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2. Wolfe JN, Evans WA. Gas in the portal veins of the liver in infantsda roentogenographic demonstration with postmortem anatomical correlation. Am J Roentgenol Radium Ther Nucl Med 1955;74: 486e488. 3. Kinoshita H, Shinozaki M, Tanimura H, et al. Clinical features and management of hepatic portal venous gasdfour case reports and cumulative review of the literature. Arch Surg 2001;136:1410e1414. 4. Wayne E, Ough M, Wu A, et al. Management algorithm for pneumatosis intestinalis and portal venous gas: treatment and outcome of 88 consecutive cases. J Gastrointest Surg 2010;14:437e448. 5. Khalil PN, Huber-Wagner S, Ladurner R, et al. Natural history, clinical pattern, and surgical considerations of pneumatosis intestinalis. Eur J Med Res 2009;14:231e239. 6. Lee JY, Han H-S, Lim S-N, et al. Pneumatosis intestinalis and portal venous gas secondary to gefitinib therapy for lung adenocarcinoma. BMC Cancer 2012;12:87. 7. Liebman PR, Patten MT, Manny J, Benfield JR, Hechtman HB. Hepatic-portal venous gas in adults: etiology, pathophysiology and clinical significance. Ann Surg 1978;187:281e287. 8. Nelson AL, Millington TM, Sahani D, et al. Hepatic portal venous gas: the ABCs of management. Arch Surg 2009;144:575e581. 9. Heye T, Bernhard M, Mehrabi A, Kauczor HU, Hosch W. Portomesenteric venous gas: is gas distribution linked to etiology and outcome? Eur J Radiol 2012;81:3862e3869. 10. Hou SK, Chern CH, How CK, et al. Hepatic portal venous gas: clinical significance of computed tomography findings. Am J Emerg Med 2004;22: 214e218.
Methylnaltrexone in Palliative Care: Further Research Is Needed To the Editor: We read with interest the comments made by Centeno et al.1 regarding their experiences with the medication methylnaltrexone and their call for more research into this medication. This call supports the observation that as a medication becomes available, the efficacy data underpinning its registration are often ignored in subsequent use, with longer duration of use, differing dosages, broader indications, and a wider population in whom it is used. Based on this phenomenon, we echo the call for more research because since the medication has been approved in Australia
Letters
e5
and elsewhere, published reports are highlighting that methylnaltrexone is being delivered in ways that differ from the use of medication on study. The problem with this is the lack of efficacy and safety data to support alternative prescribing practices. The fact that the medication is being used in alternative ways has been highlighted by Watkins et al.2 and also in work we have done. This includes a retrospective clinical audit,3 which observed that not only was prescription contrary to the evidence base from which the drug was approved but also clinicians were failing to pay attention to other risk factors for constipation and hence interventions. These include, but are not limited to, inadequate hydration, reduced mobility, poor oral intake, and other medications such as those with anticholinergic effects. Furthermore, factors that may predispose people to adverse effects of methylnaltrexone were not adequately assessed before the medication’s administration, with at least one person having a plain abdominal radiograph that was suggestive of a bowel obstruction. On a larger scale, we also have demonstrated that the medication is being used in a manner inconsistent with the way it was originally studied. This statement is based on the results of an audit of 12 months of pharmacy claims for methylnaltrexone that are made to the Australian government for universal subsidy of the medication in the community. This audit was undertaken to explore if the volume of actual use of methylnaltrexone aligned with the predicted volume of use. The results of this audit highlighted that uptake of the medication was far less than expected, with only 261 patients treated with 