Clinical Experience With Oral Methadone ...

Clinical Experience With Oral Methadone Administration in the Treatment of Pain in 196 Advanced Cancer Patients By Franco De Conno, Liliana Groff, Cinzia Brunelli, Ernesto Zecca, Vittorio Ventafridda, and Carla Ripamonti Purpose: The aims of this study were to describe the analgesia, side effects, and dosage and the causes of suspension of treatment in a large sample of advanced cancer patients with pain after treatment with oral methadone from 7 to 90 days. Patients and Methods: In a retrospective study, data collected for 196 advanced cancer outpatients with moderate to severe pain treated at 8-hour intervals with oral methadone in solution form from February 1993 to February 1995 were analyzed at baseline (time 0) and then at 7, 15, 30,45,60, and 90 days. The following parameters were assessed: Karnofsky Performance Status, intensity of pain (using the Integrated Pain Score [IPS], intensity of pain, insomnia, drowsiness, confusion, dry mouth, nausea, vomiting, constipation, and dyspnea (using the Therapy Impact Questionnaire [TIQ], mean daily dose of drug administered, and reasons for withdrawal from study. The period when pain was reduced by 35% with respect to baseline was evaluated with the Palliation Index. The association of the degree of palliation of pain with the age of the patients, tumor site, analgesic treatment taken at baseline, and daily mean dose of methadone administered during the follow-up period was analyzed by means of the Kruskal-Wallis test. Results: A reduction in pain intensity with respect to baseline occurred at each analysis time, and in 55. 1% of

the patients the reduction during the follow-up period was 2 35% according to the Palliation Index. The mean dose of oral methadone ranged from 14 mg at day 7 to 23.65 mg at day 90. There was an overall worsening of the other symptoms, but a high percentage of the patients reported an amelioration of insomnia with respect to baseline. There was a statistically significant association (P < .0001) between the Palliation Index and the analgesic therapy administered at baseline. Only 11.2% of the patients withdrew from the study due to analgesic inefficacy and 6.6% due to methadone-related side effects (10 patients with drowsiness and three with severe constipation). Conclusion: Oral methadone administered every 8 hours was shown to be an appropriate analgesic therapy in the treatment of advanced cancer-related pain. The worsening of the other symptoms under study can be considered linked to the progression of the disease, and in fact, only a small percentage of the patients reported methadone-related side effects that warranted suspension of treatment. We consider oral methadone to be a useful analgesic therapy, and it should be considered in clinical practice for the treatment of cancer pain. J Clin Oncol 14:2836-2842. © 1996 by American Society of Clinical Oncology.

THE RELIEF OF cancer-related

phine,2 ' 10 the analgesic efficacy of the two drugs is similar." -13 However, knowledge about the pharmacodynamics of long-term oral methadone therapy in the treatment of cancer patients is still limited. Methadone is available in different forms, which thus allows administration via oral, nasogastric, percutaneous gastric, or ileostomy tube routes both in tablet form and in liquid solution preparation. Methadone is almost entirely absorbed by the gastrointestinal (GI) tract, and the oral bioavailability was estimated to be 80% (range, 41% to

pain can be achieved with a simple and low-cost pharmacologic treatment by means of a three-step analgesic ladder that ranges from nonopioids (first step), to opioids for mild to moderate pain (second step), and to opioids for moderate to severe pain (third step), as indicated in the World Health Organization (WHO) guidelines.' Among the opioids, oral methadone is considered a useful alternative to oral morphine to treat moderate to severe pain. Although the physicochemical and pharmacokinetic characteristics of methadone differ from those of mor-

From the Divisions of Pain Therapy and Palliative Care and Psychological Research, National Cancer Institute; and Floriani Foundation, Milano, Italy. Submitted August 8, 1995; accepted April 11, 1996. Supported in part by ItalianNational Research Council grant no. ACRO 9501260PF and Italian Association for Cancer Research grant no. AIRC 198512. Address reprint requests to Carla Ripanmonti, MD, Pain Therapy and Palliative Care Division, National Cancer Institute, Via Venezian, 1, 20133 Milano, Italy: Email [email protected]. © 1996 by American Society of Clinical Oncology. 0732-183X/96/1410-0028$3.00/0

2836

2 99%). .514

These values are threefold the values for bio-

availability of oral morphine.2 ' 5" 6 Moreover, a larger coefficient of variation among patients for oral bioavailability was shown for morphine (50%) compared with methadone (15%). 2 Methadone has rapid and extensive distribution phases (half-life [t,, 2], 2 to 3 hours) followed by a slow elimination phase (tl/2, 15 to 60 hours). 5" 0' 7 According to Plummer et al,' 0 there are outlier patients who have terminal elimination tl,2 values that are considerably longer, even extending to 120 hours. This may have important clinical implications linked to drug accumulation and particularly the potential for delayed toxicity.

