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Respiratory depression in a patient receiving oral methadone for cancer pain
vo~ lo No. 51,,~ 1995
lo,,,~t o/Cain ana S~,.pto,. Ma,~g~,~t 401
Palliative Care Rounds
Respiratory Depression in a Patient Receiving Oral Methadone for Cancer Pain Gordon Hunt, MD, and Eduardo Bruera, MD Palliative Care Program, Edmonton General Hospital, Edmonton, Canada
Abgcraet
Methadone is a synthetic opioid with excellent oral bioavailability, variable, but long duration of action and extremely low cost. Our group has found that methadone is well tolerated in patients with diffwult pain syndromes who are receiving high dose opioids. Howeveg, because of high interpersonal variation in oavailability and the long duration of action of this drug, treatments should be highly personalized, We report on a 61 year old cancer patient who was switchedfrom 84 rag~day of subcutaneous hydronur@hone to 90 mg/day of oral methadone. On this dose, she d e , loped respiratory depression and non-cardiogenic pulmonary edema that responded to subcutaneous naloxone and methadone discontinuation. Our findings suggest that standard eqularudgesic tables are unreliable for methadone titration. Switchovers should take place slowly and in a personalized fashion. J Pain Symptom Manage 1995;10:401-404.
Methadone, canceg, pain, respiratory depression
Introduction The majority of cancer patients require opioid analgesics before death. In some of those patients, the responsiveness to both morphine and hydromorphone may decrease over time, making pain control difficult. 1 Methadone is a synthetic opioid with excellent oral bioavailability, variable but long duration of action, and extremely low cost. ~ Our group has found that methadone is well tolerated in patients with difficult pain syndromes who are receiving high doses of opioids? Because of the high individual variation in bioavailability and the long duration of action of this drug,
Address reprint requests to: Eduardo Bruera, MD, Palliative Care Program, Edmonton General Hospital, 11111 Jasper Avenue, Edmonton, Alberta, Canada TSK 0L4. Acceptedfor publication: December20, 1994. © U.S. Cancer Pain ReliefCommittee, 1995 Published by Elsevier, NewYork, NewYork
however, treatments should be highly personalized. To illustrate the potential difficulties that may arise with methadone therapy, we report the case of a patient who developed severe sedation, respiratory depression, and noncardiogenic pulmonary edema after several days of treatment with a low equianalgesic dose of oral methadone.
Case R e p o r t A 61-year-old woman with a 30 pack-year history of smoking was admitted to the Palliative Care Unit (PCU) at the Edmonton General Hospital (EGH) with bone metastases from a primary bronchogenic carcinoma. Six' months prior to her admission, she had presented with severe left hip pain which, on bone scintigram, was compatible with widely disseminated bony metastases involving skull, spine, ribs, pelvis, and femora. Computerized tomography (CT) 0885-3924/95/$9.50 SSDI 0885-3924(95)00021@
402
Hunt and Bruera
of the thorax revealed a right-sided neoplasm with mediastinal lymphadenopathy and a pleural effusion. One month prior to admission, she was given palliative radiotherapy to the left hip for worsening pain. Repeat bone scintigram at that time showed progression of the disease. She was requiring increasing doses of hydromorphone, which resulted in drowsiness, myoclonicjerks, hallucinations, and nausea. On admission to the PCU, she was in pain from her left hip, but denied hallucinations. She had psychomotor agitation and occasional myodonicjerks. Her vital signs were normal and her lungs were clear on examination. She scored 28/30 on the Folstein Mini-Mental Status Examination (MMSE) 4 and 0 / 4 on the CAGE questionnaire screening for alcoholism. 