Download Methadone Versus Morphine As a First-Line Strong

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JANUARY
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2004
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Methadone Versus Morphine As a First-Line Strong
Opioid for Cancer Pain: A Randomized,
Double-Blind Study
Eduardo Bruera, J. Lynn Palmer, Snezana Bosnjak, Maria Antonieta Rico, Jairo Moyano,
Catherine Sweeney, Florian Strasser, Jie Willey, Mariela Bertolino, Clarissa Mathias, Odette Spruyt,
and Michael J. Fisch
From the Department of Palliative Care
and Rehabilitation Medicine, the University of Texas M.D. Anderson Cancer
Center, Houston, TX; Institute for Oncology and Radiology of Serbia, Belgrade, Yugoslavia-Serbia; Instituto Nacional del Cancer, Santiago, Chile;
Departamento de Anestesia, Clinica de
Dolor, Fundacion Santafe de Bogota,
Bogota, Colombia; Unidad de Cuidados
Paliativos Hospital Enrique Tornu-Fundacion FEMEBA, Buenos Aires, Argentina;
Nucleo de Oncolgia da Bahia, Bahia,
Brazil; and Peter Mac Callum Cancer
Institute, Department of Pain and Palliative Care, East Melbourne, Australia.
Submitted March 27, 2003; accepted
October 24, 2003.
Supported in part by the Brown Foundation, Houston, TX, and the Tobacco
Settlement Foundation. Florian Strasser
is supported by a grant from Swiss
Cancer Research (BIL grant KFS 95009-1999).
Authors’ disclosures of potential conflicts of interest are found at the end of
this article.
Address reprint requests to Eduardo
Bruera, MD, Department of Palliative
Care & Rehabilitation Medicine (Unit
0008), the University of Texas M.D.
Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-0049;
e-mail: [email protected].
© 2004 by American Society of Clinical
Oncology
0732-183X/04/2201-185/$20.00
DOI: 10.1200/JCO.2004.03.172
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Purpose
To compare the effectiveness and side effects of methadone and morphine as first-line treatment with
opioids for cancer pain.
Patients and Methods
Patients in international palliative care clinics with pain requiring initiation of strong opioids were
randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as
needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The
study duration was 4 weeks.
Results
A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the
morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and
constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than
those receiving morphine (three of 54; 6%; P ⫽ .019). The opioid escalation index at days 14 and 28 was
similar between the two groups. More than three fourths of patients in each group reported a 20% or
more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement
in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the
morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly
identical to the pain response rates and did not differ between the treatment groups.
Conclusion
Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with
morphine as a first-line strong opioid for the treatment of cancer pain.
J Clin Oncol 22:185-192. © 2004 by American Society of Clinical Oncology
INTRODUCTION
Cancer is among the most feared chronic
illnesses [1], and more than two thirds of
patients with metastatic cancer experience
pain [2]. The great majority of these patients
require opioid analgesics for appropriate
pain control [3]. Morphine has been shown
to be an effective analgesic, and it is recommended as a first-line opioid in the WHO
Cancer Pain Relief Guidelines [4]. However,
only level C evidence supports this recommendation, reflecting the paucity of goodquality clinical studies in cancer pain [5].
Morphine undergoes hepatic metabolism and renal elimination [6]. Some of its
active metabolites can accumulate in situations such as chronic treatment, dose escalation, dehydration, or renal failure [6,7].
Opioid metabolite accumulation has been
considered one of the major causes of opioid-induced neurotoxicity [7,8]. Other opioid agonists such as hydromorphone, oxycodone, or codeine also result in opioid
metabolite accumulation [7,9]. Although its
manufacture is simple, the price of morphine ranges according to the international
price of the poppy, and even the immediate185
Bruera et al
release morphine preparation can be prohibitively expensive in developing countries [10]. Other opioid agonists,
particularly the slow-release preparations, are generally unaffordable in developing countries [11,12].
Methadone has a number of potential advantages compared with other opioids, including morphine. Methadone
is synthetic and easily manufactured. Thus, it could be a
good choice of an opioid for first-line cancer pain treatment
for low-income populations or in developing countries.
