Journal of Pain & Palliative Care Pharmacotherapy. 2015;29:48–50. Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2014.997850
PATIENT EDUCATION AND SELF-ADVOCACY: QUESTIONS AND RESPONSES ON PAIN MANAGEMENT Edited by Yvette Col´on
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Gazi Univ. on 05/06/15 For personal use only.
Chronic Opioid Pain Management for Chronic Kidney Disease Vittal R. Nagar and Pravardhan Birthi AB STRACT Questions from patients about pain conditions, pain treatment, and responses from authors are presented to help educate patients and make them effective self-advocates. The topics addressed in this issue are renal or kidney failure and chronic pain management with opioids, morphine, and oxycodone effect in the body over a period of time. This includes process of absorption, distribution, localization in tissues, biotransformation and excretion in chronic kidney disease, expected side effects and recommendations. KEYWORDS opioid, nephropathy, kidney disease, chronic, dialysis
kidney filtration capacity is less than 15 mL/minute.1 The dialysis population is increasing at a rate of 10% for each year in developed countries. This is due to increase in aging population and substantial increase in prevalence of Type 2 diabetes mellitus.2 Medical care for people with ESRD, focusing on providing relief from the symptoms of pain, and stress to improve their quality of life is gaining high priority within the renal field.3 The measure of removal of any drug from the body is proportional to the glomerular filtration rate (GFR) which measures filtration capacity. Opioids are weak organic bases and changes in the urine pH can alter kidney filtration capacity and elimination.4 Some recommendations suggest adjustment of opioid dosage based on GFR.5 Processing of morphine in the body occurs in the liver to mainly morphine-3-glucuronide (M-3G) (55%), morphine-6 glucuronide (M-6-G) (10%), and normorphine (4%). All these are excreted by kidney, along with about 10% of the parent compound, in subjects with normal kidney function.6 Morphine6-glucuronide is also removed by hemodialysis, but it diffuses out of the central nervous system (brain and spinal cord) very slowly and may not be completely eliminated during dialysis.
QUESTION FROM A PATIENT I have chronic degenerative disc disease and used to take morphine and Percocet for pain control. After my recent hospitalization, my chronic kidney failure has worsened and my doctor says I may require chronic dialysis; I still have a lot of pain in my back. What are the best opioid treatment options available for kidney failure and dialysis patients and how can I better control pain without major side effects? I’m 67 years old and have diabetes and hypertension.
RESPONSE End-stage renal disease (ESRD) is defined by the National Kidney Foundation as the most advanced stage of kidney dysfunction (stage 5), when the estimated glomerular filtration rate (eGFR), which measures Vittal R. Nagar, MD, PhDc, is a Resident Physician and Doctoral Candidate in the Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY. Pravardhan Birthi, MD, is with Pain Management at Saint Francis Medical Center, Grand Island, Nebraska. Address correspondence to: Vittal R. Nagar, MD, Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY. Tel: 859257-4890, Fax: 859-323-1123. (E-mail: [email protected])
48
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Gazi Univ. on 05/06/15 For personal use only.