Journal of Clinical Oncology, Vol 14, No 10 (October), 1996: pp 2836-2842

Information downloaded from jco.ascopubs.org and provided by at Universidade Federal do Rio de Janeiro on July 16, 2011 from Copyright © 1996 American Society of Clinical Oncology. All rights reserved. 146.164.3.197

2837

ORAL METHADONE FOR CANCER-RELATED PAIN Although morphine and methadone demonstrate approximately equal analgesic potency after single-dose administration,' 8 when methadone is given in a multidose analgesic regimen it can be administered at lower doses and with longer dosing intervals to maintain analgesia, 2 1 920 in comparison to morphine.2, ,1 This appears to be not only a consequence of methadone kinetics but also of a relatively higher potency of methadone with respect to morphine during long-term administration. Notwithstanding the WHO cancer pain relief guidelines, oral methadone seems to be significantly underused as an analgesic in clinical practice, and few data are available in the literature about the efficacy, tolerability, and 7 appropriate treatment schedule of this drug. 2 '"2 ' '5' Apparently, no data have been published for a substantial number of patients treated with oral methadone for cancerrelated pain over a long period. The aims of this study were as follows: (1) to describe the analgesia, tolerability, and dosage and the causes of suspending treatment in a large sample of patients with cancer-related pain treated with oral methadone for a period of 2 7 days to < 90 days; (2) to evaluate the side effects (ie, symptoms the patient reported as directly associated with methadone administration) for which the patient requested suspension of treatment; (3) to describe the trend of other symptoms reported by the patient before and during methadone treatment; and (4) to determine if there is any relationship between analgesia and the age of the patient, cancer site, dosage of methadone, and previous analgesic treatment. PATIENTS AND METHODS Patients In this retrospective study, we analyzed data collected from 196 advanced cancer outpatients with moderate to severe pain consecutively treated at 8-hour intervals with oral methadone in solution form from February 1993 to February 1995 at the Palliative Care Division of the National Cancer Institute of Milan.

Data Collection Data for sex, age, primary/secondary tumor site, oncologic treatment (chemotherapy/radiotherapy), Karnofsky Performance Status, intensity of pain and other symptoms, level (step) of the WHO analgesic ladder used (first, second, or third; 0 = no treatment), and type and route of drug administration and analgesic drug dosage were recorded by the patient on a specific assessment chart routinely used in our Division, which was returned by the patient at the weekly appointment at the Palliative Care Unit. The intensity and duration of pain was reported daily by the patient by means of an Integrated Pain Score (IPS).21 '2 2 Moreover, pain intensity and the intensity of other physical and emotional symptoms were reported weekly by the patient by means of a Therapy Impact Questionnaire (TIQ).23 '24 Data collected in this way are detailed and precise and are not

collected by the person who manages the therapy. If necessary, the patient could contact a physician or nurse from the Palliative Care Unit between appointments, and the analgesic therapy could be modified according to the patient's needs day by day. We considered the baseline (time 0) as the moment when oral methadone was first prescribed by the treating physician. Assessments performed at time 0 and then at 7, 15, 30, 45, 60, and 90 days were analyzed. At each time of assessment (with reference to the previous week), the following parameters were evaluated: (1) median daily pain score measured by the IPS; (2) intensity of pain, drowsiness, insomnia, confusion, dry mouth, nausea, vomiting, constipation, and dyspnea evaluated according to the TIQ; (3) methadone-related side effects, ie, symptoms the patient reported as directly associated with methadone administration and for which the patient requested suspension of treatment; (4) mean daily dose of oral methadone; and (5) Karnofsky Performance Status. The IPS is a way to evaluate pain by integrating the intensity and duration of pain into a single score. Using five key words (slight, moderate or troublesome, severe or exhausting, terrible, excruciating or killing), a patient can describe the pain intensity for the preceding 24 hours. The exact value to be attributed to these key words has already been established numerically.2 5 To obtain a daily pain score, the hours of pain (defined by each key word) are multiplied by a corresponding factor (slight = 1, troublesome = 2.5, exhausting = 5, terrible = 7.5, and excruciating = 10) and then totaled. For this method, the scores range from 0 to 240. This number, which we call the IPS, can be easily and quickly totaled. The TIQ is a tool used to evaluate the quality of life. It includes 36 items to assess the degree of discomfort experienced and evaluated subjectively by the cancer patient through a verbal Likert scale with four possible answers (not at all, slight, a lot, or very much). The period of reference is the previous 7 days. Of 36 items on the TIQ, answers with regard to pain, drowsiness, insomnia, confusion, dry mouth, nausea, vomiting, constipation, and dyspnea were taken into consideration for this study. These particular symptoms were selected because they most frequently occur in patients who receive analgesics and especially opioids. Since these symptoms are also associated with progression of the disease, we considered them as methadone-related side effects when the patient reported a direct association of the symptoms with administration of the drug; therefore, treatment was suspended according to the patient's request.