93 prescriptions for continuing use.4,5 This is in the context that up to 5000 Australians per annum are expected to experience opioid-induced constipation, although not all are expected to experience resistant problems. There is no doubt that methylnaltrexone has a role in the management of constipation that is assessed as being the result of opioid analgesia in advanced disease. But the way the medication is being administered in the postmarketing phase is without supporting data. As a result, there are very limited data to define who is most likely to benefit or who may be harmed and at what cost? There is a real need for data to be systematically collated, with the aim of answering these questions around the
e6
medication’s net worth (toxicity vs. benefits) in real clinical environments. Collecting data in this way is feasible and achievable in palliative care as demonstrated by the Australian Palliative Care Clinical Studies Collaborative, which has developed an international, web-based, 128-bit secure initiative to collect pharmacovigilance data documenting clinical benefit and safety of commonly used medications in palliative care.6 Thus far, data have been collected on metoclopramide,7 haloperidol,8 and most recently, gabapentin and pregabalin (in progress). Even beyond this, more work is required to consider the evidence that underlies the problem of disturbed bowel function in palliative care, which must include documentation of underlying physical changes. We have illustrated that this is feasible in palliative care, with early results suggesting a significant proportion of palliative care patients are likely to have impaired pelvic floor function accompanying changes in colon transit times.9 Such work offers the opportunity to better understand risk factors for constipation, which must include more than opioids. Katherine Clark, MBBS, MMed Department of Palliative Care Calvary Mater Newcastle The University of Newcastle Waratah, New South Wales, Australia E-mail: [email protected] David C. Currow, BMed, MPH, FRACP Discipline of Palliative and Supportive Services Flinders University Adelaide, South Australia, Australia http://dx.doi.org/10.1016/j.jpainsymman.2013.11.004
References 1. Centeno C, Carranza O, Zuriarrain Y, et al. A prospective study of methylnaltrexone for opioidinduced constipation in advanced illness: should we use it or not? J Pain Symptom Manage 2013;46: e1ee3. 2. Watkins JL, Eckmann KR, Mace ML, et al. Utilization of methylnaltrexone (relistor) for opioidinduced constipation in an oncology hospital. P T 2011;36:33e36. 3. Clark K, Byfieldt N, Dawe M, Currow DC. Treating constipation in palliative care: the impact of other factors aside from opioids. Am J Hosp Palliat Care 2012;29:122e125.
Letters
Vol. 47 No. 2 February 2014
4. Rowett DS, Clark K, Robinson MK, Currow DC. Subsidised use of methylnaltrexone in Australia for palliative care. Med J Aust 2012;197:492. 5. Clark K, Rowett DS, Robinson MK, Currow DC. Uptake of methylnaltrexone in Australian patients with opioid-induced constipation: a review of the number of prescriptions presented in the first 12 months of subsidisation. BMJ Support Palliat Care 2012;3:98e102. 6. Currow DC, Rowett D, Doogue M, To THM, Abernethy AP. An international initiative to create a collaborative for pharmacovigilance in hospice and palliative care clinical practice. J Palliat Med 2012;15:282e286. 7. Currow DC, Vella-Brincat J, Fazekas B, et al. Pharmacovigilance in hospice/palliative care: rapid report of net clinical effect of metoclopramide. J Palliat Med 2012;15:1071e1075. 8. Crawford GB, Agar MM, Quinn SJ, et al. Pharmacovigilance in hospice/palliative care: net effect of haloperidol for delirium. J Palliat Med 2013;16: 1335e1341. 9. Clark K, Currow DC. A pilot study to assess the feasibility of measuring the prevalence of slow colon transit or evacuation disorder in palliative care. J Palliat Med 2013;16:774e779.