5 She had been on morphine until 2 weeks before admission, when she was changed to hydromorphone 84 rag/day subcutaneously because of hallucinations. As she was now experiencing toxicity from the hydromorp h o n e as well, we decided to change the opioid to methadone. The standard conversion rate of subcutaneous (SC) hydromorphone to oral morphine is 1:20. This made her morphine equivalent daily dose (MEDD) equal to 1680 mg of oral morphine. The literature to date continues to favor a 1:1 conversion of parenteral morphine to parenteral methadone, although there is growing debate about this issue. We are currently using a dose ratio of 5:1. Because of her r e c e n t adverse reactions to opioids, we decided to give cautiously a much lesser dose of methadone (30 mg orally every 8 hr). For the first 2 days, she remained somewhat agitated without any serious complaints of pain. She never marked her visual analogue higher than 4/10 after her first day in the PCU. The staff noticed intermittent episodes of confusion and disinhibited behavior, which were mild at first, but when her oxygen saturations were measured, they were found to be marginally low in the range of 88%--89%, and she was started on O~ to keep her saturations above 90%. A C T of the head was performed without contrast and was reported to be normal. Over the next 3 days, she had more frequent episodes of delirium, with extreme listlessness and bizarre behavior. Her methadone dose was tapered after day 4 and discontinued on day 8. By day 8, she was significantly hypox-
Vol. I 0 No. 5 Ju!y 1995
emic with apneic episodes. Her end-tidal CO2 levels were measured at 35 mm Hg while her respiratory rate (RR) was 6 per rain and her O~ saturation by pulse oximeter was 66%. Naloxone, 0.4 mg, was given SC, and the RR i n c r e a s e d to 26 and the end-tidal CO~ dropped to 20 mm Hg. Her chest radiograph showed interstitial and intraalveolar fluid compatible with n o n c a r d i o g e n i c p u l m o n a r y edema. Her white blood cells decreased from 14.3 on admission to 12.2 on day 9. Througho u t this whole e p i s o d e , h e r lung fields remained clear to auscultation, and there were no signs of congestive heart failure. By day 10, her diffuse interstitial and alveolar pattern had improved markedly on the chest radiograph. Her cognitive status, endtidal CO~ levels, and hypoxia also started to improve. However, she developed consolidation in both bases, and subsequent blood and sputum cultures demonstrated H. influenzae. Her pneumonia resolved rapidly following treatment with ciprofloxacin. Because of recurrent pain, she was restarted on subcutaneous hydromorphone at a much lower equianalgesic dose.
D/sruss/on Our patient presented with severe pain that responded poorly to doses of morphine and hydromorphone associated with severe toxicity. After a switch to oral methadone at a dose approximately 10 times lower than the equianalgesic dose, progressive confusion, sedation, and respiratory depression developed. While respiratory depression and confusion due to methadone have been described before, 2 our patient is unique in the fact that this toxicity presented several days after the patient was started on a very low equianalgesic dose. Due to the presence of delirium, the dose of methadone was reduced. It is clear that a complete discontinuation of the dose might have been a better management, particularly since pain appeared to be under excellent control. As the toxic event was observed days after starting methadone, it is very likely that accumulation of the drug took place. It is impossible in the absence of methadone plasma levels, however, to say if the event was related more to pharmacokinetic or pharmacodynamic factors. Our observations suggest that
VoL 10 No. 5 gu~ 1995
Respirator7 Depression and Methadone
100
7O
i~
°
N
6O
1oo contused
3o
I'.
2°
?
10
6 5 4 3
2 1
d
T "~ ~ ; ~ ~ ; ; ~ 101112131415 ...... 1~11~'I'11'+~o
F c
g
aoo
0
[ MEI'HADONE J
100
I
HYDROMORPHONE
----
,; ~, ~ Mini-mental status exam I 2S (out o! 30)
~ :
2S
-- .
.
.
.
]
.
~--,-,
, , , , , , , , , , 9 10 11 12131415 1617 1819 20 Time in Olys 0 24 2S J
Fig. 1.Changes in the visual analogue scale, oxygen requirements, equianalgesic dose of morphine and the Mini-Mental State Examination during the course of admission. patients started on m e t h a d o n e should be closely monitored for at least 1-2 weeks after starting treatment. The presence of noncardiogenic pulmonary edema complicated the patient's management. While n o n c a r d i o g e n i c p u l m o n a r y edema has been frequently associated with opioid overdose in addicts, it has only been recognized recently as one of the complications of opioid therapy of cancer pain. 6 Our patient had the features of acute onset of severe hypoxia and radiographic changes compatible with pulmonary edema in the absence of congestive heart failure. Both the hypoxemia and the radiological changes resolved quickly after the discontinuation of methadone (Figure 1).
