Case Report
Methadone and oedema in the palliative care setting: a case report and review of the literature
Scottish Medical Journal 2014, Vol. 59(2) e11–e13 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933014530057 scm.sagepub.com
Camilla Dawson1, Fiona Paterson2, Fiona McFatter3 and Deans Buchanan4
Abstract Introduction: Methadone is a synthetic opioid which is being used with increased frequency in the palliative care setting for management of complex pain. There have been cases published reporting the development of oedema with methadone maintenance therapy but no cases on the association with methadone and peripheral oedema in the palliative care setting. As yet, the underlying mechanisms are unclear. Case presentation: This case report describes a gentleman with ependymoma and difficult-to-control lower back pain and scrotal pain. This pain had failed to respond to other strong opioids. He was prescribed methadone and then subsequently developed bilateral peripheral oedema. Case management: Peripheral oedema resolved following cessation of methadone. Conclusions: This highlights an important potential adverse effect of methadone in a society of increased methadone prescription for pain control. The published literature to date is reviewed and possible underlying mechanisms explored.
Keywords Methadone, oedema, pain, palliative
Introduction
Case presentation
Methadone is a synthetic opioid with action at multiple receptors. It is being used with increasing frequency in the palliative care setting for management of moderate to severe pain, particularly if poorly responsive to other opioids.1 The adverse side-effect profile of methadone is similar to that of morphine but can be more pronounced with repeated doses due to the tendency of methadone to accumulate.1 Opioid-induced peripheral oedema is a rare side effect of methadone treatment in the palliative setting. There have been five published cases of the development of peripheral oedema following methadone, where most of these relate to methadone maintenance therapy.2–6 This is the first report on the development of significant peripheral oedema following methadone treatment for neuropathic pain in the palliative care setting. The oedema subsequently resolved following cessation of methadone.
A 42-year-old gentleman was diagnosed in December 2009 with Grade 1 ependymoma at the thoracolumbar spine from T11 to L2. Ependymoma is a rare primary central nervous system tumour in adults, where treatment primarily involves surgical excision with or without radiotherapy. This gentleman underwent subtotal excision and radical radiotherapy in the first instance. 1 Palliative Medicine Registrar, Department of Palliative Care, Ninewells Hospital, Dundee, UK 2 Specialty Doctor, Department of Palliative Care, Ninewells Hospital, Dundee, UK 3 Palliative Medicine Consultant, Department of Palliative Care, Ninewells Hospital, Dundee, UK 4 Clinical Lead and Palliative Medicine Consultant, Department of Palliative Care, Ninewells Hospital, Dundee, UK
Corresponding author: Camilla Dawson, 24 Morley Street, Flat 3/2, Glasgow, G42 9JB, UK. Email: [email protected]
e12 Despite showing an early response to treatment, his tumour progressed. He was referred for palliative care input to control severe nociceptive and neuropathic pain of his lower back and scrotum. Morphine sulphate, gabapentin and amitriptyline were titrated with initial analgesic benefit. He then presented in December 2010 with bilateral lower limb oedema. No past medical history of note and a Doppler ultrasound, computed tomography chest/abdomen/pelvis was normal. Circulatory levels of albumin were normal. Peripheral oedema is a well-recognised side effect of both gabapentin and pregabalin.7 Therefore, gabapentin was switched to pregabalin with resolution of lower limb oedema within four weeks. Over the following few months, his lower back and groin pain escalated, with increasing bowel, bladder and sexual dysfunction. Morphine sulphate was switched to oxycontin and titrated to 160 mg twice daily, with the addition of ketamine and lidocaine. Pregabalin dose was optimised to 300 mg twice daily. His pain unfortunately remained inadequately controlled; using a modified ESAS tool,8 his pain score was 8. Following discussion with the wider team, including the Chronic Pain team, he was admitted to the Acute Palliative Care Unit in March 2012, where he was converted to methadone. The starting dose was 20 mg twice daily, increased over three days to 40 mg twice daily with no initial adverse reactions. His pain score improved from 8 prior to methadone treatment, to 4 after nine days on methadone. One week after commencing methadone, he developed bilateral pitting lower limb oedema. A Doppler ultrasound demonstrated no underlying venous thromboemboli. He was discharged home and reviewed on two occasions as an outpatient, where further investigations were organised due to persistent lower limb oedema. An electrocardiography, echocardiogram, chest radiograph were all normal. Given the recognised side-effect profile of pregabalin, the dose was reduced by half to 150 mg twice daily. He was reviewed four weeks later, and peripheral oedema had worsened. This was reported both objectively from clinical examination and self report from the patient, who was now no longer able to fit his normal jeans. Despite introduction of methadone, pain remained problematic, and he was admitted in April 2012 for an intrathecal trial. In preparation for an intrathecal analgesia trial, methadone was stopped and switched to short-acting alfentanil via subcutaneous syringe driver. Within three days of stopping methadone, the oedema steadily improved. When admitted in July 2012 for a permanent intrathecal device, his bilateral lower limb oedema had completely resolved. This was observed from physical examination, and the patient also commented that he was able to fit into his
Scottish Medical Journal 59(2) normal jeans again. Signed written consent was obtained from the patient prior to publication.
