The Oncologist, 2022, 27, 323–327

https://doi.org/10.1093/oncolo/oyab081
Advance access publication 5 March 2022
Original Article

Methadone as First-line Opioid for the Management of

Cancer Pain
Sebastiano Mercadante1,∗, Claudio Adile1, Patrizia Ferrera1, Maria Caterina Pallotti2,
Marianna Ricci2, Giuseppe Bonanno1, Alessandra Casuccio3
1
Main Regional Center for Pain Relief & Supportive/Palliative Care, La Maddalena Cancer center, Palermo, Italy
2
Palliative Care Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy

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3
Department of Health Promotion, Maternal and Infant Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo,
Palermo, Italy
∗Corresponding author: Sebastiano Mercadante, MD, Main Regional Center for Pain Relief & Supportive/Palliative Care, La Maddalena Cancer center, La
Maddalena, Via San Lorenzo 312, 90146 Palermo, Italy. Email: [email protected], 03sebellemail.com

Abstract
Aim: The aim of this study was to assess the efficacy and adverse effects of methadone when used as first-line therapy in patients that are
either receiving low doses of opioids or none.
Methods: Patients with advanced cancer were prospectively assessed. Opioid-naive patients (L-group) were started with methadone at 6 mg/
day. Patients receiving weak or other opioids in doses of <60 mg/day of OME (H-group) were started with methadone at 9 mg/day. Methadone
doses were changed according to the clinical needs to obtain the most favorable balance between analgesia and adverse effects. Edmonton
Symptom Asssement Score (ESAS), Memorial Delirium Assessment Score (MDAS), doses of methadone, and the use of adjuvant drugs were
recorded before starting the study treatment (T0), 1 week after (T7), 2 weeks after (T14), 1 month after (T30), and 2 months after (T60).
Methadone escalation index percent (MEI%) and in mg (MEImg) were calculated at T30 and T60.
Results: Eighty-two patients were assessed. In both groups H and L, there were significant changes in pain and symptom intensity at the dif-
ferent times during the study. Adverse effects as causes of drop-out were minimal. Mean MEImg was 0.09 (SD 0.28) and 0.02 (SD 0.07) at T30
and T60, respectively. MEI% was 1.01 (SD 3.08) and 0.27 (SD 0.86) at T30 and T60, respectively.
Conclusion: Methadone used as a first-line opioid therapy provided good analgesia with limited adverse effects and a minimal opioid-induced
tolerance.
Key words: cancer pain; opioids; methadone.

Implications for Practice

Methadone initiated at low doses in opioid-naive patients or those receiving low doses of opioids are effective and highly tolerated.
The tendency to develop tolerance seems to be negligible. Methadone seems to be easier to use as first-line drug than for opioid
switching, for which high experience is needed.

Introduction overexpression (that is associated with tolerance and hyper-

About 60% of cancer patients will suffer from pain that be- algesia), and acts on the pain modulating descending tracts
comes moderate or severe in intensity.1 The pain tends to get in the medulla, also affecting reuptake of serotonin and nor-
worse as the disease progresses. The majority of cancer pa- epinephrine.7 As opioid dose escalation may cause hyper-
tients with pain will respond to opioid therapy.2 Opioid anal- algesia mediated by the N-methyl-D-aspartate (NMDA)
gesics remain of paramount importance for the management pathway, a peculiar opioid such as methadone may prevent
of cancer pain, and each of these drugs may have a role in par- or inhibit the development of tolerance and hyperalgesia
ticular conditions, thus increasing the chances of the achieve- through blockade of NMDA receptor, especially at low
ment of good analgesia for most patients.3,4 doses.8,9
A large availability of drugs is a fundamental oppor- Currently, methadone has been reported to be highly ef-
tunity in treating a condition like cancer pain in individ- fective for opioid switching10 in patients poorly responsive to
uals.5,6 Methadone is a strong opioid drug that displays a previous opioid. The pharmacokinetic profile of methadone
an important peculiarity: it binds to μ-receptor like other is complex and in some circumstances, even low doses can
strong opioids, but unlike the others, its continuous admin- result in an unpredictable response or opioid overdose, par-
istration induces much less N-methyl-D-aspartate (NMDA) ticularly when switching from an opioid given at high doses.11

Received: 25 May 2021; Accepted: 13 October 2021.