Patient Education and Self-Advocacy
About 8 to14% of oxycodone is excreted as conjugated and free oxycodone, some other breakdown products include: noroxycodone, conjugated oxycodone, conjugated oxymorphone, and oxymorphone.7 The elimination half-life (the time taken for the body to eliminate half of the drug then in the system) of oxycodone is lengthened in patients with excessive kidney waste products in body, and excretion of breakdown products is severely impaired.8 Studies have shown central nervous system toxicity and sleepiness with regular doses in kidney failure patients.9 The role of dialysis in the elimination of a drug and/or its breakdown products is complex. Therefore, properties of the parent drug and its breakdown products have to be considered, as well as technical factors related to the dialysis procedure. The rate at which waste substances are cleared from the blood is the sum of its kidney and nonkidney clearances.4 Thus, the likelihood of removal of any drug molecule in blood by dialysis depends upon the molecular weight, water solubility, and volume of distribution. The drug molecule’s degree of protein binding affects it’s clearing by dialysis. However, the degree of protein binding can be altered in patients with excessive kidney waste product in body.4 The lower the molecular weight, the more likely the drug molecule is to pass through a given dialysis filter; but greater the protein binding, less likely the drug molecule will be removed from the kidney. Similarly, greater the water solubility, more likely the drug molecule will be removed; greater the volume of distribution, less is removed per unit time.4 In addition, the surface area, pore size, and geometry of the filter; and the technique also determine the elimination of drug molecule through kidney. Morphine has low protein-binding and protein in body is somewhat reduced in patients with excessive kidney waste product in body, and significantly reduced in patient without functioning kidney. Morphine is moderate water-solubility and so is usually removed by most dialysis procedures.4,10 Studies have shown that, in patients with chronic kidney disease morphine is eliminated through dialysis using abdominal tissue layers but glucuronide breakdown products would accumulate since they have low water-solubility.11 Oxycodone has a greater volume of distribution than hydromorphone, is nearly 50% protein bound, and has moderate water solubility.4 There is scarcity of data on the effect of dialysis of oxycodone. However, studies on absorption and excretion properties suggest that it would be cleared by dialysis to some extent.
C
2015 Informa Healthcare USA, Inc.
49
One would expect that as kidney failure develops, the excretion of the breakdown products and/or parent drug would decrease, and gradual accumulation would occur, with associated clinical effects. The signs and symptoms of opioid overdose in the kidney compromised patient, compared with those in the person with normal kidney function, have rarely been reported in the literature.4 As per recommendations, in kidney failure patients who do not undergo dialysis, morphine should not be used due to the difficulty in managing the complicated adverse effects of the breakdown products.4 For oxycodone, there is insufficient data to make a recommendation. If used, administration should be done with great caution and careful monitoring. The active breakdown products, free oxymorphone, is produced in very small amounts, but does accumulate, along with the parent drug, in kidney failure.8 There is a report of oxycodone causing toxic effect and central nervous system depressant effects in patients with kidney failure. In dialysis patients, morphine, the parent compound and the breakdown products can be removed by dialysis,10,12 but sometimes drug and/or breakdown products re-equilibrate between central nervous system and blood.12 The breakdown products would accumulate in between dialysis sessions and extra dosing may be needed during or after dialysis. There are better alternatives; therefore morphine is best avoided in dialysis patients. There is no data on the effect of dialysis on oxycodone and its breakdown products. Until such data are obtained, the use of oxycodone in dialysis patients should be avoided.4 Among opioids, methadone and fentanyl appears to be safe. The methadone breakdown products are seemingly inactive. The parent compound and the breakdown products are excreted into the gut in both normal and kidney failure population.13,4 Whereas with Fentanyl, the breakdown products are completely inactive.10,4 Many of the common causes of pain in kidney patients are long term, and this may influence both patient attitude to the pain, and the healthcare professional’s approach to identifying and addressing it. There is evidence that severe chronic pain in these patients is common and often under recognized and undertreated.14 Adjuvant painkiller and the pain therapy which does not include drugs are important to consider. Pain therapies are categorized according to the steps of the World Health Organization ladder.15 The World Health Organization has promoted effective pain relief in cancer.16 which has more recently been adapted for use with patients with kidney insufficiency. In Step 1, nonopioids, such as acetaminophen
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Gazi Univ. on 05/06/15 For personal use only.