Discussion Methadone is a synthetic opioid developed over 60 years ago principally for use as an analgesic. It is a potent agonist at the mu opioid receptors, with some action at the delta opioid receptor. It also antagonises activity at the N-methyl-D-aspartate receptor and inhibits the reuptake of both noradrenaline and serotonin.1 Its action at multiple receptors makes it an attractive alternative to other strong opioids in the management of cancer pain. It can also be used in renal and hepatic impairment, with most of the drug being metabolised to inactive metabolites in the liver.9 Methadone is highly lipophilic, with a high volume of distribution and high affinity for tissues. As a result, it tends to accumulate after multiple administrations, with a high risk of toxicity. There is no single potency ratio between morphine and methadone.9 It is positioned at step 3 of the WHO analgesic ladder as a strong opioid, but most guidelines would advise specialist input for its use as an analgesia. It is clear that the above pharmacokinetics must be appreciated in order for it to be used safely and effectively, due to the high risk of toxicity. Commonly reported side effects are similar to that of morphine and include confusion, constipation, dizziness, drowsiness, hypotension, headache and nausea.1 There have been five publications describing a potential link with methadone in non-palliative care setting and peripheral oedema.2–6 The earliest being Longwell2 who describes three patients prescribed methadone for treatment of opioid addiction. All develop peripheral oedema within three to six months of commencing methadone, and in all cases, the oedema improves with subsequent reduction or stopping of methadone maintenance treatment. Kharlamb and Kourlas describe a case where peripheral oedema develops within one week of commencing methadone for chronic back pain. The oedema resolved once methadone was reduced and subsequently stopped.3 The published cases report an onset of oedema from one week to six months after starting methadone. The severity of oedema appears to be dose dependant, and oedema improves as the dose of methadone is reduced. The mechanism by which methadone causes peripheral oedema is unclear. The high volume of distribution and accumulation of methadone in tissues results in higher oncotic pressures in the tissues. This in combination with reduced oncotic pressures in blood vessels due to venodilatation may be a contributing factor. A recently published paper by Gardner Nix4 reports five cases where opioids appear to cause or contribute to the development of peripheral oedema. The opioids
Dawson et al. including methadone and were all prescribed for treatment of non-cancer pain. They postulate a link between opioid-induced histamine release and smooth muscle relaxation contributing to oedema. Another theory would be the negative inotropic effect exerted from opioids. Methadone-related bradycardia has been described in the palliative care setting10; here, the calcium-channel antagonistic effect of methadone is also described. Due to the complex nature of methadone’s action, it is likely that the development of peripheral oedema is multi-factorial. Further research would be needed to understand the underlying mechanisms and to consider individuals who may be more likely to develop this side effect. Clinicians using methadone in the palliative care setting for treatment of complex, morphine resistant pain must be aware that significant peripheral oedema can result as a rare but reversible side effect.