© The Author(s) 2022. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/),
which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
324 The Oncologist, 2022, Vol. 27, No. 4

The use of oral low-dose methadone added to existing tool for measuring the principal physical and psychological
opioid therapy to treat cancer pain is a promising option in symptoms on a scale from 0 to 10.18 MDAS is a 10-item
preliminary reports where its use provided an improvement in clinician-rated assessment scale that has been validated for
pain and was well tolerated. The opioid escalation index sig- the assessment of delirium in cancer patients.19 Causes of
nificantly decreased after adding methadone in low doses and drop-out, including uncontrolled pain, adverse effects, poor
this trend was also maintained for weeks, without inducing complicance, or death, were recorded. Methadone escal-
significant opioid-related adverse effects.12-15 Indeed, the ation index percent (MEI%) was calculated at T30 and T60.
pharmacological properties of methadone suggest that its use This score expresses the mean increase of opioid dosage
would be more convenient when started at low doses and then percent from methadone starting dose (MSD), according to
escalated slowly. Starting with a small dose and increasing the following formula: [(MMD-MSD)/MSD]/days × 100,
gradually should be expected to be safer, also allowing for where MMD is the maximal dose of methadone. MEI in mg
methadone to be initiated in outpatients. Some case series (MEI mg) was calculated as the mean increase of methadone
have shown that methadone could be used as the first-line dosage in milligrams using the following formula: (MMD
opioid therapy.16 However, all these studies were retrospective - MSD)/days.20

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and interpretation may be problematic. Recently, a short-term
titration study has shown that first-line, low-dose methadone Ethical Considerations
resulted in a rapid decrease in pain intensity, with minimal All patients provided written informed consent. The study
need for titration and no evidence of accumulation or sed- was approved by the Ethical committee of the University of
ation.17 The aim of this prospective study was to assess the Palermo (n.6/2016 on June 22, 2016),
efficacy and adverse effects of methadone when used as first-
line therapy in patients not receiving opioids or receiving low Statistics
doses of opioids. The secondary outcome was to assess the The sample size was based on previous studies examining
need for dose escalation in a relatively long-term period of 2 the use of other opioids started at low doses.21-23 Continuous
months. variables are presented as mean (SD) and categorical vari-
ables are expressed as a number of patients (percentage).
Chi-square or Fisher exact tests were used for categorical
Methods
variables, as appropriate, and the univariate analysis of
Study Design variance (ANOVA) test was performed to evaluate mean
This is a prospective longitudinal study conducted in 2 pallia- differences between patient groups. The repeated measures
tive care centers in Italy, for a period of 1 year (from January ANOVA test was used to compare continuous variables at
2020 to December 2020). Consecutive patients who agreed different time intervals. The data were analyzed by the SPSS
or were able to be re-assessed subsequently up to 2 months software, version 22 (SPSS Inc., Chicago, IL, USA). All stat-
were selected. istical tests were 2-tailed, and statistical significance was de-
fined as P ≤ .05.
Patients
Adults patients with cancer pain who required opioid therapy Results
were screened. Inclusion criteria were age >18, cancer diag-
nosis, Karnofsky level ≥ 40%, chronic pain with moderate- Eighty-two patients met inclusion and exclusion criteria. The
severe intensity, with no opioid treatment, or receiving main characteristics of patients are described in Table 1. Pain
oral morphine equivalents (OME) of less than 60  mg/day. mechanisms were (rank order) the following: mixed (n.49),
Exclusion criteria were the use of ≥ 60  mg/day of OME,
contraindications to the use of opioids, severe liver dysfunc-
tion, an expected survival of less than 30 days, cognitive Table 1. Characteristics of patients.
failure measured by the Memorial Delirium Assessment Scale
(MDAS ≥ 13), or poor collaboration. Age, mean (SD) 66.6 (11.2)
In opioid-naive patients (L-group), methadone was started Gender, M/F, N° (%) 43 (52.4)/39 (47.6)
in doses of 6  mg/day (2  mg, 3 times a day). In patients re-
Karnofsky, mean (SD) 56.4 (12.6)
ceiving weak opioids, like codeine or tramadol, or other opi-
OME mg, mean (SD) 27.0 (12.6)
oids in doses of <60 mg/day of OME (H-group), methadone
was started at 9  mg/day (3  mg, 3 times a day). Methadone MDAS (SD) 4.2(2.9)
doses were changed according to the clinical needs to obtain Primary tumor
the most favorable balance between analgesia and adverse ef-  Lung 18 (22)
fects. The study was concluded in 2 months.  Breast 14 (17.1)
 Gynecological 5 (6.1)
Measurements
 Urogenital 6 (7.3)
Age, gender, primary diagnosis, the use or disease-oriented  Gastrointestinal 19 (23.2)
treatment, and Karnofsky status were recorded. Previous
 Prostate 10 (12.2)
analgesic treatment was also recorded. Pain mechanism
and pain sites were assessed. The Edmonton Symptom  Hematologic 1 (1.2)
Assessment Score (ESAS), Memorial Delirium Assessment  Head and neck 4 (4.9)
Scale (MDAS), doses of methadone, and the use of adju-  Others 5 (6.1)
vant drugs were recorded before starting the study treat-
ment (T0), 1 week after (T7), 2 weeks after (T14), 1 month Abbreviations: MDAS, Memorial Delirium Assessment Score; OME, oral
after (T30), and 2 months after (T60). ESAS is a validated morphine equivalents.
The Oncologist, 2022, Vol. 27, No. 4 325