Importantly, methadone does not have any known active
metabolites and does not undergo significant renal elimination [13]. Another potential advantage of methadone over
other opioids is that it has been found to be a relatively
potent N-methyl-D-aspartate (NMDA) receptor antagonist
[14]. Excitatory amino acids such as NMDA have been
implicated in the development of neuropathic pain and
opioid tolerance [15,16]. One disadvantage of using methadone is that it has a long and unpredictable half-life, which
can makes titration difficult to achieve [13,17,18]. Titration
might be easier and safer in patients who have not previously received strong opioids [19].
The purpose of this randomized, double-blind study
was to determine whether a specific dose and schedule of
oral methadone would produce superior analgesic efficacy
at 4 weeks compared with a commonly used oral sustainedrelease morphine regimen for the management of cancer
pain in ambulatory cancer patients requiring initiation of
strong opioid therapy outside of the United States. We also
sought to compare the tolerability of methadone compared
with morphine in this setting.
PATIENTS AND METHODS
Study Design
This double-blind parallel trial was conducted by seven international palliative care groups (Table 1): Argentina, Yugoslavia,
Brazil, Columbia, Chile, Australia, and Spain. The Department of
Palliative Care and Rehabilitation Medicine at the University of
Texas M.D. Anderson Cancer Center (Houston, TX) coordinated
the study but did not enroll patients. The institutional review
boards of the coordinating institution and all participating institutions approved the protocol.
Eligibility Criteria and Randomization
Patient eligibility criteria included poor control of pain
caused by advanced cancer necessitating initiation of strong opioids, normal renal function, life expectancy at least 4 weeks as
assessed by the investigating physician, normal cognition as defined by the Mini-Mental State Examination adjusted for education and age [20], and written informed consent. Patients were not
eligible if they were already receiving strong opioids, radiation
therapy for pain control, or antineoplastic therapy expected to
produce an analgesic response. All consenting patients were registered in M.D. Anderson’s Clinical Oncology Research System.
The random allocation sequence was generated centrally by
computer-generated numbers stratified by center (site) and by
neuropathic pain. Each participating center pharmacy received
186
Table 1. Enrollment by Study Site (n ⫽ 103)
No. of Assessable
Patients
Study Site
1
2
3
4
5
6
7
Total
Methadone
Morphine
Day 8
Day 29
2
17
3
9
15
2
1
49
5
17
3
12
15
2
0
54
7
31
6
20
25
3
0
92
7
23
3
16
18
2
0
66
their site-specific randomized sequential assignment numbers,
and the treatment allocation code was kept in a sealed envelope
and was made available to the treating physicians in case of emergency. Pain was characterized as neuropathic or nonneuropathic
according to the judgment of the treating physician regarding the
mechanism of pain. Patients, treating physicians, and research
staff assessing the outcomes remained blinded to the identity of
the opioid until the end of the study.
Study Plan and Treatment
Patients were randomly assigned to receive either oral methadone 7.5 mg every 12 hours and methadone 5 mg every 4 hours as
needed for breakthrough pain or slow-release morphine 15 mg
twice daily and immediate-release morphine 5 mg every 4 hours as
needed for breakthrough pain. The capsules containing the drugs
were identical. Patients were instructed to take the first dose at 8 AM
on day 1 and subsequent doses at 12-hour intervals. The dose of
the study drug was increased if the patient received more than two
breakthrough doses per day. The dose increase was decided by the
investigator after a daily phone or personal assessment during the
first 8 days and weekly thereafter. Dose changes were not less than
30% of the daily opioid dose. For patients reporting clinical
sedation, the daily dose was reduced by approximately 30%. All
supportive medication, such as laxatives, antiemetics, and
other drugs, were continued as required during the study period. All nonopioid analgesic drugs were discontinued on admission to the study.
The duration of the study was 4 weeks. Patients were monitored daily for the first 8 days by either phone calls or clinic visits.
Patients also underwent assessments in person on days 8, 15, 22,
and 29 of treatment. The protocol required that a patient would be
removed from the study if pain became intractable, defined as the
patient needing six or more breakthrough analgesic doses in a
24-hour period, absence of pain relief after three consecutive dose
increases, or the development of a new, severely painful location
(for example, a fracture or acute abdominal pain); an acute complication of the cancer or its treatment developed, including sudden acute changes in the patient’s clinical condition, such as sepsis,
cardiovascular events, or delirium; the patient was unable to receive two consecutive doses of the regular analgesic because of
nausea or dysphagia; or severe opioid-related side effects (such as
sedation or nausea) developed.