Conclusions . Methadone is being used with increased frequency in the palliative care setting for management of complex pain. . Methadone has a complex pharmacokinetic and pharmacodynamic profile. . This is the first published case to report a link between use of methadone and peripheral oedema in the palliative care setting. . The mechanism underlying is at present unclear but likely multi-factorial. Declaration of conflicting interests The authors declare that they have no competing interests.
e13 Funding This paper received no specific grant from any funding agency in the pubic, commercial, or not-for-profit sectors.
Author contributions All authors contributed to the final paper. CD performed the literature review and wrote the original manuscript. All authors edited and proved the final submitted manuscript. CD and DB are guarantors of the paper.
References 1. Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev 2007; 17: CD003971. 2. Longwell B. Weight and edema on methadone maintenance therapy. Int J Addict 1979; 14: 329–335. 3. Kharlamb V and Kourlas H. Edema in a patient receiving methadone for chronic low back pain. Am J Health Syst Pharm 2007; 64: 2557–2560. 4. Gardner-Nix J. Opioids causing peripheral oedema. J Pain Symptom Manage 2002; 23: 453–455. 5. O’Connor LM, Woody G, Yeh H, et al. Methadone and edema. J Subst Abuse Treat 1991; 8: 153–155. 6. Mahe I, Chassany O, Grenard A, et al. Methadone and edema: a case-report and literature review. Eur J Clin Pharmacol 2004; 59: 923–924. 7. Jensen TS, Madsen CS and Finnerup NB. Pharmacology and treatment of neuropathic pains. Curr Opin Neurol 2009; 22: 467–474. 8. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method for assessment of palliative care patients. J Palliat Care 1991; 7: 6–9. 9. Fainsinger R, Schoeller T and Bruera E. Methadone in management of cancer pain: a review. Pain 1993; 52: 137–147. 10. Buchanan D. Sinus bradycardia related to methadone in a patient with myeloma receiving thalidomide therapy. Palliat Med 2010; 24: 742–743.
Methadone and oedema in the palliative care setting: a case report and review of the literature
Scottish Medical Journal 2014, Vol. 59(2) e11–e13 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933014530057 scm.sagepub.com
Camilla Dawson1, Fiona Paterson2, Fiona McFatter3 and Deans Buchanan4
Abstract Introduction: Methadone is a synthetic opioid which is being used with increased frequency in the palliative care setting for management of complex pain. There have been cases published reporting the development of oedema with methadone maintenance therapy but no cases on the association with methadone and peripheral oedema in the palliative care setting. As yet, the underlying mechanisms are unclear. Case presentation: This case report describes a gentleman with ependymoma and difficult-to-control lower back pain and scrotal pain. This pain had failed to respond to other strong opioids. He was prescribed methadone and then subsequently developed bilateral peripheral oedema. Case management: Peripheral oedema resolved following cessation of methadone. Conclusions: This highlights an important potential adverse effect of methadone in a society of increased methadone prescription for pain control. The published literature to date is reviewed and possible underlying mechanisms explored.
Keywords Methadone, oedema, pain, palliative
Introduction
Case presentation
Methadone is a synthetic opioid with action at multiple receptors. It is being used with increasing frequency in the palliative care setting for management of moderate to severe pain, particularly if poorly responsive to other opioids.1 The adverse side-effect profile of methadone is similar to that of morphine but can be more pronounced with repeated doses due to the tendency of methadone to accumulate.1 Opioid-induced peripheral oedema is a rare side effect of methadone treatment in the palliative setting. There have been five published cases of the development of peripheral oedema following methadone, where most of these relate to methadone maintenance therapy.2–6 This is the first report on the development of significant peripheral oedema following methadone treatment for neuropathic pain in the palliative care setting. The oedema subsequently resolved following cessation of methadone.
