Care of the Dying: Is Pain Control Compromised or Enhanced by Continuation of the Fentanyl Transdermal Patch in the Dying Phase?

Transcription

1 398 Journal of Pain and Symptom Management Vol. 24 No. 4 October 2002 Original Article Care of the Dying: Is Pain Control Compromised or Enhanced by Continuation of the Fentanyl Transdermal Patch in the Dying Phase? John E. Ellershaw, FRCP, Carol Kinder, BSc Hons, Judith Aldridge, MA, Mark Allison, MB ChB, and Jennifer C. Smith, MB ChB Marie Curie Center (J.E.E., C.K., M.A., J.C.S.), Liverpool; and Department of Applied Social Science (J.A.), University of Manchester, Manchester, United Kingdom Abstract The introduction of fentanyl transdermal patches has led to concern and confusion regarding the management of pain control in the dying phase. Data were collected retrospectively from 94 dying patients. Two groups were identified patients treated with fentanyl transdermal patch who remained on the patch in the dying phase and patients on oral morphine who converted to a 24-hour subcutaneous infusion of diamorphine via a syringe driver in the dying phase. Both the fentanyl group and the diamorphine group had good pain control in the last 48 hours of life. During the last 48 hours of life, the proportion of patients with controlled pain was statistically significant in favor of the fentanyl group in 2 of the 12 observations undertaken, in particular whether the fentanyl transdermal patch should be continued or discontinued. Patients in the fentanyl group received fewer as required opioid doses compared to patients in the diamorphine group, although the difference was statistically significant only for the last day of life. This study showed that pain control was not compromised in the dying phase with continued use of the fentanyl patch. J Pain Symptom Manage 2002;24: U.S. Cancer Pain Relief Committee, Key Words Pain, drug therapy, palliative treatment, opioid analgesics, fentanyl, transdermal patch, dying phase Introduction One of the most important aspects of care of the dying is the control of pain. 1 5 In some settings, cancer patients who are in the dying phase Address reprint requests to: John E. Ellershaw, FRCP, Marie Curie Center, Speke Road, Woolton, Liverpool L25 8QA, United Kingdom. Accepted for publication: December 14, and are no longer able to take oral morphine are switched to an equivalent dose of subcutaneous diamorphine, which is delivered subcutaneously as an infusion via a syringe driver over 24 hours. As required subcutaneous diamorphine is also prescribed for breakthrough pain. 6,7 This practice has evolved with the introduction of the fentanyl transdermal patch, the use of which in the control of cancer pain has been well documented However, there has U.S. Cancer Pain Relief Committee, /02/$ see front matter Published by Elsevier, New York, New York PII S (02)

2 Vol. 24 No. 4 October 2002 Transdermal Fentanyl Use in Dying Patients 399 been a lack of clarity in the literature regarding the continued use of the fentanyl transdermal patch and control of pain in the dying phase. In particular, there has been confusion among health care professionals regarding the continuation or discontinuation of the fentanyl transdermal patch in the dying phase. If the fentanyl transdermal patch is removed during the dying phase, a subcutaneous infusion of diamorphine over 24 hours is required. However, this raises a number of concerns. First, it is difficult to be accurate in the dose conversion and, second, calculating the correct timing of initiation of the diamorphine infusion is complex due to the long half-life of the fentanyl transdermal patch This may lead to overtreatment or undertreatment of the patient s pain. A further consideration is the view maintained by patient and carers. If the patient s pain has been stabilized on a fentanyl transdermal patch, there may be understandable concern in discontinuing the patch. This concern also may extend to the healthcare professionals caring for the patient. In view of these concerns, local guidelines have been developed in which the fentanyl transdermal patch is continued at the same dose in the dying phase and diamorphine is given as required for breakthrough pain (Table 1). In addition, if two or more doses of diamorphine are required over a 24-hour period, then a continuous subcutaneous diamorphine infusion via a syringe driver is initiated. 17 This study compares two groups of patients, one who had been receiving oral morphine and were converted to a subcutaneous infusion of diamorphine in the dying phase, and another who were receiving the fentanyl transdermal patch and followed the guidelines, as outlined above, for the continuation of the fentanyl transdermal Table 1 Guidelines for the Use of Fentanyl Transdermal Patch in the Dying Patient Fentanyl transdermal patch strength ( g/h) 4-hourly dose of diamorphine s/c (mg) patch in the dying phase. The aim of this study was to compare pain control with the opioid requirements of the two groups in the dying phase. Methods A retrospective study was conducted in a specialist palliative care unit between February 1997 and August Two groups of dying patients were identified: patients who were treated with the fentanyl transdermal patch and then remained on a fentanyl transdermal patch in the dying phase (the fentanyl group) and patients on oral morphine who converted to a 24-hour subcutaneous infusion of diamorphine via a syringe driver in the dying phase (the diamorphine group). Patients were matched for sex, age within 7 years, and diagnosis. Patients included in the study had been placed on The Liverpool Care Pathway for the Dying Patient (LCP). 3,18,19 The LCP is a multiprofessional document that coordinates and records care in the dying phase (i.e., the last hours/days of life). It includes four hourly observations of symptom control recorded by the nursing staff. Pain is recorded as controlled or uncontrolled. The manufacturer s recommendations on dose conversion between morphine and fentanyl were used to calculate the correct doses. 20 Outcomes measured included type and dose of continuous opioid analgesic administered; the dose and frequency of breakthrough opioid analgesic administered (subcutaneous diamorphine and oral immediate-release morphine); and increases in diamorphine dose via a syringe driver (for the diamorphine group) or commencement of a syringe driver (for the fentanyl group) during the last three days of life. Four-hourly pain assessments were recorded on the LCP as pain controlled or pain uncontrolled during the last 48 hours of life. Statistical Analysis Data were summarized using the number and percentage, the mean, and median and range. Differences between values were tested at the 5% level of significance using the paired and the independent t-test and chi-squared test, as appropriate. Results Data were collected for 94 dying patients, 47 in the fentanyl group and 47 in the diamor-