Assessments
The baseline evaluation included a complete history and
physical examination. The pain syndrome was assessed clinically
JOURNAL OF CLINICAL ONCOLOGY
Methadone Versus Morphine for Cancer Pain
and by using the Edmonton Staging System for Cancer Pain [21],
which had been used previously by these investigators. The intensity of pain, sedation, confusion, nausea, and constipation was
measured on a 0 to 10 numerical scale (0, symptom absent; 10,
worst possible symptom). In addition to rating of constipation on
a numerical rating scale, bowel movements were categorized as
absent, small, moderate, or large.
During each of the first 8 days, assessment involved evaluation of pain and other symptoms using the same tools that were
used for the baseline measurements. The weekly assessments included assessment of pain, other symptoms, cognitive function,
and the global assessment by both the patient and the investigator
of overall benefit. Assessment of overall benefit was on a 1 to 7 scale
(1, no important benefit; 2, slightly important benefit; 3, some
important, consistent benefit; 4, moderately important, consistent
benefit; 5, much important, good deal of benefit; 6, very important
benefit; and 7, greatly important benefit).
After patients completed the study, opioid escalation indices
on days 14 and 28 were calculated as follows:
Day 14 opioid escalation index ⫽
total dose on day 14 ⫺ total dose on day 1
⫻ 100
total dose on day 1
Day 28 opioid escalation index ⫽
total dose on day 28 ⫺ total dose on day 1
⫻ 100
total dose on day 1
Statistical Methods
Descriptive summaries are provided for patient demographics, reasons for withdrawal from the study, and pain and side
effects at each of the time periods examined (Fig 1). Differences
between numbers of patients who withdrew overall and according
to specific reasons were compared using ␹2 tests. Pearson correlation coefficients were used to correlate outcome measures.
The primary objective of the study was to evaluate the difference in pain intensity measured on a 0 to 10 scale comparing the
baseline score with the score at week 4 for each study arm. Our
sample size calculation was based on having 80% power to detect a
20% difference in the ratio between the baseline and week 4 pain
scores with a two-sided significance level of .05 and assuming that
the standard deviation of the average difference score would be
approximately one half of that score. We sought to enroll 100
patients per study arm. The primary end point and other major
outcomes were dichotomized such that patients were considered
responders or nonresponders. Missing data could not be ignored;
Fig 1. Patient flow chart.
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Bruera et al
as such, patients who were inassessable were categorized as nonresponders for all dichotomized end points.
In addition to the primary end point, we also evaluated the
change in toxicity. A composite toxicity score was calculated as the
sum of the following individual symptom items: sedation, nausea,
confusion, and constipation. An increase of 20% or greater was
considered clinically significant toxicity. We defined patients as
having obvious benefit if they were assessable at baseline and at 4
weeks, had a 20% or greater pain response, and did not have a 20%
or greater increase in the composite toxicity score. Nonparametric
statistics were used to calculate P values (the Wilcoxon rank sum
test for continuous and categoric variable combinations, and Fisher’s exact test for categoric variables) because of the nonnormal
distribution of several variables and the limited sample size at the
close of the study. Differences between the methadone and morphine groups between baseline and day 8 were also evaluated for
descriptive purposes regarding the pattern of symptom changes.
codeine in 30 patients, acetaminophen in 13 patients, and
dextropropoxyphene in one patient. The type of analgesia
did not differ between the morphine and methadone group.
During the study, patients received 50 different laxatives
(some patients received more than one drug): senna in 28
patients, lactulose in 13 patients, and mineral oil in nine
patients. Patients received antiemetics consisting of metoclopramide in 26 cases and cisapride in two cases. Titration
of both antiemetics and laxative was allowed. In all instances, patients continued to receive the same antiemetic
and/or laxative until day 8.