Parkinson’s Disease-Associated Fatigue: Emerging New Therapeutic Options To the Editor: I read with great interest the recent article by Nilsson et al.1 The prevalence of fatigue in Parkinson’s disease (PD) varies from 35.4% to 59.1% and is impacted significantly by the severity of the underlying PD.2 Quality of life is significantly impacted by PD-related fatigue.3 Altered sleep patterns are often seen in PD patients and contribute significantly to fatiguelike symptomatology. Orthostatic hypotension in PD patients also can contribute to the etiology of PD-associated fatigue. As well, underlying depression is a key factor that influences PD-related fatigue and needs to be addressed as soon as it is recognized.4 Interestingly, the past few years have seen the identification of new therapeutic modalities for the management of PD-related fatigue. One agent that has shown considerable promise in mitigating PD-associated fatigue is pramipexole.5 This has been confirmed by Morita et al. in a recent study in which they reported
2. Wolfe JN, Evans WA. Gas in the portal veins of the liver in infantsda roentogenographic demonstration with postmortem anatomical correlation. Am J Roentgenol Radium Ther Nucl Med 1955;74: 486e488. 3. Kinoshita H, Shinozaki M, Tanimura H, et al. Clinical features and management of hepatic portal venous gasdfour case reports and cumulative review of the literature. Arch Surg 2001;136:1410e1414. 4. Wayne E, Ough M, Wu A, et al. Management algorithm for pneumatosis intestinalis and portal venous gas: treatment and outcome of 88 consecutive cases. J Gastrointest Surg 2010;14:437e448. 5. Khalil PN, Huber-Wagner S, Ladurner R, et al. Natural history, clinical pattern, and surgical considerations of pneumatosis intestinalis. Eur J Med Res 2009;14:231e239. 6. Lee JY, Han H-S, Lim S-N, et al. Pneumatosis intestinalis and portal venous gas secondary to gefitinib therapy for lung adenocarcinoma. BMC Cancer 2012;12:87. 7. Liebman PR, Patten MT, Manny J, Benfield JR, Hechtman HB. Hepatic-portal venous gas in adults: etiology, pathophysiology and clinical significance. Ann Surg 1978;187:281e287. 8. Nelson AL, Millington TM, Sahani D, et al. Hepatic portal venous gas: the ABCs of management. Arch Surg 2009;144:575e581. 9. Heye T, Bernhard M, Mehrabi A, Kauczor HU, Hosch W. Portomesenteric venous gas: is gas distribution linked to etiology and outcome? Eur J Radiol 2012;81:3862e3869. 10. Hou SK, Chern CH, How CK, et al. Hepatic portal venous gas: clinical significance of computed tomography findings. Am J Emerg Med 2004;22: 214e218.
Methylnaltrexone in Palliative Care: Further Research Is Needed To the Editor: We read with interest the comments made by Centeno et al.1 regarding their experiences with the medication methylnaltrexone and their call for more research into this medication. This call supports the observation that as a medication becomes available, the efficacy data underpinning its registration are often ignored in subsequent use, with longer duration of use, differing dosages, broader indications, and a wider population in whom it is used. Based on this phenomenon, we echo the call for more research because since the medication has been approved in Australia
Letters
e5
and elsewhere, published reports are highlighting that methylnaltrexone is being delivered in ways that differ from the use of medication on study. The problem with this is the lack of efficacy and safety data to support alternative prescribing practices. The fact that the medication is being used in alternative ways has been highlighted by Watkins et al.2 and also in work we have done. This includes a retrospective clinical audit,3 which observed that not only was prescription contrary to the evidence base from which the drug was approved but also clinicians were failing to pay attention to other risk factors for constipation and hence interventions. These include, but are not limited to, inadequate hydration, reduced mobility, poor oral intake, and other medications such as those with anticholinergic effects. Furthermore, factors that may predispose people to adverse effects of methylnaltrexone were not adequately assessed before the medication’s administration, with at least one person having a plain abdominal radiograph that was suggestive of a bowel obstruction. On a larger scale, we also have demonstrated that the medication is being used in a manner inconsistent with the way it was originally studied. This statement is based on the results of an audit of 12 months of pharmacy claims for methylnaltrexone that are made to the Australian government for universal subsidy of the medication in the community. This audit was undertaken to explore if the volume of actual use of methylnaltrexone aligned with the predicted volume of use. The results of this audit highlighted that uptake of the medication was far less than expected, with only 261 patients treated with 93 prescriptions for continuing use.4,5 This is in the context that up to 5000 Australians per annum are expected to experience opioid-induced constipation, although not all are expected to experience resistant problems. There is no doubt that methylnaltrexone has a role in the management of constipation that is assessed as being the result of opioid analgesia in advanced disease. But the way the medication is being administered in the postmarketing phase is without supporting data. As a result, there are very limited data to define who is most likely to benefit or who may be harmed and at what cost? There is a real need for data to be systematically collated, with the aim of answering these questions around the
