driver had inadequate analgesia. Other publications from these 0885-3924/03/$–see front matter
590
authors2 suggest that they use a potency ratio of 3:1 when changing from diamorphine subcutaneously to morphine orally, but many of my local colleagues would favor a potency ratio of 2:1, especially in the dying phase. Even a major authoritative textbook does not tell us what potency ratio should be used, and provides a table that is internally contradictory.3 The Liverpool Care Pathway is clearly a potent observational tool, and it would be possible to clarify these issues by conducting two properly randomized studies. The first could compare patients whose transdermal fentanyl patch was left in place, as in this study, with patients whose patch was removed, and who had a subcutaneous infusion of diamorphine. The second could compare two different potency ratios of oral morphine to subcutaneous diamorphine. Both of these studies would be of enormous potential benefit to dying patients, and could provide definitive answers to what are undoubtedly difficult questions. Stephen R. Kirkham, MA, FRCP Poole Hospital NHS Trust Poole, Dorset, UK doi:10.1016/S0885-3924(03)00223-9
References 1. Ellershaw JE, Kinder C, Aldridge J, et al. Is pain control compromised or enhanced by continuation of the fentanyl transdermal patch in the dying phase? J Pain Symptom Manage 2002;24(4): 398–403. 2. Ellershaw J, Ward C. Care of the dying patient: the last hours or days of life. BMJ 2003;326:30–34. 3. In: Doyle D, Hanks GWC, MacDonald N, (eds). Oxford Textbook of Palliative Medicine. 2nd edition. Oxford: Oxford Medical Publications, 1998:334.
Author’s Response To the Editor: The aim of this paper was to establish whether continuing fentanyl in the dying phase, with an appropriate protocol for breakthrough pain, was as effective as the approach used for those patients treated with oral preparations of morphine, who were converted to subcutaneous diamorphine with appropriate breakthrough medication. There is no suggestion that the paper intended to look at whether it was more
Letters
Vol. 26 No. 1 July 2003
effective to continue transdermal fentanyl compared to withdrawing it. The two groups of patients were identified by first identifying a cohort of patients on the fentanyl transdermal patch in the dying phase and matching them for age and diagnosis with patients who have been converted from oral morphine to subcutaneous diamorphine in the dying phase. Because this study did not aim to look at whether it was better to remove the patch or to continue it in the dying phase, the possibility that removal of the patch and use of an alternative strong opioid may lead to suboptimal pain control requires further research. This was not a conclusion of the study. The statistical advice and reporting were prepared and presented with expert advice and were found appropriate by the reviewers of the original paper. The potency ratio used in the study was 1:3 diamorphine to morphine. A study to compare the potency of oral morphine to subcutaneous diamorphine would be valuable and would not necessarily need a randomized study. In order to conduct a randomized study in which patients whose transdermal fentanyl patch is left in place compared with patients whose patch is removed would require ethical approval and consent from relatives. This was deemed inappropriate by both our research and clinical staff and was the reason we used the observational approach and retrospective review using the Liverpool Care Pathway. Finally, the inference about funding is quite unacceptable. The funding from the manufacturer of the analgesic enabled us to employ a Research Assistant to undertake the study, but in no way influenced the presentation or conclusions of the study. John Ellershaw, FRCP Marie Curie Center Liverpool & Royal Liverpool University Hospitals Trust Liverpool, United Kingdom doi:10.1016/S0885-3924(03)00222-7
Knowledge and Attitudes of Italian Medical Oncology Residents Toward the Approach and Treatment of Pain To the Editor: In 2001, Visentin et al.1 presented data regarding a survey performed in an Italian hospital
Journal of Pain and Symptom Management
589
Letters
Re: The Fentanyl Transdermal Patch in the Dying Phase To the Editor: In the title of their recent paper,1 Ellershaw and colleagues ask “Is pain control compromised or enhanced by continuation of the fentanyl transdermal patch in the dying phase?” It would perhaps be surprising if they had found that withdrawing an analgesic had improved pain control, particularly bearing in mind that the study itself was funded by the manufacturers of that analgesic. The paper contains no statement of any conflict of interest, but its primary conclusion is that pain control is not compromised if transdermal fentanyl is continued and appropriate guidelines are followed for managing breakthrough pain. Unfortunately, even this apparently simple conclusion cannot be justified from the study. The authors note that ‘two groups of dying patients were identified,’ but give no information as to how either sample was selected. Comparing the two groups is, therefore, meaningless, as we do not know what potential biases were introduced at the time of selection. The first group consisted of patients who had been treated, presumably with good analgesia, with transdermal fentanyl. In the last three days of their life, these patients were given extra doses of opioid as needed, either as oral morphine or as subcutaneous diamorphine. On the day before they died, half of the group required on average 2 extra doses of extra analgesia, and no fewer than 85% of the group had a syringe driver set up to administer a subcutaneous infusion of diamorphine in the dying phase. Clearly, the transdermal fentanyl patch was not providing them with adequate analgesia. No patient had the transdermal fentanyl patch
쑖 2003 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