A 42-year-old gentleman was diagnosed in December 2009 with Grade 1 ependymoma at the thoracolumbar spine from T11 to L2. Ependymoma is a rare primary central nervous system tumour in adults, where treatment primarily involves surgical excision with or without radiotherapy. This gentleman underwent subtotal excision and radical radiotherapy in the first instance. 1 Palliative Medicine Registrar, Department of Palliative Care, Ninewells Hospital, Dundee, UK 2 Specialty Doctor, Department of Palliative Care, Ninewells Hospital, Dundee, UK 3 Palliative Medicine Consultant, Department of Palliative Care, Ninewells Hospital, Dundee, UK 4 Clinical Lead and Palliative Medicine Consultant, Department of Palliative Care, Ninewells Hospital, Dundee, UK
Corresponding author: Camilla Dawson, 24 Morley Street, Flat 3/2, Glasgow, G42 9JB, UK. Email: [email protected]
e12 Despite showing an early response to treatment, his tumour progressed. He was referred for palliative care input to control severe nociceptive and neuropathic pain of his lower back and scrotum. Morphine sulphate, gabapentin and amitriptyline were titrated with initial analgesic benefit. He then presented in December 2010 with bilateral lower limb oedema. No past medical history of note and a Doppler ultrasound, computed tomography chest/abdomen/pelvis was normal. Circulatory levels of albumin were normal. Peripheral oedema is a well-recognised side effect of both gabapentin and pregabalin.7 Therefore, gabapentin was switched to pregabalin with resolution of lower limb oedema within four weeks. Over the following few months, his lower back and groin pain escalated, with increasing bowel, bladder and sexual dysfunction. Morphine sulphate was switched to oxycontin and titrated to 160 mg twice daily, with the addition of ketamine and lidocaine. Pregabalin dose was optimised to 300 mg twice daily. His pain unfortunately remained inadequately controlled; using a modified ESAS tool,8 his pain score was 8. Following discussion with the wider team, including the Chronic Pain team, he was admitted to the Acute Palliative Care Unit in March 2012, where he was converted to methadone. The starting dose was 20 mg twice daily, increased over three days to 40 mg twice daily with no initial adverse reactions. His pain score improved from 8 prior to methadone treatment, to 4 after nine days on methadone. One week after commencing methadone, he developed bilateral pitting lower limb oedema. A Doppler ultrasound demonstrated no underlying venous thromboemboli. He was discharged home and reviewed on two occasions as an outpatient, where further investigations were organised due to persistent lower limb oedema. An electrocardiography, echocardiogram, chest radiograph were all normal. Given the recognised side-effect profile of pregabalin, the dose was reduced by half to 150 mg twice daily. He was reviewed four weeks later, and peripheral oedema had worsened. This was reported both objectively from clinical examination and self report from the patient, who was now no longer able to fit his normal jeans. Despite introduction of methadone, pain remained problematic, and he was admitted in April 2012 for an intrathecal trial. In preparation for an intrathecal analgesia trial, methadone was stopped and switched to short-acting alfentanil via subcutaneous syringe driver. Within three days of stopping methadone, the oedema steadily improved. When admitted in July 2012 for a permanent intrathecal device, his bilateral lower limb oedema had completely resolved. This was observed from physical examination, and the patient also commented that he was able to fit into his
Scottish Medical Journal 59(2) normal jeans again. Signed written consent was obtained from the patient prior to publication.
