Keywords
methadone - cancer pain - opioid rotation - equianalgesic conversion - pain relief
- side effects
Introduction
Palliative care aims to enhance the quality of life for individuals facing life-limiting
illnesses, focusing on the relief of suffering and the provision of physical, psychosocial,
and spiritual support. Effective pain management lies at the core of palliative care.[1] Opioids have long been the mainstay of analgesic therapy in palliative care, providing
effective pain relief for patients with moderate to severe pain. Among the opioids
used, methadone has emerged as a distinctive and increasingly utilized option. Originally
developed as a long-acting analgesic and an alternative to morphine for chronic pain
management, methadone's unique pharmacological properties make it an asset in the
palliative care setting.[2]
As a long-acting opioid agonist and N-methyl-D-aspartate (NMDA) receptor antagonist,
methadone is useful for treating both nociceptive and neuropathic pain. It is a racemic
combination of R and S enantiomers, with R being 8 to 50 times more powerful than
the S enantiomer[3] ([Fig. 1]). Methadone's mechanism of action involves blocking the reuptake of serotonin and
norepinephrine, as well as binding noncompetitively to NMDA receptors. Furthermore,
methadone interacts with opioid receptors, specifically the mu, kappa, and delta subtypes.[3] Its distinct mode of action is thought to be what reduces the potential tolerance
that can arise with long-term opioid pain management. Patients with renal and hepatic
impairment, who have few options left for opiates, benefit the most from methadone.
Rotations to methadone are complex. Various methods can be employed to transition
to methadone, including rapid conversion or the stop-and-go approach (which entails
ceasing the initial opioid and switching to methadone at an equianalgesic dosage),
cross tapering, the 3-day switch (which involves gradually reducing the current opioid
dosage while progressively increasing the daily methadone dose over a 3-day period)
and ad libitum (wherein patients self-adjust their methadone dosage using pro re nata).
However, no evidence suggests that any of these methods is more efficacious than the
others.[2]
[4]
[5]
Fig. 1 Methadone chemical formula. (Adapted from: PubChem [Internet]. Bethesda (MD): National
Library of Medicine (US), National Center for Biotechnology Information; 2004. PubChem
Compound Summary for CID 4095, Methadone [cited August 28, 2023]. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Methadone.)
In India, methadone was first made available in 2012 as a substitute therapy drug
to treat opioid addiction. In 2014, it was made available commercially for the treatment
of pain.[6] In 2017, oral methadone was added to the 20th edition of the World Health Organization's
standard list of essential medications.[7] Methadone proves highly effective in the treatment of complex pain syndromes often
seen in India's prevalent types of cancer, such as head and neck, genitourinary, breast,
and gastrointestinal cancers. These pain syndromes involve a combination of nociceptive
and neuropathic pain.[8] In clinical practice, when considering the appropriate choice among methadone, morphine,
fentanyl, buprenorphine, tapentadol, and tramadol for managing cancer pain, it is
imperative to adopt a comprehensive and evidence-based approach. These analgesic agents
possess varying pharmacological profiles, efficacy, and potential adverse effects.
The selection of the most suitable option should be guided by the principles of personalized
medicine, considering patient-specific factors and the nature of the pain being addressed.[9] Methadone, an opioid with NMDA receptor antagonist properties, can be considered
when there is neuropathic pain or opioid resistance. However, careful dose titration
and monitoring of electrocardiogram parameters, especially the QT interval, are crucial
due to the potential for QT prolongation and torsades de pointes (TdP) (distinctive
form of polymorphic ventricular tachycardia).[4] Morphine, a classic opioid, remains a cornerstone for cancer pain management. Its
wide range of formulations (immediate-release, extended-release, and intravenous)
allows tailoring of treatment to the patient's pain pattern. The equianalgesic conversions
between opioids should be followed meticulously to ensure a smooth transition.[10] Fentanyl, available in various delivery forms (transdermal patches, buccal lozenges,
and parenteral formulations), is advantageous for patients who have difficulty with
oral medications such as in head–neck cancers or require rapid onset of action (intravenous
route). Dose titration is essential to avoid overdosing when switching to or from
fentanyl due to its potent nature.[11] Buprenorphine, a partial mu-opioid receptor agonist, can be considered for patients
with a history of substance abuse or for those needing long-term pain management.
Its ceiling effect on respiratory depression contributes to its relative safety, although
its efficacy in severe cancer pain might be limited.[12] Tapentadol could be considered for moderate to severe pain with neuropathic components.