Patient Flow
As shown in Figure 1, 92 of 103 patients (89%) were
assessable at day 8 and 66 of 103 patients (64%) were assessable at day 29. By day 8, seven of 49 patients (14%) receiving
methadone and four of 54 patients (7%) receiving morphine had withdrawn from the study (P ⫽ .13). By day 29,
20 of 49 patients (41%) receiving methadone and 17 of 54
patients (31%) receiving morphine had withdrawn from
the study (P ⫽ .16). The reasons for withdrawal from the
study did not differ significantly (Fig 1). By day 8, six of 49
patients (12%) receiving methadone had withdrawn because of opioid side effects (four because of sedation and
two because of nausea), and none of the 54 patients receiving morphine had withdrawn because of opioid side effects
(P ⫽ .01). The number of withdrawals from the study
because of opioid side effects was also significantly greater
for patients receiving methadone than for patients receiving
RESULTS
A total of 103 patients were randomly assigned to treatment
between May 2000 and November 2001 (this was the total
patient accrual at the requested time of closure for this
study). Forty-nine patients (48%) received methadone and
54 patients (52%) received morphine. Patient clinical and
demographic information at baseline are summarized in
Table 2. Baseline symptom scores for registered and assessable patients are summarized in Table 3. Before the study,
99 of 103 patients were receiving 143 different analgesics
(some patients received more than one drug): nonsteroidal
anti-inflammatories in 59 patients, tramadol in 40 patients,
Table 2. Baseline Clinical and Demographic Characteristics by Treatment Arm
Methadone Arm (n ⫽ 49)
Characteristic
Age, years
Median
Range
Female sex
Primary cancer diagnosis
Gastrointestinal
Breast
Gynecologic or genitourinary
Thoracic
Other
Edmonton pain staging, one missing in each group
Low risk
Moderate risk
High risk
Folstein Mini-Mental Status Examination score ⱖ 27
Neuropathic pain component
ⱖ 1 Opioid toxicity symptom score of ⱖ 7ⴱ
Composite opioid toxicity score†
Standard deviation
No. of
Patients
Morphine Arm (n ⫽ 54)
%
59.0
No. of
Patients
%
60.0
33
26-84
67
33
31-87
61
8
9
12
5
15
16
18
24
10
30
13
10
17
7
7
24
18
31
13
14
17
8
23
32
19
23
8.94
35
17
48
65
38.8
47
20
6
27
37
21
19
7.74
38
11
51
69
38.9
35
7.7
7.1
ⴱ
Symptoms were evaluated using an 11-point numerical rating scale (range, 1 ⫽ 10).
†Represents the sum of the opioid toxicity items (sedation, nausea or vomiting, confusion, and constipation).
188
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Methadone Versus Morphine for Cancer Pain
Table 3. Comparisons of Symptom Difference Scores From Baseline to Day 8
Day 8 ⫺ Baseline
Baseline
Methadone
Registered
(n ⫽ 49)
Morphine
Assessable
(n ⫽ 42)ⴱ
Registered
(n ⫽ 54)
Assessable
(n ⫽ 50)ⴱ
Methadone
(n ⫽ 42)ⴱ
Morphine
(n ⫽ 50)ⴱ
Symptom
Mean Score†
SD
Mean Score
SD
Mean Score
SD
Mean Score
SD
Mean Score
SD
Mean Score
SD
P
Pain
Sedation
Nausea
Confusion
Constipation
7.7
2.0
1.9
0.5
4.6
2
3
3
2
4
7.6
2.3
2.1
0.6
4.5
2
3
3
2
4
7.8
1.4
1.8
0.4
4.1
2
3
3
1
4
7.8
1.2
1.6
0.3
4.0
2
2
3
1
4
⫺4.9
2.2
⫺0.3
0.6
⫺1.5
3
4
4
3
4
⫺4.7
1.5
⫺0.8
0.4
⫺1.8
3
4
3
2
4
.80
.35
.45
.68
.75
Abbreviation: SD, standard deviation.
ⴱ
Patients who completed the first 7 days of treatment.
†Categorical scale 0 –10: 0, best; 10, worst.
morphine by day 29 (11 of 49 v three of 54; P ⫽ .02). The
opioid side effects resulting in withdrawal of patients receiving methadone by day 29 were sedation, vomiting, and
myoclonus (six, three, and two patients, respectively). The
opioid side effects resulting in withdrawal of patients receiving morphine by day 29 were vomiting and delirium
(two and one patients, respectively). Two patients died
while enrolled onto the study (one patient from the methadone group and one patient from the morphine group).
Both deaths were a result of disease progression and were
counted as treatment failures.
Day 8 Trends
Pain and other symptom score differences between
baseline and day 8 were compared for both drugs (Table 3).
Of note, the development of sedation in the methadone
group showed a distinct pattern, with a more delayed onset
of symptom severity than in the morphine group (Fig 2).
The proportion of patients with a 20% or more improvement in pain expression at day 8 was similar for both
groups, with 37 of 49 patients (75.5%; 95% CI, 62% to 89%)
in the methadone group and 41 of 54 patients (75.9%; 95%
CI, 63% to 89%) in the morphine group.