403
While pain reappeared during day 3 after the episode of respiratory depression, it was managed very successfully thereafter with a dose of hydromorphone that was significantly lower than the dose of hydromorphone required to control the pain before the change to methadone. Although the reason for this decrease in requirement is unclear, one possible explanation is that there was very limited cross-tolerance between methadone and hydromorphone in this patient. This would explain both the development of respiratory depression on a relatively low methadone dose and the ability of the patient to regain responsiveness to hydromorphone after having received no hydromorphone for 10 days (the duration of her methadone treatment). An alternative explanation could be a decrease in baseline pain as a delayed effect of radiation therapy. This is unlikely as the patient had experienced increasing pain during the 4 weeks following the completion of radiotherapy. Another explanation could be the presence of circulating hyperalgesic metabolites of morphine or hydromorphone.7's Methadone is an effective and low-cost opioid analgesic. Until we gain better understanding on its toxicity and issues of equianalgesic doses in tolerant patients, however, its use should be limited to groups with expertise in cancer pain management. Because of the high interindividual variability in equianalgesic doses and the lack of reliable equianalgesic doses, titration should take place slowly and in a personalized fashion.
RefeTt~e$ 1. Portenoy RK, Foley KM, Inturrisi CE. The nature of opioid responsiveness and its implications for neuropathic pain. Pain 1990; 43:273-286. 2. Fainsinger R, Schoeller T, Bruera E. Methadone in the management of cancer pain: a review. Pain 1993; 52:137-147. 3. Bruera E, Velasco A, Fainsinger R, Miller M, Spachynski K, Inturrisi C. Custom made suppositories of methadone (CMSM): an effective and simple alternative in patients (PTS) receiving high dose parenteral opioids (O). Proc of ASCO 1993;12:457. 4. Folstein MF, Folstein S, McHugh PR. "Minimental state": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198. 5. Buchsbaum DG, Buchanan RG, Centor RM, et al. Screening for alcohol abuse using CAGE scores
404
Hunt and Bruera
VoL 10 No. 5 ~uly 1995
and likelihood ratios. Ann Intern Med 1991;115: 774-777.
glucuronide: a potent antagonist of morphine analgesia. Life Sci 1990;47:579-585.
6. Bruera E, Miller MJ. Non-cardiogenic pulmonary edema after narcotic treatment for cancer pain. Pain 1989; 39:297-300. 7. Smith MT, Watt JA, Cramond T. Morphine-3-
8. Yaksh TL, Harry GJ. Pharmacology of the ailodynia in rats evoked by high dose intrathecal morphine. J Pharmacol Experimental Ther 1988;244: 501-507.
lo,,,~t o/Cain ana S~,.pto,. Ma,~g~,~t 401
Palliative Care Rounds
Respiratory Depression in a Patient Receiving Oral Methadone for Cancer Pain Gordon Hunt, MD, and Eduardo Bruera, MD Palliative Care Program, Edmonton General Hospital, Edmonton, Canada
Abgcraet
Methadone is a synthetic opioid with excellent oral bioavailability, variable, but long duration of action and extremely low cost. Our group has found that methadone is well tolerated in patients with diffwult pain syndromes who are receiving high dose opioids. Howeveg, because of high interpersonal variation in oavailability and the long duration of action of this drug, treatments should be highly personalized, We report on a 61 year old cancer patient who was switchedfrom 84 rag~day of subcutaneous hydronur@hone to 90 mg/day of oral methadone. On this dose, she d e , loped respiratory depression and non-cardiogenic pulmonary edema that responded to subcutaneous naloxone and methadone discontinuation. Our findings suggest that standard eqularudgesic tables are unreliable for methadone titration. Switchovers should take place slowly and in a personalized fashion. J Pain Symptom Manage 1995;10:401-404.
Methadone, canceg, pain, respiratory depression
Introduction The majority of cancer patients require opioid analgesics before death. In some of those patients, the responsiveness to both morphine and hydromorphone may decrease over time, making pain control difficult. 1 Methadone is a synthetic opioid with excellent oral bioavailability, variable but long duration of action, and extremely low cost. ~ Our group has found that methadone is well tolerated in patients with difficult pain syndromes who are receiving high doses of opioids? Because of the high individual variation in bioavailability and the long duration of action of this drug,
Address reprint requests to: Eduardo Bruera, MD, Palliative Care Program, Edmonton General Hospital, 11111 Jasper Avenue, Edmonton, Alberta, Canada TSK 0L4. Acceptedfor publication: December20, 1994. © U.S. Cancer Pain ReliefCommittee, 1995 Published by Elsevier, NewYork, NewYork
however, treatments should be highly personalized. To illustrate the potential difficulties that may arise with methadone therapy, we report the case of a patient who developed severe sedation, respiratory depression, and noncardiogenic pulmonary edema after several days of treatment with a low equianalgesic dose of oral methadone.