e6
medication’s net worth (toxicity vs. benefits) in real clinical environments. Collecting data in this way is feasible and achievable in palliative care as demonstrated by the Australian Palliative Care Clinical Studies Collaborative, which has developed an international, web-based, 128-bit secure initiative to collect pharmacovigilance data documenting clinical benefit and safety of commonly used medications in palliative care.6 Thus far, data have been collected on metoclopramide,7 haloperidol,8 and most recently, gabapentin and pregabalin (in progress). Even beyond this, more work is required to consider the evidence that underlies the problem of disturbed bowel function in palliative care, which must include documentation of underlying physical changes. We have illustrated that this is feasible in palliative care, with early results suggesting a significant proportion of palliative care patients are likely to have impaired pelvic floor function accompanying changes in colon transit times.9 Such work offers the opportunity to better understand risk factors for constipation, which must include more than opioids. Katherine Clark, MBBS, MMed Department of Palliative Care Calvary Mater Newcastle The University of Newcastle Waratah, New South Wales, Australia E-mail: [email protected] David C. Currow, BMed, MPH, FRACP Discipline of Palliative and Supportive Services Flinders University Adelaide, South Australia, Australia http://dx.doi.org/10.1016/j.jpainsymman.2013.11.004
References 1. Centeno C, Carranza O, Zuriarrain Y, et al. A prospective study of methylnaltrexone for opioidinduced constipation in advanced illness: should we use it or not? J Pain Symptom Manage 2013;46: e1ee3. 2. Watkins JL, Eckmann KR, Mace ML, et al. Utilization of methylnaltrexone (relistor) for opioidinduced constipation in an oncology hospital. P T 2011;36:33e36. 3. Clark K, Byfieldt N, Dawe M, Currow DC. Treating constipation in palliative care: the impact of other factors aside from opioids. Am J Hosp Palliat Care 2012;29:122e125.
Letters
Vol. 47 No. 2 February 2014
4. Rowett DS, Clark K, Robinson MK, Currow DC. Subsidised use of methylnaltrexone in Australia for palliative care. Med J Aust 2012;197:492. 5. Clark K, Rowett DS, Robinson MK, Currow DC. Uptake of methylnaltrexone in Australian patients with opioid-induced constipation: a review of the number of prescriptions presented in the first 12 months of subsidisation. BMJ Support Palliat Care 2012;3:98e102. 6. Currow DC, Rowett D, Doogue M, To THM, Abernethy AP. An international initiative to create a collaborative for pharmacovigilance in hospice and palliative care clinical practice. J Palliat Med 2012;15:282e286. 7. Currow DC, Vella-Brincat J, Fazekas B, et al. Pharmacovigilance in hospice/palliative care: rapid report of net clinical effect of metoclopramide. J Palliat Med 2012;15:1071e1075. 8. Crawford GB, Agar MM, Quinn SJ, et al. Pharmacovigilance in hospice/palliative care: net effect of haloperidol for delirium. J Palliat Med 2013;16: 1335e1341. 9. Clark K, Currow DC. A pilot study to assess the feasibility of measuring the prevalence of slow colon transit or evacuation disorder in palliative care. J Palliat Med 2013;16:774e779.
Parkinson’s Disease-Associated Fatigue: Emerging New Therapeutic Options To the Editor: I read with great interest the recent article by Nilsson et al.1 The prevalence of fatigue in Parkinson’s disease (PD) varies from 35.4% to 59.1% and is impacted significantly by the severity of the underlying PD.2 Quality of life is significantly impacted by PD-related fatigue.3 Altered sleep patterns are often seen in PD patients and contribute significantly to fatiguelike symptomatology. Orthostatic hypotension in PD patients also can contribute to the etiology of PD-associated fatigue. As well, underlying depression is a key factor that influences PD-related fatigue and needs to be addressed as soon as it is recognized.4 Interestingly, the past few years have seen the identification of new therapeutic modalities for the management of PD-related fatigue. One agent that has shown considerable promise in mitigating PD-associated fatigue is pramipexole.5 This has been confirmed by Morita et al. in a recent study in which they reported