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V. R. Nagar and P. Birthi
(paracetamol) are preferred. Whereas, in step 2, if the patient is still in pain, use of mild opioid analgesics such as tramadol can be done with caution.9 Finally, in Step 3, if pain still persists, substitution (and titration) of strong opioid analgesics such as morphine in place of the Step 2 opioid, until the patient is free of pain can be considered. Finally, there are interventional treatments of refractory pain such as nerve blocks.17 Opioid pain medications such as morphine have many side effects, including constipation, urinary retention, sleepiness, hormonal abnormalities, and respiratory depression. Generally, these side effects are made worse by increasing doses of the medication. In addition, patients develop tolerance to opioid pain medications with long-term use and increasing doses are required over time to generate the same effect.18 The safe opioids (fentanyl and methadone) are not cleared through dialysis. So, as with all of the opioids, caution is needed while prescribing these drugs in kidney failure/dialysis patients and close monitoring is advised for an extended period of time. In summary, chronic pain is a common problem in people with chronic kidney disease and opioids are commonly prescribed for pain control. Opioids can be judiciously used for pain control in patients with chronic kidney disease with or without dialysis. Patients should be educated about absorption, distribution, and excretion of commonly used opioid medication such as morphine, oxycodone, methadone, and fentanyl during clinic visits. There is evidence that tolerance develops with long-term use. These medications do have significant side effect profile, primarily sedation, nausea and vomiting, constipation, sexual dysfunction, physical dependence, and respiratory depression and patients do need to be monitored for these throughout treatment. Awareness among patients about opioid pain management for chronic kidney disease will help them to cope and advocate for themselves as opioids are one of the effective treatment option available for chronic pain. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
REFERENCES [1] Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014;63(5):713–35.
[2] Ansell, D, Tomson, CRV. UK renal registry 11th annual report (December 2008): Chapter 2 introduction to the 2008 UK renal registry report. Nephron Clin Pract. 2009;111(suppl 1):c3–c12. [3] Levy JB, Chambers EJ, Brown EA. Supportive care for the renal patient. Nephrol Dial Transpl. 2004;19(6):1357–60. [4] Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28(5):497–504. [5] Ashley C, Currie A, editors. The Renal Drug Handbook. 3rd edition. Oxford, Radcliffe Medical Press, 2008. [6] Wittwer E, Kern SE; Role of morphine’s metabolites in analgesia: Concepts and controversies. AAPS J. 2006;8(2): E348–E352. [7] Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother. 2004;18(4):17–30. [8] Kirvela M, Lindgren L, Seppala T, Olkkola KT. The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation. J Clin Anaesthesia. 1996;8:13–18. [9] Murtagh FE, Chai MO, Donohoe P, Edmonds PM, Higginson IJ. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: Recommendations for practice. J Pain Palliat Care Pharmacother. 2007;21(2):5–16. [10] Borland M, Jacobs I, King B, O’Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med. 2007;49(3): 335–40. [11] Pauli-Magnus C, Hofmann U, Mikus G, Kuhlmann U, Mettang T. Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant. 1999;14:903–9. [12] Parmar MS, Parmar KS. Management of acute and postoperative pain in chronic kidney disease [v3; ref status: indexed, Available at http://f1000r.es/10f] F1000Research 2013, 2:28. [13] Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7): 613–24. [14] Harris TJ, Nazir R, Khetpal P, Peterson RA, Chava P, Patel SS, Kimmel PL. Pain, sleep disturbance and survival in hemodialysis patients. Nephrol Dial Transplant. 2012;27(2):758– 65. ¨ [15] Pergolizzi J, Boger RH, Budd K, Dahan A, Erdine S, Hans G, et al. Opioids and the management of chronic severe pain in the elderly: Consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).Pain Pract. 2008;8(4):287–313. [16] Pain relief ladder. World Health Organization web site. Available at http://www.who.int/cancer/palliative/painladder/en/. Accessed September 22, 2014. [17] Birthi P, Sloan P. Interventional treatment of refractory cancer pain. Cancer J. 2013;19(5):390–6. [18] Hamza M, Doleys D, Wells M, Weisbein J, Hoff J, Martin M, et al. Prospective study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. Pain Med. 2012;13(10):1304–13.
RECEIVED: 14 September 2014 REVISED: 13 November 2014 ACCEPTED: 4 December 2014
Journal of Pain & Palliative Care Pharmacotherapy
PATIENT EDUCATION AND SELF-ADVOCACY: QUESTIONS AND RESPONSES ON PAIN MANAGEMENT Edited by Yvette Col´on
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Gazi Univ. on 05/06/15 For personal use only.