nociceptive (n.29 = somatic n.7, visceral n.6, somatic-visceral in opioid-naive patients or patients receiving low doses of
n.16), and neuropathic (n.4). Thirty-five patients dropped out opioids. Methadone provided significant analgesia and was
before 2 months for different reasons; in rank order: uncon- well tolerated for the 2 months taken into consideration for
trolled pain (n.1 and n.1 in group L and H, respectively), ad- the study. Other than pain, most symptoms improved, as a
verse effects (n.9 and n.2 in group L and H, respectively), poor consequence of a typical comprehensive palliative care ap-
compliance (n.3 and n.1 in group L and H), and death (n.16 proach. Moreover, the dose increases of methadone were
and n.2 in group L and H, respectively). Analgesics and doses minimal (35% and 15% in 2 months in groups H and L,
of opioids used before starting methadone are listed in Table respectively). In comparison with other studies assessing
2. In both groups H and L, there were significant changes in the OEI of buprenorphine, fentanyl, and morphine, given
symptom intensity at the different intervals of the study period at low starting doses,21-23 MEI was minimal. This finding
(Tables 3 and 4). Methadone doses significantly increased at suggests that methadone has a low potential for inducing
T60 (P = .03) in group L, but not in group H. MEImg was opioid tolerance, confirming data gathered from experi-
0.09 (SD 0.28) and 0.02 (SD 0.07) at T30’ and T60’, respect- mental studies.24
ively. MEI% was 1.01(SD 3.08) and 0.27 (SD 0.86) at T30’ Some retrospective studies have shown the benefit of

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and T60’, respectively. No differences in MEI% and MEImg using low doses of methadone. In a retrospective study,
either at T30’ and T60’ between groups H and L were found. methadone was given in median doses of 5 mg/day at first
and 7.5  mg/day mg at the final assessment. Patients on
methadone were less likely to be switched to other opioids
Discussion and had a longer time to switch than patients on other opi-
This is the first study assessing the efficacy and adverse ef- oids.25 The use of very-low-dose methadone (median 5 mg)
fects of low doses of methadone, used as a first-line opioid in conjunction with haloperidol resulted in excellent pain
control with no relevant dose escalation or opioid-induced
hyperalgesia, for both cancer and noncancer diseases.26 In
Table 2. Analgesics used before starting methadone. another series, the use of median methadone dose of 10 mg
daily in outpatients provided high success rates and low
Frequence Percentage Mean dose side effect profiles.27 Of interest, low doses of methadone
have been also reported as add-on therapy, as methadone
No analgesics 31 37.8
would be an adjuvant able to improve the response to other
Non-opioid analgesics 11 13.5 opioids.12,13,15,28
Weak-opioids 17 20.7 While promising, most of these studies were biased by meth-
(codeine-tramadol) odology issues and the quality of data due to the retrospective
Morphine 1 1.2 36 mg (0) design. Of interest, a regimen of flexible self-administered
Fentanyl 1 1.2 12 mcg/h (0) oral methadone was planned to achieve adequate analgesia,
Oxycodone 5 6.2 21 mg (8) while preventing toxic effects of methadone accumulation. In
Tapentadol 7 8.5 121 mg (27) the priming period of 3 days fixed doses of 9  mg for naive
Hydromorphone 1 1.2 8 mg (0) patients were given, then doses were given as needed. The ma-
jority of patients achieved good pain relief until death, with
Buprenorphine 1 1.2 8 mcg/h (0)
an escalation index of 0.3 mg a day. A mean of 2.4 doses a
Oxycodone/Naloxone 7 8.5 22/11 mg (7)
day was reported, including the fixed night-time dose. The
Total 82 100.0 extent of side effects was considered acceptable.29 The pre-
sent study confirmed this pioneer finding reporting a rela-
Opioid doses are expressed as mean (SD). Fentanyl = transdermal fentanyl. tively long-term evaluation at different time intervals. The