It combines mu-opioid agonism with norepinephrine reuptake inhibition. Side effects
include potential for serotonin syndrome in combination with serotonergic medications.[13] Tramadol, an atypical opioid, has both mu-opioid receptor agonism and serotonin–norepinephrine
reuptake inhibition. It can be useful in mild to moderate cancer pain with a neuropathic
component. Caution is advised in patients with a predisposition to seizures, as tramadol
lowers the seizure threshold.[14]
In all cases, an individualized approach should be followed, considering factors such
as the patient's pain intensity, previous opioid exposure, comorbidities, concurrent
medications, and potential drug interactions. Regular assessment of pain relief and
monitoring for adverse effects are pivotal. Multidisciplinary collaboration involving
pain specialists, oncologists, pharmacists, and palliative care experts can further
optimize pain management strategies ([Supplementary Materials 1] and [2]). Cost can be a guiding factor while choosing pain medications, especially in settings
where patients must pay out of pocket.[15] For a weeks' supply, fentanyl is available as expensive transdermal patches (for
fentanyl 25 µg transdermal patch [one patch lasts for 3 days]: INR 1000 – INR 2000
compared with INR 150 – INR 300 for equianalgesic dose of morphine, INR 600 – INR
1000 for buprenorphine patch [one patch lasts for 7 days], INR 400 – INR 600 for tapentadol,
and INR 200 – INR 300 for tramadol). Methadone, on the other hand, is cheap (INR 150
– INR 200 for equianalgesic dose of methadone supply for a week) and a suitable alternative
for opioid rotation in refractory cases.[16]
The primary goal of this study is to provide a review of our experience using methadone
as either a coanalgesic or primary option for cancer pain management. Additionally,
we aim to increase awareness about the use of opioids, particularly methadone, for
cancer pain relief.
Methods
We conducted a retrospective analysis of the anonymized medical records of cancer
patients who were initiated on oral methadone for pain management at the palliative
medicine outpatient clinic in a tertiary cancer center. The review encompassed the
period from February 2020 to June 2021. The data extracted from patients' medical
records encompass various aspects, including demographic characteristics, diagnosis,
comprehensive pain description (including type, severity, and baseline morphine equivalent
daily doses [MEDD]), concurrent usage of other analgesics, rationale for transitioning
to methadone, approach employed for rotation, ultimate and anticipated methadone dosage,
clinical outcomes related to pain management, any observed adverse effects, and information
pertaining to the withholding or discontinuation of methadone treatment. These patients
were routinely followed up at 1-, 2-, and 4-week intervals after starting methadone,
and the pain scores, MEDD, and methadone requirements were charted at each follow-up.
Results
Between February 2020 and June 2021, 44 patients received methadone as a coanalgesic
(41/44) or primary opioid (3/44) ([Table 1]). Among the participants, 24 individuals experienced a combination of somatic nociceptive
and neuropathic pain, while 15 individuals reported a mixture of visceral nociceptive
and neuropathic pain. Additionally, three participants exclusively had somatic nociceptive
pain, and two patients specifically reported neuropathic pain. Refractory cancer pain
not responding to “standard” treatments was the indication for methadone for 41 patients,
the rest had a deranged liver function and one deranged renal function. Before methadone,
the median numeric rating scale pain score was 8 (severe), standard deviation (SD)
1.4, with 53.49% MEDD ranging from 60 to 120 mg (median: 120 mg, SD: 74.9 mg). Forty-one
had undergone rotation to methadone as a coanalgesic with a nonmethadone opioid, while
three were solely on methadone. All patients received adjuvant analgesics as needed.
The method used for opioid conversion was as per dosing ratio given by Ripamonti et
al for opioid switching.[17] Those patients where low-dose methadone was added as coanalgesic, opioid semiswitching
was done using the method described by Mercadante et al.[18] The dose was gradually titrated up in subsequent outpatient consultations as per
requirement.
Table 1
Demographics of patients (n = 44)
|
Items
|
Numbers
|
Percentage
|
|
Gender distribution
|
|
Male
|
24
|
55.81%
|
|
Female
|
20
|
44.19%
|
|
Age distribution (y)
|
|
18–20
|
2
|
4.65%
|
|
21–40
|
16
|
37.21%
|
|
41–60
|
17
|
37.21%
|
|
61–80
|
9
|
20.93%
|
|
Site of primary cancer
|
|
Bone and soft tissue
|
8
|
18.60%
|
|
Breast
|
4
|
6.98%
|
|
Gastrointestinal
|
3
|
6.98%
|
|
Genito urinary
|
9
|
20.93%
|
|
Head and neck
|
8
|
18.60%
|
|
Hematological and lymphoid
|
1
|
2.33%
|
|
Hepatopancreatobiliary
|
3
|
6.98%
|
|
Lung
|
7
|
16.28%
|
|
Primitive neuroectodermal tumor
|
1
|
2.33%
|
|
Comorbidities
|
|
None
|
32
|
74.42%
|
|
Hypertension
|
5
|
11.63%
|
|
Diabetes mellitus
|
3
|
4.65%
|
|
Hepatitis B
|
1
|
2.33%
|
|
Multiple comorbidities
|
3
|
6.98%
|
|
Type of pain[a]
|
|
Somatic nociceptive and neuropathic
|
24
|
53.49%
|
|
Visceral nociceptive and neuropathic
|
15
|
34.88%
|
|
Pure neuropathic
|
2
|
4.65%
|
|
Somatic nociceptive
|
3
|
6.98%
|
|
MEDD prior to starting methadone (mg)
|
|
60–120
|
23
|
53.49%
|
|
121–180
|
5
|
9.30%
|
|
181–240
|
14
|
32.56%
|
|
>240
|
2
|
4.65%
|
|
Median score
|
Standard deviation
|
|
Numerical rating scale for pain (0–10)
|
|
Before starting on methadone
|
8
|
1.4
|
|
Week 1
|
3
|
1.6[b]
|
|
Week 2
|
2
|
1.6[b]
|
|
Week 4
|
2
|
1.3
|
|
MEDD (mg)
|
|
Before starting on methadone
|
120
|
74.9
|
|
Week 1
|
60
|
40.5[b]
|
|
Week 2
|
60
|
44.5
|
|
Week 4
|
60
|
24.8
|
|
Starting daily dose of methadone (mg)
|
|
At start
|
5
|
1.5
|
|
Week 1
|
7.5
|
2
|
|
Week 2
|
7.5
|
2.8
|
|
Week 4
|
10
|
3.2
|
|
QTc interval before starting methadone (ms)
|
|
Before starting on methadone
|
418
|
25.2
|
|
Week 1
|
447
|
26
|
|
Week 2
|
428.5
|
25.1
|
|
Week 4
|
425.5
|
18.5
|
Abbreviation: MEDD, morphine equivalent daily doses.