Dosing Outcomes
The daily methadone dose was a median of 17.5 (range,
7.5 to 40 mg) and 20 mg (range, 7.5 to 55 mg) on days 14
and 28, respectively. The morphine dose was a median of 40
(range, 15 to 100 mg) and 45 mg (range, 15 to 150 mg) on
days 14 and 28, respectively. The daily breakthrough dose in
the methadone group was a median of 0.5 (range, 0 to 15
mg) and 0 mg (range, 0 to 20 mg) on days 14 and 28,
respectively, versus 0.5 (range, 0 to 20 mg; P ⫽ .55) and 0 mg
(range, 0 to 80 mg; P ⫽ .79) for the morphine group.
The opioid dose escalation index for the methadone
group was a median of 12.5 (range, ⫺50 to 100) and 18.3
(⫺50 to 200) on days 14 and 28, respectively, versus 16.7
(range, ⫺14 to 500; P ⫽ .07) and 16.7 (range, ⫺57 to 900;
P ⫽ .5) for the morphine group. The opioid dose escalation
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indices in patients with or without neuropathic pain were
similar in the morphine and the methadone groups.
Bowel Movements
The quantity of bowel movements did not differ at
baseline between the two groups. The difference of the
number of bowel movements compared with baseline was
not different between the groups at any time.
Day 29 Outcomes
Patients were categorized as responders or nonresponders for the purpose of evaluating the primary and
secondary outcomes (Table 4). The proportion of patients
reporting at least moderate global benefit (a score of 4 or
greater on the 7-point ordinal scale) was similar to the
proportion of pain responders. The proportion of patients
Fig 2. Mean sedation scores for patients receiving methadone and
morphine for baseline through day 8.
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Bruera et al
Table 4. Day 29 Outcomes by Intention-to-Treat Analysis (n ⫽ 49 methadone, 54 morphine)
Parameter
Pain response of 20% or greater
Methadone
Morphine
Composite toxicity worse by 20% or more
Methadone
Morphine
Pain response with stable composite opioid toxicity (obvious benefit)
Methadone
Morphine
Patient-reported global benefit (at least moderate)
Methadone
Morphine
with both pain response and stable composite toxicity
scores (the obvious benefit group) was half as great as the
pain response rate for both treatment groups. Although
there were no significant differences between the treatment
groups, the final sample size allowed only 0.46 power to
detect a 20% difference in proportions. However, it had
more than 80% power to detect a 30% or greater difference.
Correlations Between Outcome Measures
The patient global satisfaction ratings on day 29 were
highly correlated with the physician global ratings (r ⫽ 0.88).
DISCUSSION
Previous studies have provided evidence that methadone is
a highly effective second-line opioid for cancer pain [17,22],
but this is the first double-blind study of methadone in
patients starting strong opioid analgesics. In this international palliative care setting, twice-daily methadone at a
total dose of 15 mg/d did not produce superior analgesia for
the treatment of cancer pain when compared with sustained-release morphine at a dose of 30 mg/d (along with
methadone v immediate-release morphine used for breakthrough pain).
The dropout rate observed in this study was consistent
with that observed in other palliative care studies [23], and
suggests that both drugs were well tolerated in this population of seriously ill cancer patients. As expected, more than
75% of patients had significant improvement in pain with
either strong opioid during the first week of treatment.
However, when inassessable patients were incorporated as
nonresponders, the overall pain response rate at 4 weeks
using oral opioids was surprisingly low for both morphine
and methadone in this first-line setting. It should be noted,
however, that a significant number of the inassessable patients at day 29 may have obtained adequate pain relief
ultimately with comprehensive medical pain management,
but were removed from this protocol for reasons such as
190
No. of
Responders
% of
Responders
24
30
49
56
34 to 64
41 to 70
.50
33
36
67
67
53 to 82
53 to 80
.94
12
16
24
30
11 to 38
16 to 43
.56
26
33
53
61
38 to 68
47 to 75
.41
95% CI (%)
P
frequent dose escalation or inadequate pain response after
three dose escalations. Opioid-related treatment outcomes
are reported in many different ways, and thus it is difficult
to compare these findings with other randomized trials of
first-line opioids. It has been noted that as many as 80% of
cancer patients require one switch in their analgesic regimen and as many as 44% require trials of two or more
systemically administered opioids [24]. Perhaps these
data are not surprising, then, if one assumes that patients
need to switch analgesic regimens because of inadequate
pain relief, unacceptable side effects, or the unacceptably
high cost of therapy.