Methadone Administration In a previous controlled clinical trial 2 that compared methadone and morphine administered orally for 2 weeks, we demonstrated that the analgesic effectiveness and tolerability of the two drugs were the same. For this reason, in our clinical practice, methadone and morphine are prescribed similarly as first-choice drugs to treat severe pain. Moreover, methadone is the only opioid that we can use for patients with solid-food-related dysphagia or for patients fed via nasogastric tube, because methadone is currently the only opioid in solution form commercially available in Italy. From long-term clinical experience, the dosage of oral methadone prescribed in our Division is approximately scheduled as follows: (1) in opioid-naive patients, the starting dose of methadone is 3 mg every 8 hours; (2) patients treated with opioids for mild to moderate pain and patients treated with morphine 5 60 mg daily are switched to a starting dose of methadone 5 mg every 8 hours; and (3) patients treated with morphine 70 to 90 mg daily are switched to a starting methadone dose that is 2 one fourth of the morphine dose, or one sixth if the daily dose of morphine is Ž 100 mg. The dosage of


2838

DE CONNO ET AL

methadone is titrated day by day till pain relief is achieved without unwanted side effects. A nonsteroidal antiinflammatory drug is prescribed for breakthrough pain. Data Analysis The degree of palliation of pain over time for each patient was expressed as a percentage on the Palliation Index (modified version26 ): (duration (days) of control of pain/duration (days) of followup period) X 100. The duration of pain control was defined as the period when pain was reduced by 2 35% with respect to baseline. For example, a Palliation Index of 60% shows that pain control (2 35% v baseline) was obtained during 60% of the follow-up period. The follow-up period started from time 0 when methadone was first prescribed to the time when the study was stopped due to suspension of treatment or death. Any period in which data were missing was not included in calculation of the Palliation Index. At each scheduled time, the percentage of patients who reported a worsening or an amelioration of each symptom with respect to baseline was evaluated. By means of the Kruskal-Wallis test, 27 we studied the association of the degree of palliation of pain with the following variables: age (< 59 and 2 59 years), primary tumor site (head and neck, lung, breast, GI tract and colon/rectum, and others), step of the WHO analgesic ladder previously used (0 to first, second and third), and mean daily dosage of methadone during the follow-up period [< 10, > 10 < 20, or

2

20 mg]).

A P value less than .05 was considered statistically significant. All tests were two-sided. Patients with missing data for an item were eliminated from the analysis for that item. RESULTS Table 1 lists the characteristics of 196 patients under study. The median age was 59 years, and 61.7% were males. At baseline, the median Karnofsky Performance Status was 60 (first to third quartile [Q1 to Q3], 50 to 70) and remained stable until 60 days, when a decline occurred to 40 (Q1 to Q3, 60 to 70). The three most frequent primary tumor sites were the head and neck (33.2%), lung (14.8%), and breast (12.2%). About 82% of the patients were no longer receiving oncologic treatment at baseline. Only six patients were not under any analgesic treatment at baseline. Four of these had only taken buprenorphine previously "as required," which they suspended because of inefficacy. The other two patients started with methadone in solution form due to severe pain and to being fed through nasogastric tubes. At baseline, 23% of the patients had been treated with nonsteroidal antiinflammatory drugs for - 2 weeks and often at a higher dose than recommended by the manufacturer. These drugs were discontinued due to poor pain control, potential toxicity, and nasogastric tubes (four patients). At baseline, the majority of patients (53.6%) were being treated with opioids for mild to moderate pain (second-step WHO). All of these patients switched to methadone due to poor pain control with the previous therapy.