3 400 Ellershaw et al. Vol. 24 No. 4 October 2002 Table 2 Patient Demographics Sample (n 94) Significance a Mean age (years) n.s. Range Mean no. of days on LCP n.s. Range Cancer Type n (%) Lung 24 (25.5) Prostate 12 (12.8) Breast 10 (10.6) Colon 8 (8.5) Stomach 8 (8.5) Rectum 6 (6.4) Pancreas 6 (6.4) Other 20 (21.3) LCP Liverpool Care Pathway for the dying patient. a Independent t-test. phine group. Patient demographics are shown in Table 2. There were more men ( %) than women ( %) in the total sample. Overall, lung cancer was the most common diagnosis (25.5%). The groups were matched on sex and diagnosis, so proportions were the same in each group. The average age within each group did not significantly differ. The mean number of days prior to death spent on the LCP was slightly higher in the fentanyl group than in the diamorphine group, although this difference was not statistically significant. The median fentanyl transdermal patch dose in the fentanyl group and the median diamorphine dose in the diamorphine group during the last three days of life are reported in Table 3. The median dose of continuous fentanyl transdermal patch and continuous diamorphine remained the same during the last three days of life for both groups. The 24-hour equivalent opioid dose was greater in the fentanyl group compared with the diamorphine group by a ratio of approximately 2:1. Four-hourly pain observations recorded during the last 48 hours of life were analyzed for frequency of pain control. Table 4 displays the frequency of recorded pain controlled observations for each group during the last 48 hours of life. A chi-square test compared pain control by group. Differences were statistically significant at 8 hours ( , df 1, P 0.002) and 20 hours ( , df 1, P 0.041) prior to death. To observe the frequency of breakthrough pain in each group, dosages of as required diamorphine and immediate-release morphine given during the last three days of life were analyzed. Table 5 shows the numbers requiring breakthrough pain relief and mean dose of as required diamorphine and immediate-release morphine for both groups. Chi-square tests of significance assessed differences in each group of numbers of patients requiring breakthrough pain relief. There were no significant differences in the number of patients in each group receiving either as required diamorphine or immediate-release morphine. Patients with the Table 3 Median Doses of Fentanyl Transdermal Patch and Diamorphine for Fentanyl and s, Respectively Group 1 ( g/hr) Day 3 Day 2 Group 2 (mg/24hrs) Day 1 (last day of life) Day 3 Day 2 Day 1 (last day of life) Median dose Range