Chronic Opioid Pain Management for Chronic Kidney Disease Vittal R. Nagar and Pravardhan Birthi AB STRACT Questions from patients about pain conditions, pain treatment, and responses from authors are presented to help educate patients and make them effective self-advocates. The topics addressed in this issue are renal or kidney failure and chronic pain management with opioids, morphine, and oxycodone effect in the body over a period of time. This includes process of absorption, distribution, localization in tissues, biotransformation and excretion in chronic kidney disease, expected side effects and recommendations. KEYWORDS opioid, nephropathy, kidney disease, chronic, dialysis
kidney filtration capacity is less than 15 mL/minute.1 The dialysis population is increasing at a rate of 10% for each year in developed countries. This is due to increase in aging population and substantial increase in prevalence of Type 2 diabetes mellitus.2 Medical care for people with ESRD, focusing on providing relief from the symptoms of pain, and stress to improve their quality of life is gaining high priority within the renal field.3 The measure of removal of any drug from the body is proportional to the glomerular filtration rate (GFR) which measures filtration capacity. Opioids are weak organic bases and changes in the urine pH can alter kidney filtration capacity and elimination.4 Some recommendations suggest adjustment of opioid dosage based on GFR.5 Processing of morphine in the body occurs in the liver to mainly morphine-3-glucuronide (M-3G) (55%), morphine-6 glucuronide (M-6-G) (10%), and normorphine (4%). All these are excreted by kidney, along with about 10% of the parent compound, in subjects with normal kidney function.6 Morphine6-glucuronide is also removed by hemodialysis, but it diffuses out of the central nervous system (brain and spinal cord) very slowly and may not be completely eliminated during dialysis.
QUESTION FROM A PATIENT I have chronic degenerative disc disease and used to take morphine and Percocet for pain control. After my recent hospitalization, my chronic kidney failure has worsened and my doctor says I may require chronic dialysis; I still have a lot of pain in my back. What are the best opioid treatment options available for kidney failure and dialysis patients and how can I better control pain without major side effects? I’m 67 years old and have diabetes and hypertension.
RESPONSE End-stage renal disease (ESRD) is defined by the National Kidney Foundation as the most advanced stage of kidney dysfunction (stage 5), when the estimated glomerular filtration rate (eGFR), which measures Vittal R. Nagar, MD, PhDc, is a Resident Physician and Doctoral Candidate in the Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY. Pravardhan Birthi, MD, is with Pain Management at Saint Francis Medical Center, Grand Island, Nebraska. Address correspondence to: Vittal R. Nagar, MD, Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY. Tel: 859257-4890, Fax: 859-323-1123. (E-mail: [email protected])
48
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Gazi Univ. on 05/06/15 For personal use only.
Patient Education and Self-Advocacy
About 8 to14% of oxycodone is excreted as conjugated and free oxycodone, some other breakdown products include: noroxycodone, conjugated oxycodone, conjugated oxymorphone, and oxymorphone.7 The elimination half-life (the time taken for the body to eliminate half of the drug then in the system) of oxycodone is lengthened in patients with excessive kidney waste products in body, and excretion of breakdown products is severely impaired.8 Studies have shown central nervous system toxicity and sleepiness with regular doses in kidney failure patients.9 The role of dialysis in the elimination of a drug and/or its breakdown products is complex. Therefore, properties of the parent drug and its breakdown products have to be considered, as well as technical factors related to the dialysis procedure. The rate at which waste substances are cleared from the blood is the sum of its kidney and nonkidney clearances.4 Thus, the likelihood of removal of any drug molecule in blood by dialysis depends upon the molecular weight, water solubility, and volume of distribution. The drug molecule’s degree of protein binding affects it’s clearing by dialysis. However, the degree of protein binding can be altered in patients with excessive kidney waste product in body.4 The lower the molecular weight, the more likely the drug molecule is to pass through a given dialysis filter; but greater the protein binding, less likely the drug molecule will be removed from the kidney. Similarly, greater the water solubility, more likely the drug molecule will be removed; greater the volume of distribution, less is removed per unit time.4 In addition, the surface area, pore size, and geometry of the filter; and the technique also determine the elimination of drug molecule through kidney. Morphine has low protein-binding and protein in body is somewhat reduced in patients with excessive kidney waste product in body, and significantly reduced in patient without functioning kidney. Morphine is moderate water-solubility and so is usually removed by most dialysis procedures.4,10 Studies have shown that, in patients with chronic kidney disease morphine is eliminated through dialysis using abdominal tissue layers but glucuronide breakdown products would accumulate since they have low water-solubility.11 Oxycodone has a greater volume of distribution than hydromorphone, is nearly 50% protein bound, and has moderate water solubility.4 There is scarcity of data on the effect of dialysis of oxycodone. However, studies on absorption and excretion properties suggest that it would be cleared by dialysis to some extent.