Table 1. Characteristics of the Patients Patients No. Sex Male Female Age, years Median

121

60

Q1 -Q3

Colon/rectum Male GU tract Female GU tract Unknown Other Multiple Total Oncologic treatment at baseline (RT or CT) Yes No

Analgesic therapy at baseline' None First step Second step Third step Missing

38.3

59 50-68

Karnofsky performance status at baseline Median

Breast GI tract

61.7

75

Q1 -Q3

Primary tumor sites Head and neck Lung

%

50-70

65

33.2

29

14.8

24 15 11 6 13 3 21

12.2 7.7 5.6 3.1 6.6 1.5 10.7

9

4.6

196

100

36 160

18.4 81.6

6 45 105 36 4

3.1 23.0 53.6 18.3 2.0

Abbreviations: GU, genitourinary; RT, radiation therapy; CT, chemotherapy. *Per WHO analgesic ladder.

Some patients (18.3%) were on oral slow-release morphine (third-step WHO) at a mean daily dose of 60 mg. Of these 36 patients, 22 switched to oral methadone solution because a nasogastric tube had been placed due to dysphagia, three because there was no effective pain control with morphine, four because of morphine-related side effects, and seven for unknown causes. Table 2 lists the median daily pain score and the mean daily dosages of methadone for the number of patients under study at each evaluation time. A reduction in the pain score with respect to baseline can be observed at every time of the analysis, which shows that pain control was maintained over a long period. To understand the magnitude of the pain reduction, it may be useful to know that patients who rated "not at all" to "slight" on the TIQ pain scale had a median pain score of 24 on the IPS scale, patients who rated "a lot" had a median pain score of 42.6, and patients


ORAL METHADONE FOR CANCER-RELATED PAIN

2839

Table 2. Pain Score in Relation to the Dose of Oral Methadone Administered During the Study Time of Evaluation (days)

No. of Patients

Median

Q1-Q3

Daily dose, mg (mean ±+SD)

Baseline 7 15 30 45 60 90

196 174 143 115 84 62 43

40 19 16 17 14 16.5 15.4

24.1-65.6 10.0-30.8 6.2-28.8 6.3-29.5 5.2-25.2 7.3-24.7 6.0-26.7

13.49 + 6.68 14.59 ± 8.86 15.97+ 12.17 17.15+ 13.55 20.16 ±+ 18.77 23.65 + 25.19

Table 3. Modifications of the Other Symptoms Under Study Day (% of cases

Daily Pain Score'

*Palliation index: Median, 100%; Q1-03, 50 to 100.

who rated "very much" had a median pain score of 73. Thus, a reduction of the IPS from 40 to 15.4 (median) may be interpreted as a decline of pain from a high level to a low level (slight or not at all). The positive analgesic result can also be observed with the Palliation Index, of which the median is equal to 100% of pain control according to the criteria defined previously. In fact, in 55.1% of the patients, the reduction of the pain score at every evaluation time is - 35% with respect to baseline. The dosage of oral methadone ranged from a minimum mean daily dose of approximately 14 mg at 7 days to 23.65 mg at 90 days, divided into 8-hour intervals. One hundred fifteen patients continued the treatment with oral methadone for 1 month, 62 for 2 months, and 43 for 3 months. Table 3 lists the percentage of cases for which there was an amelioration or a worsening of the other symptoms under study with respect to baseline. An overall worsening of the symptoms is observed over time, particularly for drowsiness, confusion, constipation, and dyspnea. As for insomnia, the percentage of patients with amelioration of the symptom was high at all the evaluation times except 90 days. Table 4 lists the association between the four variables under study and the Palliation Index. No significant association is observed with respect to age, tumor site, and mean daily dose of methadone. A statistically significant association (P < .0001) appears between the Palliation Index and analgesic treatment at baseline. Table 5 lists the causes of study withdrawal, which are as follows: inability to swallow, which thus required an alternative route of analgesic administration (10.7% of the patients); analgesic inefficacy (11.2%); methadone-related side effects (6.6%: drowsiness in 10 patients and constipation in three); lost to follow-up study (32.2%); and death (39.3%). No severe side effects such as respiratory depression, coma, or halluci-