Case R e p o r t A 61-year-old woman with a 30 pack-year history of smoking was admitted to the Palliative Care Unit (PCU) at the Edmonton General Hospital (EGH) with bone metastases from a primary bronchogenic carcinoma. Six' months prior to her admission, she had presented with severe left hip pain which, on bone scintigram, was compatible with widely disseminated bony metastases involving skull, spine, ribs, pelvis, and femora. Computerized tomography (CT) 0885-3924/95/$9.50 SSDI 0885-3924(95)00021@
402
Hunt and Bruera
of the thorax revealed a right-sided neoplasm with mediastinal lymphadenopathy and a pleural effusion. One month prior to admission, she was given palliative radiotherapy to the left hip for worsening pain. Repeat bone scintigram at that time showed progression of the disease. She was requiring increasing doses of hydromorphone, which resulted in drowsiness, myoclonicjerks, hallucinations, and nausea. On admission to the PCU, she was in pain from her left hip, but denied hallucinations. She had psychomotor agitation and occasional myodonicjerks. Her vital signs were normal and her lungs were clear on examination. She scored 28/30 on the Folstein Mini-Mental Status Examination (MMSE) 4 and 0 / 4 on the CAGE questionnaire screening for alcoholism. 5 She had been on morphine until 2 weeks before admission, when she was changed to hydromorphone 84 rag/day subcutaneously because of hallucinations. As she was now experiencing toxicity from the hydromorp h o n e as well, we decided to change the opioid to methadone. The standard conversion rate of subcutaneous (SC) hydromorphone to oral morphine is 1:20. This made her morphine equivalent daily dose (MEDD) equal to 1680 mg of oral morphine. The literature to date continues to favor a 1:1 conversion of parenteral morphine to parenteral methadone, although there is growing debate about this issue. We are currently using a dose ratio of 5:1. Because of her r e c e n t adverse reactions to opioids, we decided to give cautiously a much lesser dose of methadone (30 mg orally every 8 hr). For the first 2 days, she remained somewhat agitated without any serious complaints of pain. She never marked her visual analogue higher than 4/10 after her first day in the PCU. The staff noticed intermittent episodes of confusion and disinhibited behavior, which were mild at first, but when her oxygen saturations were measured, they were found to be marginally low in the range of 88%--89%, and she was started on O~ to keep her saturations above 90%. A C T of the head was performed without contrast and was reported to be normal. Over the next 3 days, she had more frequent episodes of delirium, with extreme listlessness and bizarre behavior. Her methadone dose was tapered after day 4 and discontinued on day 8. By day 8, she was significantly hypox-
Vol. I 0 No. 5 Ju!y 1995
emic with apneic episodes. Her end-tidal CO2 levels were measured at 35 mm Hg while her respiratory rate (RR) was 6 per rain and her O~ saturation by pulse oximeter was 66%. Naloxone, 0.4 mg, was given SC, and the RR i n c r e a s e d to 26 and the end-tidal CO~ dropped to 20 mm Hg. Her chest radiograph showed interstitial and intraalveolar fluid compatible with n o n c a r d i o g e n i c p u l m o n a r y edema. Her white blood cells decreased from 14.3 on admission to 12.2 on day 9. Througho u t this whole e p i s o d e , h e r lung fields remained clear to auscultation, and there were no signs of congestive heart failure. By day 10, her diffuse interstitial and alveolar pattern had improved markedly on the chest radiograph. Her cognitive status, endtidal CO~ levels, and hypoxia also started to improve. However, she developed consolidation in both bases, and subsequent blood and sputum cultures demonstrated H. influenzae. Her pneumonia resolved rapidly following treatment with ciprofloxacin. Because of recurrent pain, she was restarted on subcutaneous hydromorphone at a much lower equianalgesic dose.