Table 3. Mean ESAS items (mean, SD) and methadone dose (mg, mean, SD) in group L.

T0 T7 T14 T30 T60 P intragroup

n = 62 n = 56 n = 52 n = 38 n = 27

Pain 5.9 (2.1) 2.6 (1.9) 2.9 (1.9) 2.7 (2.2) 2.9 (2.6) <.0005
Weakness 5.7 (2.4) 4.1 (2.4) 4.2 (2.4) 3.7 (2.5) 3.8 (3.3) <.0005
Nausea 1.5 (2.4) 0.5 (1.4) 0.6 (1.4) 1.0 (2.1) 0.9 (1.7) .001
Depression 3.2 (3.3) 2.5 (2.7) 2.5 (2.6) 2.2 (2.5) 2.6 (3.4) <.0005
Anxiety 3.9 (3.6) 2.7 (2.6) 2.6 (2.7) 2.5 (2.8) 2.6 (2.7) <.0005
Drowsiness 2.8 (2.4) 2.2 (2.5) 2.5 (2.7) 2.3 (2.5) 1.8 (2.0) <.0005
Dyspnea 1.6 (2.5) 0.8 (1.8) 1.2 (2.2) 1.3 (2.4) 1.2 (2.9) .006
Insomnia 4.3 (3.2) 2.1 (2.5) 1.4 (1.8) 1.7 (2.3) 1.2 (2.0) <.0005
Poor appetite 3.2 (3.4) 2.1 (2.4) 2.2 (2.5) 2.2 (3.0) 2.1 (2.6) <.0005
Poor well-being 4.9 (3.0) 3.3 (2.7) 3.1 (2.5) 2.6 (2.7) 2.9 (2.8) <.0005
Total ESAS 36.6 (15.8) 23.1 (13.8) 23.4 (13.1) 22.3 (13.3) 21.9 (17.5) <.0005
Methadone doses 6 6.2 (1.6) 6.6 (2.7) 7.2 (4.2) 9.1 (4.9) .03
326 The Oncologist, 2022, Vol. 27, No. 4

Table 4. Mean ESAS items (mean, SD) and methadone dose (mg, mean, SD) in group H.

T0 T7 T14 T30 T60 P intragroup

n = 20 n = 18 n = 16 n = 15 n = 13

Pain 6.7 (2.1) 3.6 (1.6) 3.4 (2.0) 3.7 (1.9) 2.5 (1.7) <.0005
Weakness 5.8 (3.0) 4.4 (2.2) 4.6 (3.0) 4.5 (2.2) 4.2 (2.6) <.0005
Nausea 1.6 (2.2) 0.3 (0.8) 1.5 (2.8) 0.5 (1.6) 1.6 (3.0) .011
Depression 3.8 (2.9) 2.1 (2.2) 2.2 (2.0) 2.0 (1.5) 3.7 (2.2) <.0005
Anxiety 3.2 (3.6) 2.8 (2.4) 2.0 (2.2) 3.1 (2.6) 3.0 (2.5) <.0005
Drowsiness 3.6 (3.1) 3.1 (2.7) 3.6 (3.2) 2.7 (2.8) 2.9 (2.5) .001
Dyspnea 1.3 (2.4) 0.7 (1.4) 1.1 (1.7) 0.8 (1.4) 0.8 (1.2) .04
Insomnia 4.0 (3.0) 1.1 (1.6) 1.2 (1.7) 1.7 (1.9) 0.9 (1.4) <.0005