4 Vol. 24 No. 4 October 2002 Transdermal Fentanyl Use in Dying Patients 401 No. of Hours Prior to Death Table 4 Frequency of Controlled Pain Observations During the Last 48 Hours of Life No. of Patients (%) (%) Significance P value n.s n.s n.s n.s n.s n.s n.s n.s n.s n.s. fentanyl transdermal patch received a higher mean dose of as required diamorphine and immediate-release morphine for breakthrough pain than did those on diamorphine (Table 5). This is likely to be due to the relatively higher regular 24-hour dose in the fentanyl group. The number and mean number of as required diamorphine and immediate-release morphine doses for the fentanyl group and the diamorphine group during the last three days of life are shown in Table 6. The diamorphine group had a higher number of as required doses of diamorphine and immediate-release morphine given for breakthrough pain compared to the fentanyl group on days 3, 1, and overall. An independent t-test comparing the means was significant only for the last day of life (day 1: t , P 0.001). A further consideration for pain control in the two groups is a comparison of the number of patients who had breakthrough pain relief via a syringe driver. For the fentanyl group this meant receiving subcutaneous diamorphine via a syringe driver and for the diamorphine group this meant an increase in the syringe driver dose of diamorphine during the last 3 days of life. More fentanyl transdermal patch patients (85%) were commenced on diamorphine via a syringe driver during the last three days of life, than diamorphine patients (47%) having an increase in their syringe driver dose of diamorphine ( , df 1, P 0.001). Table 5 Number of Patients Receiving As Required Subcutaneous Diamorphine and Oral Immediate-Release Morphine and the Mean Dosage Given n (%) Significance As required diamorphine Day 3 16 (34.0) 15 (31.9) n.s. mean a Day 2 23 (48.9) 17 (36.2) n.s. mean Day 1 (last day of life) 9 (19.1) 11 (23.4) n.s. mean As required immediate-release morphine Day 3 14 (29.8) 15 (31.9) n.s. mean Day 2 7 (14.9) 10 (21.3) n.s. mean Day 1 (last day of life) - 3 (6.4) - mean 16.7 a Mean dose in mg.

5 402 Ellershaw et al. Vol. 24 No. 4 October 2002 Days Prior to Death Table 6 Number and Mean Number of As Required Diamorphine and Immediate-Release Morphine Doses During the Last 3 Days of Life Fentanyl No. of doses (mean) Diamorphine No. of doses (mean) Significance P value Day 3 39 (0.83) 48 (1.02) n.s. Day 2 45 (0.96) 41 (0.87) n.s. Day 1 12 (0.26) 26 (0.55) Total 96 (2.04) 125 (2.45) n.s. Discussion Overall, this study demonstrates little difference in the success of pain control of dying patients in the two groups studied. Both the fentanyl group and the diamorphine group had good pain control in the last 48 hours of life. This result is consistent with previous findings that pain was controlled in 88% of dying patients across all observations. 3 During the last 48 hours of life, the proportion of patients with controlled pain was statistically significant in favor of the fentanyl group in only 2 of the 12 observations. Over the last three days of life, the median fentanyl transdermal patch dose was unchanged in the fentanyl group, in line with the guidelines. 17 The median diamorphine dose in the diamorphine group was also unchanged, at 30 mg. The equivalent dose of opioid was greater in the fentanyl group; this may be because the fentanyl transdermal patch is currently prescribed as a second-line opioid and therefore patients often have more complex pain problems requiring higher equivalent doses of opioid. Overall, patients in the fentanyl group had a higher mean dose of as required diamorphine and immediate-release morphine for each day than the patients in the diamorphine group. This result is consistent with the previous finding, as it would be expected that patients on a higher dose of regular opioid would require a higher dose of as required diamorphine and immediaterelease morphine. 6,7 Similar results were found for the number of patients receiving as required diamorphine in the fentanyl group for days 3 and 2 when compared to the diamorphine group. The number of patients in the diamorphine group receiving as required immediate-release morphine during the last three days of life was higher than for patients in the fentanyl group, but this did not reach statistical significance. Patients in the fentanyl group received fewer as required doses of diamorphine and immediate-release morphine compared to patients in the diamorphine group, though the difference was statistically significant only for the last day of life. This suggests that patients in the fentanyl group had more stable pain control on the last day of life. A further method of observing the difference in pain control between the two groups was to compare the number of patients in the diamorphine group who had an increase in the dose of diamorphine in their syringe drivers and the number of fentanyl transdermal patch patients who were commenced on a diamorphine syringe driver during the last three days of life. There was a statistically significant greater number of patients in the fentanyl group started on a syringe driver in the last three days of life compared to the number of patients in the diamorphine group who had an increase in their syringe driver dose. This could be due to the high awareness among staff regarding the guidelines relating to continuation of the fentanyl transdermal patch and the indications for initiating a subcutaneous diamorphine infusion with a syringe driver. In contrast, there may have been less awareness of the indications for increasing the dose of diamorphine in a syringe driver. This could also explain the larger number of as required doses of diamorphine and immediate-release morphine given in the diamorphine group. One limitation to the study is that the pain recordings were observer-rated (i.e., made by the nursing staff, as the patient in the dying phase is usually obtunded or in a coma). However, because data collection was retrospective, the nurses undertaking the observations were unaware of any comparative study between the two groups. Therefore, patients in both groups were subjected to the same biases. Furthermore, patients in the study were matched for age, sex, and diagnosis to reduce individual variances between the two groups.