Symptom

Insomnia Exacerbated Ameliorated Drowsiness Exacerbated Ameliorated Confusion Exacerbated Ameliorated Dry mouth Exacerbated Ameliorated Nausea Exacerbated Ameliorated Vomiting Exacerbated Ameliorated Constipation Exacerbated Ameliorated Dyspnea Exacerbated Ameliorated

7

15

30

45

60

90

16.8 30.4

18.1 35.4

15.2 30.3

17.3 36.0

18.9 20.8

22.2 13.9

43.1 9.4

40.5 17.5

42.3 11.3

45.2 9.6

53.8 9.6

47.2 11.1

28.3 10.7

28.6 12.7

24.7 9.3

35.1 12.2

38.5 17.3

36.1 13.9

26.7 17.4

24.6 23.8

28.9 18.6

28.4 17.6

26.9 19.2

22.2 19.4

24.4 15.0

19.0 15.9

24.7 13.4

24.3 16.2

19.2 13.5

13.9 11.1

21.9 10.6

16.7 10.3

20.6 15.5

24.3 12.2

17.3 13.5

15.0 12.8

32.1 17.0

34.9 18.3

34.0 25.8

32.4 23.0

36.9 20.8

77.8 22.2

20.6 15.0

19.0 16.7

24.7 15.5

21.6 17.6

31.4 5.9

19.4 2.8

nations were observed. No deaths were related to the methadone treatment. Moreover, most of the patients were able to spend more of their remaining life at home. Table 4. Association of the Palliation Index With Different Variables Mean

Variable

Age, years < 59 2 59 Primary tumor site Head and neck Lung Breast GI tract + colon/rectum Others Analgesic therapy at baseline* None/first step Second step Third step Mean daily dose of methadone during follow-up (mg) < 10 2

Palliation Index %)

No. of Patients

P

73.97 67.68

95 101

.16 (NS)

69.05 75.89 64.97 71.2 72.3

65 29 24 26 52

.95 (NS)

85.83 72.46 45.86

51 105 36

< .0001

.056

82.28

45

10 < 20

68.95

104

20

62.14

43

Abbreviation: NS, not significant. *Per WHO analgesic ladder.


2840

DE CONNO ET AL Table 5. Reasons for Study Withdrawal Patients Reason

No.

%

Alternative administration route Analgesic inefficacy Unwanted side effects Lost to follow-up evaluation Death

21 22 13 63 77

10.7 11.2 6.6 32.2 39.3

DISCUSSION

Different investigators report that methadone can present advantages over other opioid analgesics for the following reasons: (1) low cost in comparison to other opioids 4 ; (2) low number of daily administrations (one to

three with respect to opioids with a short terminal halflife, and consequently increased outpatient compliance 1220; (3) potential to control pain that does not respond to other opioids, because methadone shows that it has incomplete cross-tolerance with other mu-opioid - ; and (4) possible use of receptor agonist analgesics2 835 methadone in place of morphine or hydromorphone when the accumulation of active metabolites is the cause of side effects such as myoclonus, sedation, confusion, nausea, and vomiting. 20' 36-38 Despite all these advantages, oral methadone is still rarely used to treat cancer-related pain in clinical practice. This seems to be linked to the fact that it is not a well-known drug because few studies have been published about it, and it is a drug that is feared due to a slow elimination phase, which can bring about accumulation with the potential of delayed toxicity, in particular when doses are too high or the dosing intervals are too close.

939 4

'

Our study involved 196 advanced cancer outpatients with pain treated with oral methadone in solution form every 8 hours over a long period. Some patients (14.3%) were treated with oral methadone because they had a nasogastric tube for enteral nutrition through which it was possible to administer an opioid in solution form only. The high frequency of nasogastric tube feeding is due to the fact that 33.2% of the patients had dysphagia due to head and neck cancer. Before switching to methadone, 53.6% of the patients were treated with codeine or dextropropoxyphene via the oral route, and 18.3% with slow-release morphine. From single-dose studies, the equianalgesic dose ratio between morphine and methadone is shown to be 1:1. In switching from morphine to methadone, the latter drug is often observed to be relatively more potent at steady-state than would be expected given the data in the literature, and thus a reduction in the calculated equianalgesic dose of

2 75% has been recommended with respect to the opioid previously administered.2 8 We routinely prescribe methadone based on the data from the literature and on our own clinical experience, as already described, which allows achievement of analgesia without immediate or delayed toxicity. During the period of observation, the treatment with oral methadone has shown a good analgesic effect as evaluated through the IPS, TIQ, and Palliation Index. This positive result confirms other studies in which different

assessment tools were used.

