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Reduction in Constipation and Laxative Requirements Following Opioid Rotation to Methadone
Vol. 18 No. 4 October 1999
Journal of Pain and Symptom Management 303
Clinical Note
Reduction in Constipation and Laxative Requirements Following Opioid Rotation to Methadone: A Report of Four Cases Paul J. Daeninck, MD, MSc, FRCPC, and Eduardo Bruera, MD Palliative Care Program, Grey Nuns Community Health Centre, and Division of Palliative Care Medicine, University of Alberta, Edmonton, Alberta, Canada
Abstract Constipation is a common symptom in cancer patients, especially in those who are receiving opioid analgesics for pain. Although several articles have recently examined constipation with respect to causation and treatment, little research has been done to elucidate the effects of different opioids on the bowel. Recent research has found that laxative doses may be lower in patients using methadone as an analgesic, but changes in constipation were not measured. We report here on four cases in which patients had improvement in constipation and decreased laxative requirements following opioid rotation to methadone. J Pain Symptom Manage 1999;18:303–309. © U.S. Cancer Pain Relief Committee, 1999. Key Words Cancer pain, opioid rotation, methadone, constipation, laxatives
Introduction Constipation is a common symptom in advanced cancer patients. Studies have demonstrated that 40 to 80% of patients on a palliative care service have constipation.1,2 This proportion increases to $90% when patients are treated with opioids.2,3 Several recent review articles have examined this problem2,4,5 with respect to causation and treatment. However, little research has been done on the differential effects of the various opioid agonists on constipation in the terminally ill cancer patient. Methadone is gaining popularity as an opioid Dr. Daeninck is a McEachern Fellow of the Canadian Cancer Society. Address reprint requests to: Eduardo Bruera, MD, Dept. of Symptom Control and Palliative Care, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA. Accepted for publication: December 8, 1998. © U.S. Cancer Pain Relief Committee, 1999 Published by Elsevier, New York, New York
analgesic because of its widespread availability, low cost, and long half-life, which decreases the need for multiple daily doses.6–9 Its lack of active metabolites is useful for those patients with opioid-induced neurotoxicity,10 and its N-methyl-Daspartate (NMDA) receptor-antagonist activity may be clinically important for patients with neuropathic pain.11,12 However, there have been no reports of improvement in opioid-induced constipation with the use of methadone. A retrospective study has found that laxative doses were significantly lower in patients using methadone as an analgesic,13 but changes in constipation were not measured. We report here on four cases where opioid rotation to methadone was followed by dramatic improvement in constipation and reduced need for laxatives.
Patients Case 1 A 51-year-old woman was admitted for opioid rotation to methadone. She had been diag0885-3924/99/$–see front matter PII S0885-3924(99)00086-X
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nosed with ductal carcinoma of the left breast with nodal involvement 21 months prior to this admission. She pursued alternative therapies until inflammatory changes involving the left breast and chest wall appeared 13 months prior to admission. Metastases to the liver and lung were also found. She underwent segmental breast resection, followed by anthracyclinebased chemotherapy and radiotherapy (RT), which produced a partial response. Within 1 month, RT was again administered to treat the rapid onset of inflammatory changes to the right breast. She was assessed at the Pain and Symptom outpatient clinic 5 months prior to admission and was found to have a mixed (visceral and neuropathic) pain syndrome involving the right thorax, which was thought to be related to the cancer recurrence and subsequent treatment. This was treated with longacting morphine. One week later, rapid dose escalation without pain relief preceded opioid rotation to hydromorphone. One month later, dexamethasone was added, which decreased breakthrough opioid requirements. Three months prior to admission, docetaxel chemotherapy was started for symptomatic relief of increased pain and swelling of both breasts. Symptomatic response was noted but febrile neutropenia with atypical pneumonia and hospitalization after the third dose (6 weeks prior to admission) caused suspension of treatment. She was found to have a malignant pleural effusion, which was drained by thoracocentesis. She was taking 216 mg of long-acting hydromorphone orally twice daily and had taken 7 to 8 breakthrough doses of 48 mg each (total daily dose of approximately 816 mg). The patient’s pain became more severe and she was again assessed in the Pain and Symptom outpatient clinic. Her opioids were increased to 254 mg long-acting hydromorphone and her breakthrough was increased to 80 mg.
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She was admitted to the Tertiary Palliative Care Unit the next day. She admitted to drowsiness, but denied any other symptoms of opioidinduced neurotoxicity. Other symptoms on admission included dyspnea and constipation. Her Mini-Mental Status Examination (MMSE)14 was 30/30 (baseline 28). Her last bowel movement was 2 days prior to admission. The patient’s bowel history prior to opioids was one bowel movement daily. Since starting on the opioid analgesics, she continued to have a bowel movement every 1–2 days. An abdominal radiograph revealed massive constipation: the lumen of the colon was completely occupied by stool (constipation score 12/1215,16). She had been on docusate calcium 240 mg twice daily, sennosides 25.8 mg (3 tablets) twice daily, and bisacodyl 10 mg at night (Table 1). On the day of admission (Day 0), she was switched to methadone, her laxatives were increased, and a cleansing enema was given. However, from Day 2 to 4, the patient had on average 3 large “explosive” bowel movements per day. She refused her laxatives on Day 3 but resumed them soon afterward, and thereafter had an average of 1.4 bowel movements daily. The patient’s pain quickly came under better control, as evidenced by a decrease in her pain scores (Day 0: 3/10; Day 5: 1/10), a decrease in her opioid intake (Table 1), and an increase in her mobility. Her course was complicated by lymphangitic metastasis to the lungs, which caused worsening dyspnea and led to an escalation in the methadone dose for symptomatic control. The patient developed delirium on Day 46 and was rotated to hydromorphone with little change. She died quietly on Day 48.