removed, so we cannot say whether it was better to remove the patch or to continue it. For the same reason, there also was no evidence to support the paper’s second conclusion, that when the patch is removed and an alternative strong opioid substituted, there is the possibility of suboptimal pain control. The second group of patients had been treated with oral morphine, and was switched to a subcutaneous infusion of diamorphine in the dying phase. The authors do not say for how long the syringe driver was used, nor what potency ratio was used in the switch. However, the median dose of diamorphine in the syringe driver over the last three days of life in this group remained unchanged at 30 mg. It would seem, therefore, that the proportion of patients needing an increase in their regular analgesia was substantially lower than 85%. The authors found that patients in the fentanyl group were significantly more likely to have been noted as having good pain control 20 hours before death (P ⫽ 0.041) and 8 hours before death (P ⫽ 0.002). However, within the paper they made 23 statistical comparisons, making it inappropriate to adopt a P value of 0.05 (the observed difference will arise by chance alone in one out of 20 observations) as signifying statistical significance. It is thus only at 8 hours before death that there was a statistically significant difference. Bearing in mind that we do not know for how long the patients had had syringe drivers at this stage, it is possible that the potency ratio being used for converting to injected diamorphine from oral morphine was too low. In that case, rather than demonstrating that patients treated with transdermal fentanyl had adequate analgesia, this observation may be showing us that this particular group of patients treated with a syringe driver had inadequate analgesia. Other publications from these 0885-3924/03/$–see front matter
590
authors2 suggest that they use a potency ratio of 3:1 when changing from diamorphine subcutaneously to morphine orally, but many of my local colleagues would favor a potency ratio of 2:1, especially in the dying phase. Even a major authoritative textbook does not tell us what potency ratio should be used, and provides a table that is internally contradictory.3 The Liverpool Care Pathway is clearly a potent observational tool, and it would be possible to clarify these issues by conducting two properly randomized studies. The first could compare patients whose transdermal fentanyl patch was left in place, as in this study, with patients whose patch was removed, and who had a subcutaneous infusion of diamorphine. The second could compare two different potency ratios of oral morphine to subcutaneous diamorphine. Both of these studies would be of enormous potential benefit to dying patients, and could provide definitive answers to what are undoubtedly difficult questions. Stephen R. Kirkham, MA, FRCP Poole Hospital NHS Trust Poole, Dorset, UK doi:10.1016/S0885-3924(03)00223-9
References 1. Ellershaw JE, Kinder C, Aldridge J, et al. Is pain control compromised or enhanced by continuation of the fentanyl transdermal patch in the dying phase? J Pain Symptom Manage 2002;24(4): 398–403. 2. Ellershaw J, Ward C. Care of the dying patient: the last hours or days of life. BMJ 2003;326:30–34. 3. In: Doyle D, Hanks GWC, MacDonald N, (eds). Oxford Textbook of Palliative Medicine. 2nd edition. Oxford: Oxford Medical Publications, 1998:334.
Author’s Response To the Editor: The aim of this paper was to establish whether continuing fentanyl in the dying phase, with an appropriate protocol for breakthrough pain, was as effective as the approach used for those patients treated with oral preparations of morphine, who were converted to subcutaneous diamorphine with appropriate breakthrough medication. There is no suggestion that the paper intended to look at whether it was more
Letters
Vol. 26 No. 1 July 2003
effective to continue transdermal fentanyl compared to withdrawing it. The two groups of patients were identified by first identifying a cohort of patients on the fentanyl transdermal patch in the dying phase and matching them for age and diagnosis with patients who have been converted from oral morphine to subcutaneous diamorphine in the dying phase. Because this study did not aim to look at whether it was better to remove the patch or to continue it in the dying phase, the possibility that removal of the patch and use of an alternative strong opioid may lead to suboptimal pain control requires further research. This was not a conclusion of the study. The statistical advice and reporting were prepared and presented with expert advice and were found appropriate by the reviewers of the original paper. The potency ratio used in the study was 1:3 diamorphine to morphine. A study to compare the potency of oral morphine to subcutaneous diamorphine would be valuable and would not necessarily need a randomized study. In order to conduct a randomized study in which patients whose transdermal fentanyl patch is left in place compared with patients whose patch is removed would require ethical approval and consent from relatives. This was deemed inappropriate by both our research and clinical staff and was the reason we used the observational approach and retrospective review using the Liverpool Care Pathway. Finally, the inference about funding is quite unacceptable. The funding from the manufacturer of the analgesic enabled us to employ a Research Assistant to undertake the study, but in no way influenced the presentation or conclusions of the study. John Ellershaw, FRCP Marie Curie Center Liverpool & Royal Liverpool University Hospitals Trust Liverpool, United Kingdom doi:10.1016/S0885-3924(03)00222-7
Knowledge and Attitudes of Italian Medical Oncology Residents Toward the Approach and Treatment of Pain To the Editor: In 2001, Visentin et al.1 presented data regarding a survey performed in an Italian hospital