'12 7 20 4 4 2- 4

.'

Only 11.2% with-

drew from the study due to analgesic inefficacy. This confirms that not all patients with cancer pain obtain complete relief with opioids, as already described in the literature.45 During the 90 days of the study, there was no rapid dose-escalation of methadone when adequate pain relief was achieved. This result agrees with the data in the literature,9 '2 whereby methadone was shown to have a low rate of induction of analgesic tolerance. 9

17,42.43.46

However, the dosage of methadone administered to our patients in both studies was lower in the titration phase and during continuation of the treatment than was reported in the literature.9 17 42-44 The main reason that the dosage of methadone in this study and the dosage of analgesic opioids in general is lower in Italy and other European countries with respect to the United States is due to the fact that, unfortunately, in our medical culture the use of opioids is aimed at patients in the advanced or terminal phase of disease, when they are sent to palliative care units. Thus, the majority of patients who come to us for the first time are opioid-naive or are being treated with opioids at low doses, often irregularly or only on request. As a result, we are treating "clean" patients in whom the development of tolerance to opioids progresses slowly. Opinions still differ about the suitable intervals of oral methadone administration. Various approaches have been used to provide a more effective and safe treatment with methadone. Some suggest 6-, 8-, or 12-hour dosing intervals to avoid accumulation risks.2 '9 '7 In this study, as in

others,1'2 20 administration of oral methadone every 8 hours both in the titration phase and during long-term treatment proved to be effective with no signs of accumulation or toxicity. On analysis of the assessment charts, during the 90 days of the study an amelioration of insomnia was observed that could be a consequence of pain control with respect to baseline and/or of methadone treatment. As for the other symptoms, a worsening occurred with respect to baseline, particularly for drowsiness, confusion,


2841

ORAL METHADONE FOR CANCER-RELATED PAIN

constipation, and dyspnea. It is difficult to establish whether the worsening of these symptoms as reported by the patients was caused only by methadone administration or, more likely, by a concomitant progression of the disease. Patients who reported dyspnea did not present any sign of respiratory depression due to methadone accumulation. It is of interest that these symptoms under study worsen in the majority of the oncologic population during the advanced and terminal phase of disease independently of tumor site or analgesic therapy,4 7 49 - to the extent that Wachtel et a147 coined the phrase "terminal common pathway" to indicate a series of prognostic symptoms of end-stage cancer. Only a small percentage of the patients (6.6%) reported a definite relationship between the analgesic therapy and drowsiness (10 patients) and constipation (three patients), which thus required suspension of the treatment upon the patient's request. These were the only cases for which the symptoms were considered unwanted side effects of the methadone treatment. In this study, there is a statistically significant association between the Palliation Index and the analgesic treatment at baseline. This means that the stronger the analgesic therapy at baseline, the lower the mean Palliation Index. Evidently, switching directly to opioids for severe pain (methadone or morphine) from a regimen of no analgesics or from a therapy with nonopioids considerably

improves the analgesic effect with respect to regular administration of drugs that act on opioid receptors. As for the association between the dosage of metha-

done and the Palliation Index, it can be seen that with an increase of the mean dose of methadone administered during the whole period of treatment, the mean Palliation Index decreased, although this is not statistically significant. This could mean that in some patients, notwithstanding an increase of the drug dose, the pain is more difficult to control than in other patients. This study can be considered descriptive only, due to the open and retrospective design. It shows that methadone in solution form administered according to our standardized method is a useful and well-tolerated analgesic in patients with cancer-related pain. The results of this clinical experience show that methadone, although until now seen as a second-choice drug with respect to morphine by the majority of physicians, is of great value in the treatment of chronic cancer pain, despite the need for a carefully scheduled administration program. It would be interesting to compare this study with an analog study in which higher doses of oral methadone are used, to see if the analgesic benefit and toxicity are compatible. Future controlled clinical trials should be performed to define the equianalgesic doses of methadone with respect to morphine and other mu-opioid agonists during long-term administration.

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