Case 2 A 60-year-old man was admitted with confusion and poor pain control. He was diagnosed approximately 2 years prior to admission with
Table 1 Changes in Constipation and Laxatives with Rotation to Methadone Patients Case 1 Case 2 Case 3 Case 4
DLD premethadone
DLD postmethadonea
BM/d premethadone
BM/d postmethadonea
MEDD premethadone
MEDD postmethadonea
9 12 9 6.7
6.67 2.3 2.5 1.2
0.5 0.5 0.33 0.33
1.36 0.92 1.5 0.63
4,000 2,400 190 1,220
1,110 208 158 495
Abbreviations: DLD 5 daily laxative dose; BM 5 bowel movements; MEDD 5 morphine equivalent daily dose (in mg). are averages from admission.
a Values
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Laxative Use and Opioid Rotation to Methadone
adenocarcinoma of the prostate, with widespread metastases to his axial skeleton. He received a trial of hormonal treatment, which was unsuccessful in decreasing the spread of bony metastasis or alleviating the pain. In the 3 months preceding admission, he underwent two separate courses of palliative radiotherapy to his pelvis, which gave at best temporary pain relief. One week prior to admission, despite a cycle of palliative chemotherapy, he required admission to another facility for pain control. He was transferred to our Tertiary Palliative Care Unit with a mixed pain syndrome (bony and neuropathic, thought to be due to nerve impingement), which had led to rapid escalation in the dose of hydromorphone and carbamazepine. He also was experiencing confusion and dizziness. Despite frequent bowel movements, he reported feeling constipated. His normal bowel pattern had been daily to every other day while on laxative preparations (Table 1). On admission, he was found to be confused despite having a MMSE of 26/30 (normal baseline of 24). This confusion was thought to be due to opioids, and a rotation from hydromorphone to methadone was initiated. His radiographic constipation score was 11/12, and he was given a cleansing enema, which yielded a large bowel movement. However, over the next 4 days (corresponding to the opioid rotation), he had on average 3 loose bowel movements daily, despite being on tapering dosages of laxatives. For the remainder of his admission, he had on average one bowel movement daily, while on only one-fourth of the previous laxative dose (Table 1). The patient’s confusion improved (MMSE 29/30) and he achieved excellent pain control with the methadone, which was reflected by decreased pain score (1/10, compared with an admission score of 6/10) and an increase in his mobility. He was discharged home after 15 days in hospital, with a 12-fold reduction in opioid dose and a 75% reduction in laxative dose (Table 1).
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developed swelling in the right neck and submandibular regions, and was admitted to her local hospital for investigation. Non-Hodgkin’s lymphoma, intermediate grade, was diagnosed following fine needle and nodal biopsies, and she received anthracycline-containing chemotherapy, as well as intrathecal methotrexate for presumed central nervous system involvement. One month prior to admission, she developed lethargy, a decreased level of consciousness and bilateral leg pain, and was admitted to her local hospital. A computerized tomogram scan of the brain revealed an abnormality in the left hemisphere, likely representing metastatic disease. She continued to have poor pain control and a fluctuating level of consciousness, and was transferred to our Tertiary Palliative Care Unit. On admission, further questioning revealed that the patient had a 40 pack-year smoking history and a history of alcohol abuse (CAGE* questionnaire score of 2/4).17 She was on a transdermal fentanyl patch and was taking hydromorphone orally for breakthrough pain. She also was taking 2 different benzodiazepines. The pain in her legs was felt to be neuropathic in nature. She also had a history of chronic difficulty with constipation and had been on long-term laxatives (Table 1). Examination revealed the patient to be drowsy, with bilateral lower limb weakness and sensory changes in the L3–L4 areas consistent with spinal stenosis. Her MMSE was 23/30 (normal baseline of 26). A constipation score, as obtained from an abdominal radiograph, was 2/ 12. She was hydrated, rotated to methadone, the benzodiazepines were stopped, and further palliative treatment for the underlying malignancy was considered. During the opioid rotation, she developed diarrhea, and had a daily average of 1.7 bowel movements, which decreased only slightly postrotation and with a reduction in laxatives (Table 1). Her MMSE improved to 28/30 on Day 4, and her pain score improved from 6/10 on admission to 1/10 by
Case 3 A 72-year-old woman was transferred from her local hospital for assessment of confusion and poor pain control. She initially presented 6 months prior to admission with diplopia and right-sided Bell’s palsy, for which no cause was identified. Within the following 6 weeks, she
* CAGE is an acronym for a questionnaire screening for alcohol abuse: Cut down on drinking Annoyed by criticism of drinking Guilty about drinking Eye-opener use (alcohol use first thing in the morning)
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Day 7. She was transferred to the local cancer institute for further investigations and consideration of treatment of the lymphoma on Day 7.
Case 4 A 73-year-old man was admitted from home for pain and symptom control, as well as a need for psychosocial support. Approximately 6 months prior to admission, he developed early satiety, weight loss, and postprandial back pain. Subsequent investigations revealed a pancreatic mass on a background of chronic calcific pancreatitis, accompanied by lymphadenopathy and splenic and mesenteric vein thrombosis. Biopsy of the mass was positive for adenocarcinoma. Two months prior to admission, he was assessed in the Pain and Symptom outpatient clinic for abdominal and back pain, anorexia, and constipation. A history of alcohol abuse was obtained (CAGE 2/4), and his MMSE was 30/30. His morphine and bowel medications (sennosides and docusate sodium) were increased, but he refused rotation to methadone at that time. Three weeks prior to admission, he continued to have poorly controlled pain, and developed hallucinations and myoclonus at home. He was assessed by the regional palliative care team, who rotated him to hydromorphone and again increased his laxatives. It was also felt that he may be suffering from depression and/or somatization. He was assessed 2 days prior to admission, at which time it was felt his pain was not improving and hospitalization was recommended. On admission, the patient denied alcohol abuse in the past and had little insight into his current condition. He had not had a bowel movement for 6 days. His MMSE was 28/30 (normal baseline 26) and he was alert and appropriate. His examination was remarkable for abdominal fullness with reproducible pain and a digital exam showed the rectum to be empty of stool. His radiographic constipation score from an abdominal radiograph was 5/12. His hydromorphone was increased and his laxatives continued at the same dose, but by Day 3 he had only one bowel movement and was experiencing hallucinations and myoclonus. Opioid rotation to methadone was initiated and his laxatives were increased. His pain was better controlled, as evidenced by improvement in the pain score and increased mobility. The frequency of his bowel movements did not change despite decreasing and subsequently discontinuing his lax-
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atives (Table 1). His pain remained under good control and his bowel movements were regular until his sudden death on Day 36.
Discussion Constipation is a common symptom in advanced cancer patients, and is reported by up to 90% of those patients treated with opioid analgesics.3 Advanced cancer patients have many risk factors, including structural abnormalities, metabolic disturbances, neurologic disorders, advanced age, inactivity, poor intake, and drug side effects.4,5 However, constipation is often not assessed, and this leads to inadequate treatment. A full assessment should include a history of bowel movements, both before and after opioid therapy, the symptoms due to constipation, and a physical examination including a digital rectal exam. A retrospective review of admissions to our palliative care unit18 found that 59% of patients did not undergo a rectal examination and there was minimal and/or insufficient documentation by both the medical and nursing staff regarding the symptoms related to constipation. In addition, simple bedside questions and clinical maneuvers may be poor predictors for the diagnosis of constipation.18 The diagnosis can be confirmed using the radiographic constipation score.15,16,18 The routine use of this score, as seen in these four cases, helps to identify those patients who have severe constipation and require prompt treatment. The score is determined by the assessment of the amount of stool in each of the four abdominal quadrants using the following system: 0 5 no stool, 1 5 stool occupying ,50% of the lumen of the colon, 2 5 stool occupying .50% of the lumen, and 3 5 stool completely occupying the lumen. The colon is scored out of 12, and a score .7/12 indicates severe constipation requiring immediate treatment.5,18 Several laxative preparations are available for the treatment of constipation. However, the different modes of action and the lack of equivalency tables makes it difficult to compare these medications. Recent reviews recommend a combination of senna and docusate as the initial treatment for opioid-induced constipation, with the addition of lactulose and magnesium sulfate for relatively refractory cases. For severe constipation, a combination of oral
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Laxative Use and Opioid Rotation to Methadone
laxatives, rectal suppositories, and enemas may be needed.2,4 To compare these four cases, 8.6 mg senna, 100 mg docusate sodium, 5 mg bisacodyl, and 15 ml of lactulose were each considered as one unit of laxative.13 Thus a patient on two tablets of senna and two capsules of docusate had a daily laxative dose of 4 units. All of the reported patients were taking at least 6 units of laxatives daily, usually with poor results (Table 1). After methadone rotation, each patient was taking less laxatives, with more frequent bowel movements. Each of our patients required opioid rotation for opioid-induced neurotoxicity or dose escalation. In each case, methadone was the opioid of choice for several reasons. First, all of the patients had used several opioid analgesics with the result being either poor long-term pain control or toxicity. Three of the patients required high doses of opioids (.1200 morphine equivalent daily dose), two had previous substance abuse histories, and at least 2 were felt to have psychologic distress (somatization), all of which are independent risk factors for poor pain control.19–21 Recent reports of NMDA receptor antagonist activity by methadone may be clinically important for the treatment of neuropathic pain,11,12 which was found in 3 of the 4 patients. Methadone has reduced cross-tolerance to other opioid agonists, as well as high potency (equianalgesic conversion of 10 mg morphine to 1 mg methadone6,23), which may also account for the reduction of the morphineequivalent daily dose (MEDD).5,22,23 Neuropathic pain syndromes, as seen in 3 of our 4 patients, often are treated with opioids as well as a variety of adjuvant medications.24,25 Several of these commonly used drugs may in fact worsen constipation in advanced cancer patients. Medications with anticholinergic activity (antidepressants, antispasmodics, and phenothiazines), anticonvulsants (e.g., carbamazepine), and antihypertensives (e.g., clonidine) have been associated with constipation.5 The approach of our group is to maximize the benefits of opioid analgesics, using those that may have intrinsic NMDA receptor activity (methadone)11,12 and make liberal use of corticosteroids, which when used for short periods to achieve pain control are not associated with severe side effects.26 Why did our patients have such remarkable
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changes in their bowel function following rotation to methadone? The overall reduction in the MEDD, due to the incomplete opioid cross-tolerance, may have caused reduced opioid effects on the bowel13 but continued to give good pain relief. The use of fentanyl for the treatment of cancer pain has also been associated with less gastrointestinal side effects, including constipation,27–31 but there have been several case reports of patients demonstrating withdrawal symptoms after rotation to transdermal fentanyl.32–36 These symptoms included abdominal cramping or pain, diarrhea, nausea, anxiety, shivering, changes in heart rate and blood pressure, and formication. Our patients had diarrhea and two complained of transient abdominal cramping, but no other evidence of opioid withdrawal. Like fentanyl, methadone is also lipophilic and is highly distributed to the body tissues. This allows a peripheral reservoir effect37 which may allow for decreased maintenance doses. These smaller doses may exert less activity on opioid receptors in the gastrointestinal tract and cause an incomplete “withdrawal syndrome” to occur. An alternative explanation may be that methadone, like fentanyl, may have a different affinity for the opioid receptors in the gut, thus causing less gastrointestinal symptoms.35,36 A report of oral patient-controlled methadone which was effective in managing abdominal pain without worsening the known chronic partial bowel obstruction in two advanced cancer patients suggests that methadone may be useful in patients with an alteration in bowel motility.38 Opioid rotation for toxicity is not a new concept, and several case series and retrospective reviews are present in the literature.10,39,40 Rotation to alternative opioids usually helps in the resolution of neurotoxic side effects and may allow a reduction in the analgesic dose. However, no reports of opioid rotation having beneficial effects for constipation exist. A retrospective study of the clinical predictors of laxative dose in advanced cancer patients revealed that patients on methadone had lower effective laxative doses than patients on other opioids,13 but the study did not show a change in postopioid rotation, as seen in the present four patients. In conclusion, the reduction in laxative dose and improvement in constipation in these four
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patients following opioid rotation to methadone suggests another option for treatment of refractory constipation. Rotation to methadone may also be beneficial for improved pain control with less risk for opioid-induced neurotoxicity.
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cancer patients: a retrospective study [abstract]. J Pain Symptom Manage 1998;15:S16. 14. Folstein MF, Folstein S, McHugh P. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psych Res 1975;12:189–198.
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1. Curtis EB, Krech R, Walsh TD. Common symptoms in patients with advanced cancer. J Palliat Care 1991;7:25–29.
16. Smith RG, Lewis S. The relationship between digital examination and abdominal radiographs in elderly patients. Age Ageing 1990;9:142–143.
2. Sykes NP. Constipation and diarrhea. In: Doyle D, Hanks G, MacDonald N, eds. Oxford textbook of palliative medicine. Oxford: Oxford University Press, 1998:513–526.
17. Ewing J. Detecting alcoholism: the CAGE questionnaire. J Am Med Assoc 1984;252:1905–1907.
3. Twycross RG, Lack SA. Symptom control in far advanced cancer: pain relief. London: Pitman, 1983:43. 4. Derby S, Portenoy RK. Assessment and management of opioid-induced constipation. In: Portenoy RK, Bruera E, eds. Topics in palliative care, Vol. 1. Oxford: Oxford University Press, 1997:95–112. 5. Mancini I, Bruera E. Constipation in advanced cancer patients: a review. Support Care Cancer 1998;6:356–364. 6. Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain 1997;70:109–115. 7. De Conno F, Groff L, Brunelli C, Zecca E, Ventafridda V, Ripamonti C. Clinical experience with oral methadone administration in the treatment of pain in 196 advanced cancer patients. J Clin Oncol 1996;14:2836–2842. 8. Vigano A, Fan D, Bruera E. Individualized use of methadone and opioid rotation in the comprehensive management of cancer pain associated with poor prognostic indicators. Pain 1996;67:115–119. 9. Bruera E, Watanabe S, Fainsinger RL, Spachynski K, Suarez-Almazor M, Inturrisi C. Custom-made capsules and suppositories of methadone for patients on high-dose opioids for cancer pain. Pain 1995;62:141–146. 10. Daeninck PJ, Bruera E. Opioid use in cancer pain: Is a more liberal approach enhancing toxicity? Acta Anaesthesiol Scand (in press). 11. Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 1997; 223:5–8. 12. Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 1997; 223:5–8. 13. Mancini I, Hanson J, Bruera E. Opioid type and other clinical predictors of laxative dose in advanced
18. Bruera E, Suarez-Almazor M, Velasco A, Bertolino M, Macdonald SM, Hanson J. The assessment of constipation in terminal cancer patients admitted to a palliative care unit: a retrospective review. J Pain Symptom Manage 1994;9:515–519. 19. Bruera E, Macmillan K, Hanson J, MacDonald RN. The Edmonton staging system for cancer pain: preliminary report. Pain 1989;37:203–209. 20. Bruera E, Watanabe S. New developments in the assessment of pain in cancer patients. Support Care Cancer 1994;2:312–318. 21. Bruera E, Schoeller T, Wenk R, MacEachern T, Marcelino S, Suarez-Almazor M, Hanson J. A prospective multi-center assessment of the Edmonton Staging System for cancer pain. J Pain Symptom Manage 1995;10:348–355. 22. Fainsinger R, Schoeller T, Bruera E. Methadone in the management of cancer pain: a review. Pain 1993;52:137–147. 23. Bruera E, Pereira J, Watanabe S, Belzile M, Kuehn N, Hanson J. Opioid rotation in patients with cancer pain: a retrospective comparison of dose ratios between methadone, hydromorphone and morphine. Cancer 1996;78:852–857. 24. Bruera E, Ripamonti, C. Adjuvants to opioid analgesics. In: Patt R, ed. Cancer pain. Philadelphia: J. B. Lippincott, 1993:143–159. 25. Martin LA, Hagen NA. Neuropathic pain in cancer patients: mechanisms, syndromes and clinical controversies. J Pain Symptom Manage 1997;14:99–117. 26. Watanabe S, Bruera E. Corticosteroids as adjuvant analgesics. J Pain Symptom Manage 1994;9: 442–445. 27. Ahmedzai S, Allan E, Fallon M, et al. The TTSfentanyl multicentre study group: transdermal fentanyl in cancer pain. J Drug Dev 1994;6:93–97. 28. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage 1997;13:254–261. 29. Donner B, Zenz M, Tryba M, Strumpf M. Direct
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conversion from oral morphine to transdermal fentanyl: a multicentre study in patients with cancer pain. Pain 1996;64:527–534.
35. Hunt R. Transdermal fentanyl and the opioid withdrawal syndrome [letter]. Palliat Med 1996;10: 347–348.
30. Donner B, Zenz M, Strumpf M. Long-term treatment of cancer pain with transdermal fentanyl. J Pain Symptom Manage 1998;15:168–175.
36. Davies AN. Transdermal fentanyl and the opioid withdrawal syndrome [letter]. Palliat Med 1996;10: 348.
31. Megens AAHP, Artois K, Vermeire J, Meert T, Awouters FHL. Comparison of the analgesic and intestinal effects of fentanyl and morphine in rats. J Pain Symptom Manage 1998;15:253–258.
37. Dole VP, Kreek MJ. Methadone plasma level: sustained by a reservoir of drug in the tissue. Proc Natl Acad USA 1973;70:10.
32. Zenz M, Donner B, Strumpf M. Withdrawal symptoms during therapy with transdermal fentanyl (fentanyl TTS)? J Pain Symptom Manage 1994;9:54–55. 33. Higgs CMB, Vella-Brincat J. Withdrawal with transdermal fentanyl [letter]. J Pain Symptom Manage 1995;10:4–5. 34. Brooks DJ, Travers M, Wooding S, Ahmedzai S. Incidence of morphine withdrawal syndrome on changing between two mu agonists. In: Pain mechanisms and management. A scientific meeting in honor of Sampson Lipton, September 21–23 1995, Liverpool. Liverpool: Pain Research Institute, 1995:73.
38. Mercadante S, Sapio M, Serretta R. Treatment of pain in chronic bowel subobstruction with selfadministration of methadone. Support Care Cancer 1997;5:327–329. 39. Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain 1997;70:99–101. 40. Fitzgibbon DR, Ready LB. Intravenous highdose methadone administered by patient controlled analgesia and continuous infusion for the treatment of cancer pain refractory to high-dose morphine. Pain 1997;73:259–261.
Journal of Pain and Symptom Management 303
Clinical Note
Reduction in Constipation and Laxative Requirements Following Opioid Rotation to Methadone: A Report of Four Cases Paul J. Daeninck, MD, MSc, FRCPC, and Eduardo Bruera, MD Palliative Care Program, Grey Nuns Community Health Centre, and Division of Palliative Care Medicine, University of Alberta, Edmonton, Alberta, Canada
Abstract Constipation is a common symptom in cancer patients, especially in those who are receiving opioid analgesics for pain. Although several articles have recently examined constipation with respect to causation and treatment, little research has been done to elucidate the effects of different opioids on the bowel. Recent research has found that laxative doses may be lower in patients using methadone as an analgesic, but changes in constipation were not measured. We report here on four cases in which patients had improvement in constipation and decreased laxative requirements following opioid rotation to methadone. J Pain Symptom Manage 1999;18:303–309. © U.S. Cancer Pain Relief Committee, 1999. Key Words Cancer pain, opioid rotation, methadone, constipation, laxatives
Introduction Constipation is a common symptom in advanced cancer patients. Studies have demonstrated that 40 to 80% of patients on a palliative care service have constipation.1,2 This proportion increases to $90% when patients are treated with opioids.2,3 Several recent review articles have examined this problem2,4,5 with respect to causation and treatment. However, little research has been done on the differential effects of the various opioid agonists on constipation in the terminally ill cancer patient. Methadone is gaining popularity as an opioid Dr. Daeninck is a McEachern Fellow of the Canadian Cancer Society. Address reprint requests to: Eduardo Bruera, MD, Dept. of Symptom Control and Palliative Care, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA. Accepted for publication: December 8, 1998. © U.S. Cancer Pain Relief Committee, 1999 Published by Elsevier, New York, New York
analgesic because of its widespread availability, low cost, and long half-life, which decreases the need for multiple daily doses.6–9 Its lack of active metabolites is useful for those patients with opioid-induced neurotoxicity,10 and its N-methyl-Daspartate (NMDA) receptor-antagonist activity may be clinically important for patients with neuropathic pain.11,12 However, there have been no reports of improvement in opioid-induced constipation with the use of methadone. A retrospective study has found that laxative doses were significantly lower in patients using methadone as an analgesic,13 but changes in constipation were not measured. We report here on four cases where opioid rotation to methadone was followed by dramatic improvement in constipation and reduced need for laxatives.
Patients Case 1 A 51-year-old woman was admitted for opioid rotation to methadone. She had been diag0885-3924/99/$–see front matter PII S0885-3924(99)00086-X
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nosed with ductal carcinoma of the left breast with nodal involvement 21 months prior to this admission. She pursued alternative therapies until inflammatory changes involving the left breast and chest wall appeared 13 months prior to admission. Metastases to the liver and lung were also found. She underwent segmental breast resection, followed by anthracyclinebased chemotherapy and radiotherapy (RT), which produced a partial response. Within 1 month, RT was again administered to treat the rapid onset of inflammatory changes to the right breast. She was assessed at the Pain and Symptom outpatient clinic 5 months prior to admission and was found to have a mixed (visceral and neuropathic) pain syndrome involving the right thorax, which was thought to be related to the cancer recurrence and subsequent treatment. This was treated with longacting morphine. One week later, rapid dose escalation without pain relief preceded opioid rotation to hydromorphone. One month later, dexamethasone was added, which decreased breakthrough opioid requirements. Three months prior to admission, docetaxel chemotherapy was started for symptomatic relief of increased pain and swelling of both breasts. Symptomatic response was noted but febrile neutropenia with atypical pneumonia and hospitalization after the third dose (6 weeks prior to admission) caused suspension of treatment. She was found to have a malignant pleural effusion, which was drained by thoracocentesis. She was taking 216 mg of long-acting hydromorphone orally twice daily and had taken 7 to 8 breakthrough doses of 48 mg each (total daily dose of approximately 816 mg). The patient’s pain became more severe and she was again assessed in the Pain and Symptom outpatient clinic. Her opioids were increased to 254 mg long-acting hydromorphone and her breakthrough was increased to 80 mg.
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She was admitted to the Tertiary Palliative Care Unit the next day. She admitted to drowsiness, but denied any other symptoms of opioidinduced neurotoxicity. Other symptoms on admission included dyspnea and constipation. Her Mini-Mental Status Examination (MMSE)14 was 30/30 (baseline 28). Her last bowel movement was 2 days prior to admission. The patient’s bowel history prior to opioids was one bowel movement daily. Since starting on the opioid analgesics, she continued to have a bowel movement every 1–2 days. An abdominal radiograph revealed massive constipation: the lumen of the colon was completely occupied by stool (constipation score 12/1215,16). She had been on docusate calcium 240 mg twice daily, sennosides 25.8 mg (3 tablets) twice daily, and bisacodyl 10 mg at night (Table 1). On the day of admission (Day 0), she was switched to methadone, her laxatives were increased, and a cleansing enema was given. However, from Day 2 to 4, the patient had on average 3 large “explosive” bowel movements per day. She refused her laxatives on Day 3 but resumed them soon afterward, and thereafter had an average of 1.4 bowel movements daily. The patient’s pain quickly came under better control, as evidenced by a decrease in her pain scores (Day 0: 3/10; Day 5: 1/10), a decrease in her opioid intake (Table 1), and an increase in her mobility. Her course was complicated by lymphangitic metastasis to the lungs, which caused worsening dyspnea and led to an escalation in the methadone dose for symptomatic control. The patient developed delirium on Day 46 and was rotated to hydromorphone with little change. She died quietly on Day 48.
Case 2 A 60-year-old man was admitted with confusion and poor pain control. He was diagnosed approximately 2 years prior to admission with
Table 1 Changes in Constipation and Laxatives with Rotation to Methadone Patients Case 1 Case 2 Case 3 Case 4
DLD premethadone
DLD postmethadonea
BM/d premethadone
BM/d postmethadonea
MEDD premethadone
MEDD postmethadonea
9 12 9 6.7
6.67 2.3 2.5 1.2
0.5 0.5 0.33 0.33
1.36 0.92 1.5 0.63
4,000 2,400 190 1,220
1,110 208 158 495
Abbreviations: DLD 5 daily laxative dose; BM 5 bowel movements; MEDD 5 morphine equivalent daily dose (in mg). are averages from admission.
a Values
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adenocarcinoma of the prostate, with widespread metastases to his axial skeleton. He received a trial of hormonal treatment, which was unsuccessful in decreasing the spread of bony metastasis or alleviating the pain. In the 3 months preceding admission, he underwent two separate courses of palliative radiotherapy to his pelvis, which gave at best temporary pain relief. One week prior to admission, despite a cycle of palliative chemotherapy, he required admission to another facility for pain control. He was transferred to our Tertiary Palliative Care Unit with a mixed pain syndrome (bony and neuropathic, thought to be due to nerve impingement), which had led to rapid escalation in the dose of hydromorphone and carbamazepine. He also was experiencing confusion and dizziness. Despite frequent bowel movements, he reported feeling constipated. His normal bowel pattern had been daily to every other day while on laxative preparations (Table 1). On admission, he was found to be confused despite having a MMSE of 26/30 (normal baseline of 24). This confusion was thought to be due to opioids, and a rotation from hydromorphone to methadone was initiated. His radiographic constipation score was 11/12, and he was given a cleansing enema, which yielded a large bowel movement. However, over the next 4 days (corresponding to the opioid rotation), he had on average 3 loose bowel movements daily, despite being on tapering dosages of laxatives. For the remainder of his admission, he had on average one bowel movement daily, while on only one-fourth of the previous laxative dose (Table 1). The patient’s confusion improved (MMSE 29/30) and he achieved excellent pain control with the methadone, which was reflected by decreased pain score (1/10, compared with an admission score of 6/10) and an increase in his mobility. He was discharged home after 15 days in hospital, with a 12-fold reduction in opioid dose and a 75% reduction in laxative dose (Table 1).
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developed swelling in the right neck and submandibular regions, and was admitted to her local hospital for investigation. Non-Hodgkin’s lymphoma, intermediate grade, was diagnosed following fine needle and nodal biopsies, and she received anthracycline-containing chemotherapy, as well as intrathecal methotrexate for presumed central nervous system involvement. One month prior to admission, she developed lethargy, a decreased level of consciousness and bilateral leg pain, and was admitted to her local hospital. A computerized tomogram scan of the brain revealed an abnormality in the left hemisphere, likely representing metastatic disease. She continued to have poor pain control and a fluctuating level of consciousness, and was transferred to our Tertiary Palliative Care Unit. On admission, further questioning revealed that the patient had a 40 pack-year smoking history and a history of alcohol abuse (CAGE* questionnaire score of 2/4).17 She was on a transdermal fentanyl patch and was taking hydromorphone orally for breakthrough pain. She also was taking 2 different benzodiazepines. The pain in her legs was felt to be neuropathic in nature. She also had a history of chronic difficulty with constipation and had been on long-term laxatives (Table 1). Examination revealed the patient to be drowsy, with bilateral lower limb weakness and sensory changes in the L3–L4 areas consistent with spinal stenosis. Her MMSE was 23/30 (normal baseline of 26). A constipation score, as obtained from an abdominal radiograph, was 2/ 12. She was hydrated, rotated to methadone, the benzodiazepines were stopped, and further palliative treatment for the underlying malignancy was considered. During the opioid rotation, she developed diarrhea, and had a daily average of 1.7 bowel movements, which decreased only slightly postrotation and with a reduction in laxatives (Table 1). Her MMSE improved to 28/30 on Day 4, and her pain score improved from 6/10 on admission to 1/10 by
Case 3 A 72-year-old woman was transferred from her local hospital for assessment of confusion and poor pain control. She initially presented 6 months prior to admission with diplopia and right-sided Bell’s palsy, for which no cause was identified. Within the following 6 weeks, she
* CAGE is an acronym for a questionnaire screening for alcohol abuse: Cut down on drinking Annoyed by criticism of drinking Guilty about drinking Eye-opener use (alcohol use first thing in the morning)
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Day 7. She was transferred to the local cancer institute for further investigations and consideration of treatment of the lymphoma on Day 7.
Case 4 A 73-year-old man was admitted from home for pain and symptom control, as well as a need for psychosocial support. Approximately 6 months prior to admission, he developed early satiety, weight loss, and postprandial back pain. Subsequent investigations revealed a pancreatic mass on a background of chronic calcific pancreatitis, accompanied by lymphadenopathy and splenic and mesenteric vein thrombosis. Biopsy of the mass was positive for adenocarcinoma. Two months prior to admission, he was assessed in the Pain and Symptom outpatient clinic for abdominal and back pain, anorexia, and constipation. A history of alcohol abuse was obtained (CAGE 2/4), and his MMSE was 30/30. His morphine and bowel medications (sennosides and docusate sodium) were increased, but he refused rotation to methadone at that time. Three weeks prior to admission, he continued to have poorly controlled pain, and developed hallucinations and myoclonus at home. He was assessed by the regional palliative care team, who rotated him to hydromorphone and again increased his laxatives. It was also felt that he may be suffering from depression and/or somatization. He was assessed 2 days prior to admission, at which time it was felt his pain was not improving and hospitalization was recommended. On admission, the patient denied alcohol abuse in the past and had little insight into his current condition. He had not had a bowel movement for 6 days. His MMSE was 28/30 (normal baseline 26) and he was alert and appropriate. His examination was remarkable for abdominal fullness with reproducible pain and a digital exam showed the rectum to be empty of stool. His radiographic constipation score from an abdominal radiograph was 5/12. His hydromorphone was increased and his laxatives continued at the same dose, but by Day 3 he had only one bowel movement and was experiencing hallucinations and myoclonus. Opioid rotation to methadone was initiated and his laxatives were increased. His pain was better controlled, as evidenced by improvement in the pain score and increased mobility. The frequency of his bowel movements did not change despite decreasing and subsequently discontinuing his lax-
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atives (Table 1). His pain remained under good control and his bowel movements were regular until his sudden death on Day 36.
Discussion Constipation is a common symptom in advanced cancer patients, and is reported by up to 90% of those patients treated with opioid analgesics.3 Advanced cancer patients have many risk factors, including structural abnormalities, metabolic disturbances, neurologic disorders, advanced age, inactivity, poor intake, and drug side effects.4,5 However, constipation is often not assessed, and this leads to inadequate treatment. A full assessment should include a history of bowel movements, both before and after opioid therapy, the symptoms due to constipation, and a physical examination including a digital rectal exam. A retrospective review of admissions to our palliative care unit18 found that 59% of patients did not undergo a rectal examination and there was minimal and/or insufficient documentation by both the medical and nursing staff regarding the symptoms related to constipation. In addition, simple bedside questions and clinical maneuvers may be poor predictors for the diagnosis of constipation.18 The diagnosis can be confirmed using the radiographic constipation score.15,16,18 The routine use of this score, as seen in these four cases, helps to identify those patients who have severe constipation and require prompt treatment. The score is determined by the assessment of the amount of stool in each of the four abdominal quadrants using the following system: 0 5 no stool, 1 5 stool occupying ,50% of the lumen of the colon, 2 5 stool occupying .50% of the lumen, and 3 5 stool completely occupying the lumen. The colon is scored out of 12, and a score .7/12 indicates severe constipation requiring immediate treatment.5,18 Several laxative preparations are available for the treatment of constipation. However, the different modes of action and the lack of equivalency tables makes it difficult to compare these medications. Recent reviews recommend a combination of senna and docusate as the initial treatment for opioid-induced constipation, with the addition of lactulose and magnesium sulfate for relatively refractory cases. For severe constipation, a combination of oral
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laxatives, rectal suppositories, and enemas may be needed.2,4 To compare these four cases, 8.6 mg senna, 100 mg docusate sodium, 5 mg bisacodyl, and 15 ml of lactulose were each considered as one unit of laxative.13 Thus a patient on two tablets of senna and two capsules of docusate had a daily laxative dose of 4 units. All of the reported patients were taking at least 6 units of laxatives daily, usually with poor results (Table 1). After methadone rotation, each patient was taking less laxatives, with more frequent bowel movements. Each of our patients required opioid rotation for opioid-induced neurotoxicity or dose escalation. In each case, methadone was the opioid of choice for several reasons. First, all of the patients had used several opioid analgesics with the result being either poor long-term pain control or toxicity. Three of the patients required high doses of opioids (.1200 morphine equivalent daily dose), two had previous substance abuse histories, and at least 2 were felt to have psychologic distress (somatization), all of which are independent risk factors for poor pain control.19–21 Recent reports of NMDA receptor antagonist activity by methadone may be clinically important for the treatment of neuropathic pain,11,12 which was found in 3 of the 4 patients. Methadone has reduced cross-tolerance to other opioid agonists, as well as high potency (equianalgesic conversion of 10 mg morphine to 1 mg methadone6,23), which may also account for the reduction of the morphineequivalent daily dose (MEDD).5,22,23 Neuropathic pain syndromes, as seen in 3 of our 4 patients, often are treated with opioids as well as a variety of adjuvant medications.24,25 Several of these commonly used drugs may in fact worsen constipation in advanced cancer patients. Medications with anticholinergic activity (antidepressants, antispasmodics, and phenothiazines), anticonvulsants (e.g., carbamazepine), and antihypertensives (e.g., clonidine) have been associated with constipation.5 The approach of our group is to maximize the benefits of opioid analgesics, using those that may have intrinsic NMDA receptor activity (methadone)11,12 and make liberal use of corticosteroids, which when used for short periods to achieve pain control are not associated with severe side effects.26 Why did our patients have such remarkable
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changes in their bowel function following rotation to methadone? The overall reduction in the MEDD, due to the incomplete opioid cross-tolerance, may have caused reduced opioid effects on the bowel13 but continued to give good pain relief. The use of fentanyl for the treatment of cancer pain has also been associated with less gastrointestinal side effects, including constipation,27–31 but there have been several case reports of patients demonstrating withdrawal symptoms after rotation to transdermal fentanyl.32–36 These symptoms included abdominal cramping or pain, diarrhea, nausea, anxiety, shivering, changes in heart rate and blood pressure, and formication. Our patients had diarrhea and two complained of transient abdominal cramping, but no other evidence of opioid withdrawal. Like fentanyl, methadone is also lipophilic and is highly distributed to the body tissues. This allows a peripheral reservoir effect37 which may allow for decreased maintenance doses. These smaller doses may exert less activity on opioid receptors in the gastrointestinal tract and cause an incomplete “withdrawal syndrome” to occur. An alternative explanation may be that methadone, like fentanyl, may have a different affinity for the opioid receptors in the gut, thus causing less gastrointestinal symptoms.35,36 A report of oral patient-controlled methadone which was effective in managing abdominal pain without worsening the known chronic partial bowel obstruction in two advanced cancer patients suggests that methadone may be useful in patients with an alteration in bowel motility.38 Opioid rotation for toxicity is not a new concept, and several case series and retrospective reviews are present in the literature.10,39,40 Rotation to alternative opioids usually helps in the resolution of neurotoxic side effects and may allow a reduction in the analgesic dose. However, no reports of opioid rotation having beneficial effects for constipation exist. A retrospective study of the clinical predictors of laxative dose in advanced cancer patients revealed that patients on methadone had lower effective laxative doses than patients on other opioids,13 but the study did not show a change in postopioid rotation, as seen in the present four patients. In conclusion, the reduction in laxative dose and improvement in constipation in these four
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patients following opioid rotation to methadone suggests another option for treatment of refractory constipation. Rotation to methadone may also be beneficial for improved pain control with less risk for opioid-induced neurotoxicity.
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cancer patients: a retrospective study [abstract]. J Pain Symptom Manage 1998;15:S16. 14. Folstein MF, Folstein S, McHugh P. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psych Res 1975;12:189–198.
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