C
2015 Informa Healthcare USA, Inc.
49
One would expect that as kidney failure develops, the excretion of the breakdown products and/or parent drug would decrease, and gradual accumulation would occur, with associated clinical effects. The signs and symptoms of opioid overdose in the kidney compromised patient, compared with those in the person with normal kidney function, have rarely been reported in the literature.4 As per recommendations, in kidney failure patients who do not undergo dialysis, morphine should not be used due to the difficulty in managing the complicated adverse effects of the breakdown products.4 For oxycodone, there is insufficient data to make a recommendation. If used, administration should be done with great caution and careful monitoring. The active breakdown products, free oxymorphone, is produced in very small amounts, but does accumulate, along with the parent drug, in kidney failure.8 There is a report of oxycodone causing toxic effect and central nervous system depressant effects in patients with kidney failure. In dialysis patients, morphine, the parent compound and the breakdown products can be removed by dialysis,10,12 but sometimes drug and/or breakdown products re-equilibrate between central nervous system and blood.12 The breakdown products would accumulate in between dialysis sessions and extra dosing may be needed during or after dialysis. There are better alternatives; therefore morphine is best avoided in dialysis patients. There is no data on the effect of dialysis on oxycodone and its breakdown products. Until such data are obtained, the use of oxycodone in dialysis patients should be avoided.4 Among opioids, methadone and fentanyl appears to be safe. The methadone breakdown products are seemingly inactive. The parent compound and the breakdown products are excreted into the gut in both normal and kidney failure population.13,4 Whereas with Fentanyl, the breakdown products are completely inactive.10,4 Many of the common causes of pain in kidney patients are long term, and this may influence both patient attitude to the pain, and the healthcare professional’s approach to identifying and addressing it. There is evidence that severe chronic pain in these patients is common and often under recognized and undertreated.14 Adjuvant painkiller and the pain therapy which does not include drugs are important to consider. Pain therapies are categorized according to the steps of the World Health Organization ladder.15 The World Health Organization has promoted effective pain relief in cancer.16 which has more recently been adapted for use with patients with kidney insufficiency. In Step 1, nonopioids, such as acetaminophen
J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by Gazi Univ. on 05/06/15 For personal use only.