6 Vol. 24 No. 4 October 2002 Transdermal Fentanyl Use in Dying Patients 403 Conclusion The findings of this study suggest that pain control is not compromised in the dying phase if a fentanyl transdermal patch is continued and appropriate guidelines are followed regarding administration of diamorphine for breakthrough pain. If the fentanyl transdermal patch is removed and an alternative strong opioid initiated, there is the possibility of suboptimal pain control. We would therefore recommend the continuation of the fentanyl transdermal patch in the dying phase. Acknowledgments This study was funded by Janssen-Cilag Ltd. We would like to thank Dr. Susan Libretto for her assistance in preparation of the manuscript. References 1. Adam J. The last 48 hours. Br Med J 1997;315: Conill C, Verger E, Henriquez I, et al. Symptom prevalence in the last week of life. J Pain Symptom Manage 1997;14: Ellershaw J, Smith C, Overill S, et al. Care of the dying: setting standards for symptom control in the last 48 hours of life. J Pain Symptom Manage 2001;21: Fainsinger R, Miller MJ, Bruera E, et al. Symptom control during the last week of life on a Palliative Care Unit. J Palliative Care 1991;7: Nauck F, Klaschik E, Ostgathe C. Symptom control during the last three days of life. Eur J Palliative Care 2000;7: Twycross R. Pain Relief in Advanced Cancer. Edinburgh: Churchill Livingstone, 1994: Working Party on Clinical Guidelines in Palliative Care. Changing gear guidelines for managing the last days of life in adults. National Council for Hospice and Specialist Palliative Care Services. Northamptomshire: Land & Unwin (Data Sciences) Ltd, Southam MA. Transdermal fentanyl therapy: system design, pharmacokinetics and efficacy. Anti- Cancer Drugs 1995;6: Simmonds MA, Blain C, Richenbacher J, et al. A new approach to the administration of opiates: TTS (fentanyl) in the management of pain in patients with cancer. J Pain Symptom Manage1988;3:S Ahmedzai S, Allan E, Fallon M, et al. Transdermal fentanyl in cancer pain. J Drug Dev 1994;6: Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. J Pain Symptom Manage 1997;13: Lehmann KA, Zech D. Transdermal fentanyl: clinical pharmacology. J Pain Symptom Manage 1992;7:S8 S Varvel JR, Shafer SL, Hwang SS, et al. Absorption characteristics of transdermally administered fentanyl. Anesthesiology 1989;70: Duthie DJR, Rowbotham DJ, Wyld R, et al. Plasma fentanyl concentrations during transdermal delivery of fentanyl to surgical patients. Br J Anesth 1988;60: Holley FO, van Steennis C. Postoperative analgesia with fentanyl: pharmacokinetics and pharmacodynamics of constant rate IV and transdermal delivery. Br J Anesth 1988;60: Gourlay GK, Mather LE. Postoperative pain management with TTS fentanyl: pharmacokinetics and pharmacodynamics. In: Lehmann KA, Zech D, eds. Transdermal fentanyl. Berlin: Springer, 1991: Mersey Palliative Care Audit Group. Standards and guidelines. Liverpool: Marie Curie Centre, 2000: Ellershaw J, Foster A, Murphy D, Shea T, Overill S. Developing an integrated care pathway for the dying patient. Eur J Palliative Care 1997;4: Ellershaw J. Integrated care pathways. In: Cooper J, ed. Stepping into palliative care. Abingdon: Radcliffe Medical Press, ABPI Data Sheet Compendium London: Datapharm, 1999: