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Custom-made suppositories of methadone for severe cancer pain
372
til. 7Jvo_ 6August 1992
Journal of Pain und S&qbtomMatug&
Palliative Care Rounds
ade Suppositories of
for
Severe Cancer Pain Eduardo Bruera, MD, Teresa Schoeller, MD, Robin L. Fainsinger, MD, and Connie Kastelan, BScPhann Palliative Care Avgram (E-B., T.S., RX), Eahonlon, Alberkz, Canada
and Phmnaq Department (C.K.), Edmonton GeneralHospital,
Case Report A 7%yr-old man with carcinoma of the prostate was admitted to the Palliative Care Unit. He had extensive bony metastases and had been treated with hormones and palliative radiotherapy on several occasions. He also had profound pancytopenia due to bone marrow i&‘&ration and a previous dose of radioactive strontium, which had also been administered for bone pain. His main problems upon admission were severe bone pain, dysphagia and nausea, asthenia, and mild drowsiness. Treatment on admission consisted of longacting morphine 300 mg every 8 hr and morphine 75 mg as required for breakthrough pain. During the first 24 hr of his admission, he received 1500 mg of oral morphine, which did not improve pain control but worsened nausea and sedation. As a consequence, morphine was discontinued, and he was administered hydromorphone 20 mg subcutaneously every 4 hr, with 20 mg every hour as needed for brealc-
This section of the Joumal ofPain and SymptumAdanagement publishes transcribed versions of Palliative Care Rounds. Authors interested in submitting materials to this section should send manuscripts to Eduardo Bruera, MD, c/o Jotcmal Pain aad @q&m Manqetnent. Questions and comments on the cases published in this section should also be addressed to Dr. Bruera.
of
Q US. Cancer Pain Relief Committee, 1992 Published by F&evier, New York, New York
through pain, using the Edmonton Injector. During the following 24 hr, he received a total of 7 extra doses of analgesic and the dose of hydromorphone was increased to 40 mg every 4 hr. Bleeding developed at the sites of injection, and this necessitated a change of the needle more than once daily. As a result, he was started on methadone suppositories 50 mg every 6 hr on day 4 of admission. On day 6, the methadone dose was increased to a lOO-mg suppository every 6 hr, and the hydromorphone was decreased to 32 mg subcutaneously every 4 hr. Over the next 4 days, the methadone was progressively increased to a total of 300 mg every 6 hr, and the hydromorphone was progressively decreased and finally discontinued. A dose of 24 mg subcutaneously of hydromorphone was allowed each hour as needed for breakthrough pain. On day i2, the subcutaneous route was discontinued entirely, and supplemental doses of hydromorphone were administered by oral route. On day 13, the dose was decreased to 200 mg of methadone suppositories every 8 hr because of excellent pain control and persistent drowsiness. Over the next 3 weeks, the dose of rectal methadone was increased to a maximum of 808 mg every 6 hr. The patient remained in moderately good pain control most of the time, except for occasional episodes during which pain
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1. Pain controland methadonedose.MMSS, Mini-Mental StateQuestionnaire.
suddenly increased. At these times of increased pain, the dose of methadone was escabted (Figure 1). Because of persistent sedation, ;lich did not respond readily to the decrease in dose without rebound pain, the patient was started on methylphenidate 15 mg a day. The dose of methylphenidate was progressively increased to a total of 40 mg a day over the next 3 weeks. During the course of his admission, the patient enjoyed home passes and visitswith relatives. His cognitive status, as assessed by the Mini-Mental State Questionnaire, was normal (X4) during his entire admissi0n.l The patient died on day 44 in good symptom control.
This patient had severe pain due to disseminated bone metastases. The presence of dysphagia, nausea, and vomiting made adequate analgesia using the oral route impossible. Other studies have suggested that the majority of patients with terminal cancer will require alternate routes of opioid administration before death.*s The subcutaneous route has been shown to be a safe and effective alternative route of administration.4 Umortunately, the presence of severe pancytopenia resulted in frequent
bleeding and short site duration in our patient. Preliminary evidence suggests that morphine and other opioids can be administered rectally. Acceptable absorption occurs with this route even if considerable interindividual variation exists.5 However, there are no controlled clinical trials that have assessed the long-term use of recta! morphine or other rectal opioids for cancer pain. e main problems with the commercially available preparations of morphine, hydromorphone, and codeine are the small dosages available (in Canada, morphine suppositoriesare available in lo-mg, 20-mg, and 30-mg preparations). These formulations make it impossible to treat patients who require a high daily dosage. Another problem is the discomfort potentially associated with the administration of suppositories every 4 hr. Methadone is a synthetic opioid that has a very long elimination halGlife.6 It is also quite inexpensive, and this may increase its appeal for patients receiving massive doses of opioids or for those in developing countxies.7 Methadone has an unpredictable h&life, however, and is potentially dangerous in patients who are not tolerant to opioids.s It also causes considerable local irritation that precludes subcutaneous administration.7
374
Bmera et al.
&cause of its long half-life, methadone suppositories could potentially be administered every 12 or 8 hr with good tolerance. In our patient, we chose a more frequent administration because of our lack of knowledge about the local rectal tolerance to very high doses of methadone. After prolonged administration of a very high dose, there was no evidence of rectal irritation or rectal pain. The suppositories were custom made in our pharmacy by dissolving methadone powder in a base containing esterified glycol stearate and hydrogenated vegetable oil. Suppositories could be prepared in approximately 15 min and could be administered after solidifying in a reftigerator after l-2 hr. The total cost of 40 days of treatment with methadone suppositories in our patient was $277.00 Canadian. This cost could be compared with an estimated cost of $2596.00 Canadian incurred by the use of subcutaneous hydromorphone during the same period. Subcutaneous infusion also produces additional cost-related infusion devices or supplies that were also not required by our patient. Our patient’s cognitive fimction was assessed every 3 days using the Mini-Mental State Questionnaire and was found to be normal during the length of his admission. His pain control, overall, was moderately good, but was characterized by sudden increases in pain that required major increases in the opioid dose. After the increase, pain returned to good control for a number of days. This pattern occurred on five occasions during the patient’s admission (Figure 1). The reason for these episodes is uncertain. It might be related to occasional erratic absorption of the preparation or to the nature of the patient’s pain syndrome. The need for massive increase in the daily total dose of methadone and the rapid improvement in pain after each dose increase indicate that rapid tolerance was occurring. The final daily dose of rectal methadone was 3200 mg, whereas the initial dose was 200 mg. Using our previously described method for the estimation of da$y percentage increase in dose,g the mean increase in daily dose was 34.5%. This increase can be compared with our previous expetiep,:.::, in which mean daily dose increase was only 2.4% f
Kl7JVb. 6Argu.d I992
1.6%, and only 15% required a daily increase of more than 5% of the initial dose.9 Thus, our patient was atypical in his rapid dose escalation, which is now recognized as a poor prognostic factor for pain control. lo Our patient tolerated frequent and massive increases in the dose of methadone with excellent cognitive status. These massive increases could only take place with the use of custom-made suppositories (the final dose was 16 times higher than the initial dose). Future research should try to better characterize the role of methadone in the treatment of cancer pain, particularly when the rectal route is used.
1. Folstein MF, Folstein S, McHugh PR. ‘Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189198. 2. Coyle N, Adelhardt J, Foley KM, Portenoy RK.. Character of terminal illness in the advanced cancer patient: pain and other symptoms during the last four weeks of life. J Pain Symptom Manage 1990;5:83-93. 3. Bruera E, Macmillan K, Hanson J, MacDonald RN. Palliative care in a cancer center: results in 1984 vs 1987. J Pain Symptom Manage 1990;5:1-5. 4. Bruera E. Subcutaneous administration of opioids in the management of cancer pain. In: Foley K, Ventafridda V, eds. Advances in pain research and therapy, vol 16. New York: Raven, 1990:203-218. 5. Ripamonti C, Bruera E. Rectal, buccal, and sublingual narcotics for the management of cancer pain. J PalIiat Care 1991;7:30-35. 6. Intunisi CE, Colbum WA, Kailko RF, et al. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pbarmacol Ther 1987;41:392-401. 7. Bruera E, Fainsinger R, Moore M, Thibault E, Spoldi V, Ventafidda V. Clinical note: local toxicity with subcutaneous methadone-experience of two centers. Pain 1991;453141-143. 8. Ettinger DS, Vitale PJ, Trump DL Important clinical pharmacological considerations in the use of methadone in cancer patients. Cancer Treat Rep 1979;63:457-459. 9. Bruera E, Chadwick S, Brenneis C, et ai. Use of the subcutaneous route for &e administration of narcotics in patients with cancer pain. Cancer 1988;62:407-411. 10. Bruera E, Macmillan K, Hanson J, MacDonald RN. The Edmonton Staging System for cancer pain: preliminary report. Pain 1989;37:203-209.
til. 7Jvo_ 6August 1992
Journal of Pain und S&qbtomMatug&
Palliative Care Rounds
ade Suppositories of
for
Severe Cancer Pain Eduardo Bruera, MD, Teresa Schoeller, MD, Robin L. Fainsinger, MD, and Connie Kastelan, BScPhann Palliative Care Avgram (E-B., T.S., RX), Eahonlon, Alberkz, Canada
and Phmnaq Department (C.K.), Edmonton GeneralHospital,
Case Report A 7%yr-old man with carcinoma of the prostate was admitted to the Palliative Care Unit. He had extensive bony metastases and had been treated with hormones and palliative radiotherapy on several occasions. He also had profound pancytopenia due to bone marrow i&‘&ration and a previous dose of radioactive strontium, which had also been administered for bone pain. His main problems upon admission were severe bone pain, dysphagia and nausea, asthenia, and mild drowsiness. Treatment on admission consisted of longacting morphine 300 mg every 8 hr and morphine 75 mg as required for breakthrough pain. During the first 24 hr of his admission, he received 1500 mg of oral morphine, which did not improve pain control but worsened nausea and sedation. As a consequence, morphine was discontinued, and he was administered hydromorphone 20 mg subcutaneously every 4 hr, with 20 mg every hour as needed for brealc-
This section of the Joumal ofPain and SymptumAdanagement publishes transcribed versions of Palliative Care Rounds. Authors interested in submitting materials to this section should send manuscripts to Eduardo Bruera, MD, c/o Jotcmal Pain aad @q&m Manqetnent. Questions and comments on the cases published in this section should also be addressed to Dr. Bruera.
of
Q US. Cancer Pain Relief Committee, 1992 Published by F&evier, New York, New York
through pain, using the Edmonton Injector. During the following 24 hr, he received a total of 7 extra doses of analgesic and the dose of hydromorphone was increased to 40 mg every 4 hr. Bleeding developed at the sites of injection, and this necessitated a change of the needle more than once daily. As a result, he was started on methadone suppositories 50 mg every 6 hr on day 4 of admission. On day 6, the methadone dose was increased to a lOO-mg suppository every 6 hr, and the hydromorphone was decreased to 32 mg subcutaneously every 4 hr. Over the next 4 days, the methadone was progressively increased to a total of 300 mg every 6 hr, and the hydromorphone was progressively decreased and finally discontinued. A dose of 24 mg subcutaneously of hydromorphone was allowed each hour as needed for breakthrough pain. On day i2, the subcutaneous route was discontinued entirely, and supplemental doses of hydromorphone were administered by oral route. On day 13, the dose was decreased to 200 mg of methadone suppositories every 8 hr because of excellent pain control and persistent drowsiness. Over the next 3 weeks, the dose of rectal methadone was increased to a maximum of 808 mg every 6 hr. The patient remained in moderately good pain control most of the time, except for occasional episodes during which pain
0885-3924/92/85.00
30
10 22
a 0
Fig.
20
22
22
22
I
I
6
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28 I
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1. Pain controland methadonedose.MMSS, Mini-Mental StateQuestionnaire.
suddenly increased. At these times of increased pain, the dose of methadone was escabted (Figure 1). Because of persistent sedation, ;lich did not respond readily to the decrease in dose without rebound pain, the patient was started on methylphenidate 15 mg a day. The dose of methylphenidate was progressively increased to a total of 40 mg a day over the next 3 weeks. During the course of his admission, the patient enjoyed home passes and visitswith relatives. His cognitive status, as assessed by the Mini-Mental State Questionnaire, was normal (X4) during his entire admissi0n.l The patient died on day 44 in good symptom control.
This patient had severe pain due to disseminated bone metastases. The presence of dysphagia, nausea, and vomiting made adequate analgesia using the oral route impossible. Other studies have suggested that the majority of patients with terminal cancer will require alternate routes of opioid administration before death.*s The subcutaneous route has been shown to be a safe and effective alternative route of administration.4 Umortunately, the presence of severe pancytopenia resulted in frequent
bleeding and short site duration in our patient. Preliminary evidence suggests that morphine and other opioids can be administered rectally. Acceptable absorption occurs with this route even if considerable interindividual variation exists.5 However, there are no controlled clinical trials that have assessed the long-term use of recta! morphine or other rectal opioids for cancer pain. e main problems with the commercially available preparations of morphine, hydromorphone, and codeine are the small dosages available (in Canada, morphine suppositoriesare available in lo-mg, 20-mg, and 30-mg preparations). These formulations make it impossible to treat patients who require a high daily dosage. Another problem is the discomfort potentially associated with the administration of suppositories every 4 hr. Methadone is a synthetic opioid that has a very long elimination halGlife.6 It is also quite inexpensive, and this may increase its appeal for patients receiving massive doses of opioids or for those in developing countxies.7 Methadone has an unpredictable h&life, however, and is potentially dangerous in patients who are not tolerant to opioids.s It also causes considerable local irritation that precludes subcutaneous administration.7
374
Bmera et al.
&cause of its long half-life, methadone suppositories could potentially be administered every 12 or 8 hr with good tolerance. In our patient, we chose a more frequent administration because of our lack of knowledge about the local rectal tolerance to very high doses of methadone. After prolonged administration of a very high dose, there was no evidence of rectal irritation or rectal pain. The suppositories were custom made in our pharmacy by dissolving methadone powder in a base containing esterified glycol stearate and hydrogenated vegetable oil. Suppositories could be prepared in approximately 15 min and could be administered after solidifying in a reftigerator after l-2 hr. The total cost of 40 days of treatment with methadone suppositories in our patient was $277.00 Canadian. This cost could be compared with an estimated cost of $2596.00 Canadian incurred by the use of subcutaneous hydromorphone during the same period. Subcutaneous infusion also produces additional cost-related infusion devices or supplies that were also not required by our patient. Our patient’s cognitive fimction was assessed every 3 days using the Mini-Mental State Questionnaire and was found to be normal during the length of his admission. His pain control, overall, was moderately good, but was characterized by sudden increases in pain that required major increases in the opioid dose. After the increase, pain returned to good control for a number of days. This pattern occurred on five occasions during the patient’s admission (Figure 1). The reason for these episodes is uncertain. It might be related to occasional erratic absorption of the preparation or to the nature of the patient’s pain syndrome. The need for massive increase in the daily total dose of methadone and the rapid improvement in pain after each dose increase indicate that rapid tolerance was occurring. The final daily dose of rectal methadone was 3200 mg, whereas the initial dose was 200 mg. Using our previously described method for the estimation of da$y percentage increase in dose,g the mean increase in daily dose was 34.5%. This increase can be compared with our previous expetiep,:.::, in which mean daily dose increase was only 2.4% f
Kl7JVb. 6Argu.d I992
1.6%, and only 15% required a daily increase of more than 5% of the initial dose.9 Thus, our patient was atypical in his rapid dose escalation, which is now recognized as a poor prognostic factor for pain control. lo Our patient tolerated frequent and massive increases in the dose of methadone with excellent cognitive status. These massive increases could only take place with the use of custom-made suppositories (the final dose was 16 times higher than the initial dose). Future research should try to better characterize the role of methadone in the treatment of cancer pain, particularly when the rectal route is used.
1. Folstein MF, Folstein S, McHugh PR. ‘Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189198. 2. Coyle N, Adelhardt J, Foley KM, Portenoy RK.. Character of terminal illness in the advanced cancer patient: pain and other symptoms during the last four weeks of life. J Pain Symptom Manage 1990;5:83-93. 3. Bruera E, Macmillan K, Hanson J, MacDonald RN. Palliative care in a cancer center: results in 1984 vs 1987. J Pain Symptom Manage 1990;5:1-5. 4. Bruera E. Subcutaneous administration of opioids in the management of cancer pain. In: Foley K, Ventafridda V, eds. Advances in pain research and therapy, vol 16. New York: Raven, 1990:203-218. 5. Ripamonti C, Bruera E. Rectal, buccal, and sublingual narcotics for the management of cancer pain. J PalIiat Care 1991;7:30-35. 6. Intunisi CE, Colbum WA, Kailko RF, et al. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pbarmacol Ther 1987;41:392-401. 7. Bruera E, Fainsinger R, Moore M, Thibault E, Spoldi V, Ventafidda V. Clinical note: local toxicity with subcutaneous methadone-experience of two centers. Pain 1991;453141-143. 8. Ettinger DS, Vitale PJ, Trump DL Important clinical pharmacological considerations in the use of methadone in cancer patients. Cancer Treat Rep 1979;63:457-459. 9. Bruera E, Chadwick S, Brenneis C, et ai. Use of the subcutaneous route for &e administration of narcotics in patients with cancer pain. Cancer 1988;62:407-411. 10. Bruera E, Macmillan K, Hanson J, MacDonald RN. The Edmonton Staging System for cancer pain: preliminary report. Pain 1989;37:203-209.