D/sruss/on Our patient presented with severe pain that responded poorly to doses of morphine and hydromorphone associated with severe toxicity. After a switch to oral methadone at a dose approximately 10 times lower than the equianalgesic dose, progressive confusion, sedation, and respiratory depression developed. While respiratory depression and confusion due to methadone have been described before, 2 our patient is unique in the fact that this toxicity presented several days after the patient was started on a very low equianalgesic dose. Due to the presence of delirium, the dose of methadone was reduced. It is clear that a complete discontinuation of the dose might have been a better management, particularly since pain appeared to be under excellent control. As the toxic event was observed days after starting methadone, it is very likely that accumulation of the drug took place. It is impossible in the absence of methadone plasma levels, however, to say if the event was related more to pharmacokinetic or pharmacodynamic factors. Our observations suggest that
VoL 10 No. 5 gu~ 1995
Respirator7 Depression and Methadone
100
7O
i~
°
N
6O
1oo contused
3o
I'.
2°
?
10
6 5 4 3
2 1
d
T "~ ~ ; ~ ~ ; ; ~ 101112131415 ...... 1~11~'I'11'+~o
F c
g
aoo
0
[ MEI'HADONE J
100
I
HYDROMORPHONE
----
,; ~, ~ Mini-mental status exam I 2S (out o! 30)
~ :
2S
-- .
.
.
.
]
.
~--,-,
, , , , , , , , , , 9 10 11 12131415 1617 1819 20 Time in Olys 0 24 2S J
Fig. 1.Changes in the visual analogue scale, oxygen requirements, equianalgesic dose of morphine and the Mini-Mental State Examination during the course of admission. patients started on m e t h a d o n e should be closely monitored for at least 1-2 weeks after starting treatment. The presence of noncardiogenic pulmonary edema complicated the patient's management. While n o n c a r d i o g e n i c p u l m o n a r y edema has been frequently associated with opioid overdose in addicts, it has only been recognized recently as one of the complications of opioid therapy of cancer pain. 6 Our patient had the features of acute onset of severe hypoxia and radiographic changes compatible with pulmonary edema in the absence of congestive heart failure. Both the hypoxemia and the radiological changes resolved quickly after the discontinuation of methadone (Figure 1).
403
While pain reappeared during day 3 after the episode of respiratory depression, it was managed very successfully thereafter with a dose of hydromorphone that was significantly lower than the dose of hydromorphone required to control the pain before the change to methadone. Although the reason for this decrease in requirement is unclear, one possible explanation is that there was very limited cross-tolerance between methadone and hydromorphone in this patient. This would explain both the development of respiratory depression on a relatively low methadone dose and the ability of the patient to regain responsiveness to hydromorphone after having received no hydromorphone for 10 days (the duration of her methadone treatment). An alternative explanation could be a decrease in baseline pain as a delayed effect of radiation therapy. This is unlikely as the patient had experienced increasing pain during the 4 weeks following the completion of radiotherapy. Another explanation could be the presence of circulating hyperalgesic metabolites of morphine or hydromorphone.7's Methadone is an effective and low-cost opioid analgesic. Until we gain better understanding on its toxicity and issues of equianalgesic doses in tolerant patients, however, its use should be limited to groups with expertise in cancer pain management. Because of the high interindividual variability in equianalgesic doses and the lack of reliable equianalgesic doses, titration should take place slowly and in a personalized fashion.
RefeTt~e$ 1. Portenoy RK, Foley KM, Inturrisi CE. The nature of opioid responsiveness and its implications for neuropathic pain. Pain 1990; 43:273-286. 2. Fainsinger R, Schoeller T, Bruera E. Methadone in the management of cancer pain: a review. Pain 1993; 52:137-147. 3. Bruera E, Velasco A, Fainsinger R, Miller M, Spachynski K, Inturrisi C. Custom made suppositories of methadone (CMSM): an effective and simple alternative in patients (PTS) receiving high dose parenteral opioids (O). Proc of ASCO 1993;12:457. 4. Folstein MF, Folstein S, McHugh PR. "Minimental state": a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198. 5. Buchsbaum DG, Buchanan RG, Centor RM, et al. Screening for alcohol abuse using CAGE scores
404
Hunt and Bruera
VoL 10 No. 5 ~uly 1995
and likelihood ratios. Ann Intern Med 1991;115: 774-777.
glucuronide: a potent antagonist of morphine analgesia. Life Sci 1990;47:579-585.
6. Bruera E, Miller MJ. Non-cardiogenic pulmonary edema after narcotic treatment for cancer pain. Pain 1989; 39:297-300. 7. Smith MT, Watt JA, Cramond T. Morphine-3-
8. Yaksh TL, Harry GJ. Pharmacology of the ailodynia in rats evoked by high dose intrathecal morphine. J Pharmacol Experimental Ther 1988;244: 501-507.