50
V. R. Nagar and P. Birthi
(paracetamol) are preferred. Whereas, in step 2, if the patient is still in pain, use of mild opioid analgesics such as tramadol can be done with caution.9 Finally, in Step 3, if pain still persists, substitution (and titration) of strong opioid analgesics such as morphine in place of the Step 2 opioid, until the patient is free of pain can be considered. Finally, there are interventional treatments of refractory pain such as nerve blocks.17 Opioid pain medications such as morphine have many side effects, including constipation, urinary retention, sleepiness, hormonal abnormalities, and respiratory depression. Generally, these side effects are made worse by increasing doses of the medication. In addition, patients develop tolerance to opioid pain medications with long-term use and increasing doses are required over time to generate the same effect.18 The safe opioids (fentanyl and methadone) are not cleared through dialysis. So, as with all of the opioids, caution is needed while prescribing these drugs in kidney failure/dialysis patients and close monitoring is advised for an extended period of time. In summary, chronic pain is a common problem in people with chronic kidney disease and opioids are commonly prescribed for pain control. Opioids can be judiciously used for pain control in patients with chronic kidney disease with or without dialysis. Patients should be educated about absorption, distribution, and excretion of commonly used opioid medication such as morphine, oxycodone, methadone, and fentanyl during clinic visits. There is evidence that tolerance develops with long-term use. These medications do have significant side effect profile, primarily sedation, nausea and vomiting, constipation, sexual dysfunction, physical dependence, and respiratory depression and patients do need to be monitored for these throughout treatment. Awareness among patients about opioid pain management for chronic kidney disease will help them to cope and advocate for themselves as opioids are one of the effective treatment option available for chronic pain. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
REFERENCES [1] Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014;63(5):713–35.
[2] Ansell, D, Tomson, CRV. UK renal registry 11th annual report (December 2008): Chapter 2 introduction to the 2008 UK renal registry report. Nephron Clin Pract. 2009;111(suppl 1):c3–c12. [3] Levy JB, Chambers EJ, Brown EA. Supportive care for the renal patient. Nephrol Dial Transpl. 2004;19(6):1357–60. [4] Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004;28(5):497–504. [5] Ashley C, Currie A, editors. The Renal Drug Handbook. 3rd edition. Oxford, Radcliffe Medical Press, 2008. [6] Wittwer E, Kern SE; Role of morphine’s metabolites in analgesia: Concepts and controversies. AAPS J. 2006;8(2): E348–E352. [7] Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother. 2004;18(4):17–30. [8] Kirvela M, Lindgren L, Seppala T, Olkkola KT. The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation. J Clin Anaesthesia. 1996;8:13–18. [9] Murtagh FE, Chai MO, Donohoe P, Edmonds PM, Higginson IJ. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: Recommendations for practice. J Pain Palliat Care Pharmacother. 2007;21(2):5–16. [10] Borland M, Jacobs I, King B, O’Brien D. A randomized controlled trial comparing intranasal fentanyl to intravenous morphine for managing acute pain in children in the emergency department. Ann Emerg Med. 2007;49(3): 335–40. [11] Pauli-Magnus C, Hofmann U, Mikus G, Kuhlmann U, Mettang T. Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant. 1999;14:903–9. [12] Parmar MS, Parmar KS. Management of acute and postoperative pain in chronic kidney disease [v3; ref status: indexed, Available at http://f1000r.es/10f] F1000Research 2013, 2:28. [13] Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7): 613–24. [14] Harris TJ, Nazir R, Khetpal P, Peterson RA, Chava P, Patel SS, Kimmel PL. Pain, sleep disturbance and survival in hemodialysis patients. Nephrol Dial Transplant. 2012;27(2):758– 65. ¨ [15] Pergolizzi J, Boger RH, Budd K, Dahan A, Erdine S, Hans G, et al. Opioids and the management of chronic severe pain in the elderly: Consensus statement of an International Expert Panel with focus on the six clinically most often used World Health Organization Step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone).Pain Pract. 2008;8(4):287–313. [16] Pain relief ladder. World Health Organization web site. Available at http://www.who.int/cancer/palliative/painladder/en/. Accessed September 22, 2014. [17] Birthi P, Sloan P. Interventional treatment of refractory cancer pain. Cancer J. 2013;19(5):390–6. [18] Hamza M, Doleys D, Wells M, Weisbein J, Hoff J, Martin M, et al. Prospective study of 3-year follow-up of low-dose intrathecal opioids in the management of chronic nonmalignant pain. Pain Med. 2012;13(10):1304–13.
RECEIVED: 14 September 2014 REVISED: 13 November 2014 ACCEPTED: 4 December 2014
Journal of Pain & Palliative Care Pharmacotherapy