Although there were no differences in the major response or toxicity outcomes at 4 weeks, the dropout rate
because of opioid side effects was higher for methadone
than for morphine at both days 8 and 29. This suggests that
the true dose ratio between methadone and morphine may
be lower than the ratio of 0.5 (7.5:15) we used in this study.
Moreover, it also is possible that methadone is more toxic
than morphine when it also is used as a breakthrough opioid. Future research should consider this issue. Half of the
patients who received methadone and dropped out of the
study because of opioid side effects did so during the first 8
days. This indicates the need for close monitoring of patients in the first week after initiation of methadone at this
dose and schedule.
There are few data on which to base the initial dosing
of methadone for cancer pain in patients not already
receiving a strong opioid. The equianalgesic dose of 1:2
(methadone-to-morphine ratio) for the regularly scheduled part of the opioid regimen was chosen on the basis
of published opioid rotation data with patients receiving
oral morphine at low doses [17,25,26]. Our findings
suggest that methadone given every 12 hours resulted in
good pain control, but it was not superior to the morphine regimen. This particular methadone regimen is
different from the 8-hour regimen reported most freJOURNAL OF CLINICAL ONCOLOGY
Methadone Versus Morphine for Cancer Pain
quently in previous studies of patients with cancer pain
[27,28]. We selected the 12-hour regimen to simplify the
study design for comparison with slow-release morphine. Our findings suggest that most patients can be
safely started on a 12-hour regimen. However, it is likely
that those patients who present with sedation or nausea
at the time of peak effect of methadone might benefit
from an 8-hour regimen.
Elimination phase half-lives for methadone with a
range of 4.2 to 130 hours have been reported in some
individuals [29]. This extended elimination phase is clinically important because it may result in drug accumulation
and toxicity [30,31]. In our study, differences in sedation
scores between methadone and morphine were highest at
day 5. This may reflect an accumulation of methadone
around this time in some patients.
The NMDA receptor antagonist activity of methadone suggests that methadone might be effective for
treatment of neuropathic pain [15,16,32]. Our findings
did not support a relatively more effective role for methadone in patients with neuropathic pain syndromes.
Similar findings have been reported by Gagnon and Bruera [33]. At this point, there is no substantial evidence
that the effect of methadone on excitatory amino acids
results in a clinical advantage in patients with neuropathic pain. However, because neuropathic pain was not
a primary end point of this study, and because the number of patients with suspected neuropathic pain was low,
additional research is needed to better characterize this
potential effect.
Opioid escalation was limited over the 4-week study
period in this patient population and was not significantly different between patients receiving methadone
and those receiving morphine. The previous randomized, open studies found more dose escalation in patients
receiving morphine than in those receiving methadone
[19,34]. Because patients in this study had not been
exposed to strong opioids, our results are of limited value
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in assessing whether methadone can obviate dose escalation in a subgroup of patients who require rapid opioid
dose increases or who are already receiving high doses
of opioids.
Previous studies have suggested that constipation improved when patients were rotated from another opioid to
methadone, an effect most likely caused by a bowel withdrawal syndrome [33,34]. No relative advantage in bowel
movements was observed when methadone was used as a
first-line opioid in this study.
Methadone is an extremely low-cost synthetic opioid analgesic. Our findings did not show an advantage
with methadone for either efficacy or tolerability over a
1-month period at the doses and schedules we compared.
Unfortunately, our study did not meet the accrual goal of
100 assessable patients per study arm. Thus, we only had
sufficient power to detect a difference of 30% or greater
in the response proportions. The absence of a large difference in outcomes does not constitute a valid claim of
equivalence. Morphine remains the international gold
standard for the first-line treatment of cancer pain. It
should be noted, however, that methadone is considerably less expensive than existing rapid-release opioids,
and even less expensive when compared with sustainedrelease opioid preparations [11,35-37]. Because of the
expense, patients around the world continue to die as a
result of cancer without having ever received a dose of a
strong opioid. Our results suggest that methadone deserves additional study as a first-line strong opioid for
cancer pain. Additional research is needed to explore
other doses and/or schedules of methadone that may
produce better results, and a properly planned equivalence trial is worth considering.
■ ■ ■
Authors’ Disclosures of Potential
Conflicts of Interest
The authors indicated no potential conflicts of interest.
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