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Poor appetite 3.6 (3.0) 1.6 (1.9) 2.2 (3.3) 0.7 (1.9) 2.2 (3.6) <.0005
Poor well-being 4.7 (3.5) 2.1 (2.4) 2.8 (2.9) 2.7 (1.4) 2.5 (2.9) .001
Total ESAS 38.4 (19.6) 21.7 (10.8) 25.2 (17.9) 22.5 (11.5) 25.2 (19.6) <.0005
Methadone dose 9 10 (3.2) 11.2 (7.9) 11.7 (8.3) 10.5 (4.7) .281

study suggests that methadone can be an effective and safe be repliable everywhere. On the other hand, the slow doses
drug also as first-line therapy, possibly with less risks that can and subsequent titration according to clinical effects should
be encountered when switching from another drug to metha- have a protective role in avoiding possible methadone ac-
done, as second-line therapy, due to difficulties in dose con- cumulation and the development of toxicity. The strengths
version ratio and modality to be used for opioid switching. were based on a pragmatic approach based on a routine clin-
A recent titration study has shown that methadone given at ical practice, individualizing the treatment according to the
low starting doses (median 5  mg/day) as the first-line drug clinical needs to obtain the best balance between analgesia
was effective and did not require relevant dose escalation in a and adverse effects, and monitoring the effects for a reliable
period of 1 week.17 period of time of 2 months. Of course, this interval is asso-
Pioneer studies, performed in patients who needed to pass ciated with more possibilities to drop out or death, that was
to the third step of the analgesic ladder, have shown that the most frequent cause of missed data at T60. This is an
methadone doses did not significantly change in time while inevitable bias in the advanced cancer population. Further
doses of morphine had to be consistently increased. The mean comparative studies should be performed to make definitive
dose of oral methadone ranged from 14 mg at day 7 to 23 mg conclusions on the advantages of methadone over other opi-
at day 90.30 In another study performed in advanced cancer oids, particularly in maintaining low doses for prolonged
patients followed at home, methadone doses were success- periods of time.
fully increased from a mean of 14 mg daily to 27 mg days,
with a slow MEI of 0.3 mg/day.31
Conclusion
In a comparison study, a clear reduction in the intensity
of the pain was seen followed by a constant control of pain Starting methadone at low doses in patients requiring opioids
during the remaining period. No statistically significant differ- for cancer pain is effective and safe, and is associated with
ences were noted in analgesic efficacy between morphine and minimal increases in opioid doses in the medium-term period.
methadone. Indeed, a 63% increase in the dose of morphine The use of low doses of methadone ab initio may be of crucial
was observed (from an initial mean of 72 mg daily up to a final importance in cancer patients with the increased survival time
of 119 mg daily), while daily doses of methadone remained improved by the current new therapies.
stable (about 18  mg daily).32 In another comparison study,
advanced cancer patients were started with a mean daily dose
of 32 mg of morphine and 13 mg of methadone. The OEI was Funding
1.3 and 0.2 mg/day in morphine and methadone groups, re- None declared.
spectively.33 A further comparative study showed that metha-
done (12 mg/day), fentanyl (25 mcg/h) and morphine (60 mg/
day) provided similar analgesia, although methadone initially Conflict of Interest
required more up and down changes until dose stabilization
The authors indicated no financial relationships.
than morphine.34 In contrast, a higher rate of dropouts due to
opioid-induced side effects during titration was found with
methadone than with morphine. This was probably due to the
strong ratio (1:2) used between morphine and methadone.35
Author Contributions
Of interest, methadone has been used for prolonged periods Conception/Design: S.M., C.A. Provision of study material/
of time, even after hospital discharge36, and its use seems to be patients: P.F., M.C.P., M.R., G.B. Collection and/or assembly
not associated with a shorter survival.37 of data: P.F., M.C.P., M.R., G.B. Data analysis and interpret-
There were some limitations of this study. Patients were ation: S.M., C.A. Manuscript writing: S.M. Final approval of
recruited in 2 experienced centers so that data could not manuscript: All authors.
The Oncologist, 2022, Vol. 27, No. 4 327

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