Discussion Methadone is a synthetic opioid developed over 60 years ago principally for use as an analgesic. It is a potent agonist at the mu opioid receptors, with some action at the delta opioid receptor. It also antagonises activity at the N-methyl-D-aspartate receptor and inhibits the reuptake of both noradrenaline and serotonin.1 Its action at multiple receptors makes it an attractive alternative to other strong opioids in the management of cancer pain. It can also be used in renal and hepatic impairment, with most of the drug being metabolised to inactive metabolites in the liver.9 Methadone is highly lipophilic, with a high volume of distribution and high affinity for tissues. As a result, it tends to accumulate after multiple administrations, with a high risk of toxicity. There is no single potency ratio between morphine and methadone.9 It is positioned at step 3 of the WHO analgesic ladder as a strong opioid, but most guidelines would advise specialist input for its use as an analgesia. It is clear that the above pharmacokinetics must be appreciated in order for it to be used safely and effectively, due to the high risk of toxicity. Commonly reported side effects are similar to that of morphine and include confusion, constipation, dizziness, drowsiness, hypotension, headache and nausea.1 There have been five publications describing a potential link with methadone in non-palliative care setting and peripheral oedema.2–6 The earliest being Longwell2 who describes three patients prescribed methadone for treatment of opioid addiction. All develop peripheral oedema within three to six months of commencing methadone, and in all cases, the oedema improves with subsequent reduction or stopping of methadone maintenance treatment. Kharlamb and Kourlas describe a case where peripheral oedema develops within one week of commencing methadone for chronic back pain. The oedema resolved once methadone was reduced and subsequently stopped.3 The published cases report an onset of oedema from one week to six months after starting methadone. The severity of oedema appears to be dose dependant, and oedema improves as the dose of methadone is reduced. The mechanism by which methadone causes peripheral oedema is unclear. The high volume of distribution and accumulation of methadone in tissues results in higher oncotic pressures in the tissues. This in combination with reduced oncotic pressures in blood vessels due to venodilatation may be a contributing factor. A recently published paper by Gardner Nix4 reports five cases where opioids appear to cause or contribute to the development of peripheral oedema. The opioids
Dawson et al. including methadone and were all prescribed for treatment of non-cancer pain. They postulate a link between opioid-induced histamine release and smooth muscle relaxation contributing to oedema. Another theory would be the negative inotropic effect exerted from opioids. Methadone-related bradycardia has been described in the palliative care setting10; here, the calcium-channel antagonistic effect of methadone is also described. Due to the complex nature of methadone’s action, it is likely that the development of peripheral oedema is multi-factorial. Further research would be needed to understand the underlying mechanisms and to consider individuals who may be more likely to develop this side effect. Clinicians using methadone in the palliative care setting for treatment of complex, morphine resistant pain must be aware that significant peripheral oedema can result as a rare but reversible side effect.
Conclusions . Methadone is being used with increased frequency in the palliative care setting for management of complex pain. . Methadone has a complex pharmacokinetic and pharmacodynamic profile. . This is the first published case to report a link between use of methadone and peripheral oedema in the palliative care setting. . The mechanism underlying is at present unclear but likely multi-factorial. Declaration of conflicting interests The authors declare that they have no competing interests.
e13 Funding This paper received no specific grant from any funding agency in the pubic, commercial, or not-for-profit sectors.
Author contributions All authors contributed to the final paper. CD performed the literature review and wrote the original manuscript. All authors edited and proved the final submitted manuscript. CD and DB are guarantors of the paper.
References 1. Nicholson AB. Methadone for cancer pain. Cochrane Database Syst Rev 2007; 17: CD003971. 2. Longwell B. Weight and edema on methadone maintenance therapy. Int J Addict 1979; 14: 329–335. 3. Kharlamb V and Kourlas H. Edema in a patient receiving methadone for chronic low back pain. Am J Health Syst Pharm 2007; 64: 2557–2560. 4. Gardner-Nix J. Opioids causing peripheral oedema. J Pain Symptom Manage 2002; 23: 453–455. 5. O’Connor LM, Woody G, Yeh H, et al. Methadone and edema. J Subst Abuse Treat 1991; 8: 153–155. 6. Mahe I, Chassany O, Grenard A, et al. Methadone and edema: a case-report and literature review. Eur J Clin Pharmacol 2004; 59: 923–924. 7. Jensen TS, Madsen CS and Finnerup NB. Pharmacology and treatment of neuropathic pains. Curr Opin Neurol 2009; 22: 467–474. 8. Bruera E, Kuehn N, Miller MJ, et al. The Edmonton Symptom Assessment System (ESAS): a simple method for assessment of palliative care patients. J Palliat Care 1991; 7: 6–9. 9. Fainsinger R, Schoeller T and Bruera E. Methadone in management of cancer pain: a review. Pain 1993; 52: 137–147. 10. Buchanan D. Sinus bradycardia related to methadone in a patient with myeloma receiving thalidomide therapy. Palliat Med 2010; 24: 742–743.