a Bone pain in 16, myofascial pain in 7, and opioid-induced hyperalgesia in 2.
b
p < 0.01 on Wilcoxon's signed ranks test.
Following the initiation of methadone therapy, all patients experienced sufficient
pain relief. The median daily dose of methadone upon commencement was 5 mg (SD 1.5 mg),
which increased to 7.5 mg (SD 2 mg) after 1 week. All patients were successfully followed
up on an outpatient/home care basis with adequate pain control. Among the patients
who initiated methadone therapy, none experienced adverse effects such as respiratory
depression. Nonetheless, in one patient, we had to discontinue the methadone after
8 weeks due to a prolonged QTc interval and chest discomfort. It is important to note
that the median QTc interval remained below 425 milliseconds for the remaining patients.
Ten patients developed constipation, in 3 patients, methadone was stopped by treating
oncologists, 5 patients continued to be on methadone, 7 stopped by themselves as they
had adequate pain control even without methadone, 2 stopped as they went back to villages
where they had no access to methadone, 22 patients died due to disease progression
within this time, and in 4 patients, interventional procedures were performed for
pain management.
Discussion
Methadone is an effective opioid for treating cancer pain, with a safety profile like
that of other opioids. Rotation to methadone was helpful in all 44 patients with cancer
pain who were being treated in this study. The neuropathic component of the pain in
40 patients may be the cause of its refractory nature. An evidence-based dose conversion
protocol[17]
[18] was used with all the patients, and it was found to be a quick and efficient technique
to determine optimal dose of methadone needed in an outpatient context. Neither the
MEDD nor the projected methadone dose corresponded to the actual methadone dose that
was needed. Considering how refractory pain can be, the MEDD may have underestimated
the number of people who needed an increase in opioid dosage but did not receive one.
Transitioning from morphine to methadone can present complexities due to the possibility
of incomplete cross-tolerance. In future prospective studies, it would be valuable
to examine patient-controlled approaches such as the Morley–Makin method as a potential
alternative to fixed ratio equianalgesic conversion tables. This is because these
patient-controlled regimes enable the use of a lower dosage of methadone (sometimes
as low as 1/30th of the previous MEDD) while still achieving satisfactory analgesic
effects.[12] In this study, it was observed that a subset of patients (n = 2) reported increased pain levels with higher dosages of methadone. It is important
to note that the experience of pain in these cases may have been influenced by a range
of factors such as psychological, spiritual, or social discomfort. Exploring and addressing
these complex issues surrounding pain and its multifaceted nature and opioid safety
were beyond the scope of this study ([Supplementary Material 3]).
Methadone, especially at higher doses, can cause TdP and prolongation of the QTc interval.
The risk is higher when the QTc interval is more than 450 milliseconds. Those having
a QTc interval at baseline longer than 500 milliseconds should not be initiated on
methadone.[19] The median time for QTc was found to be 425 milliseconds in this analysis.
Given the limited participant size and retrospective design of the case series, it
is important to approach the interpretation of these findings with caution. Our comparison
table also does not include adjuvant analgesics or the different suggested methadone
conversion factors. Our results contribute to the mounting body of research suggesting
that patients' maintenance doses of methadone may be much different from what is suggested
by equianalgesic conversion tables and guidelines.[20]
Conclusion
When conventional drugs and therapies prove insufficient in providing relief for severe
and unmanageable cancer pain, an alternative option is to consider opioid rotation
to methadone. The recommended approach for opioid rotation to methadone, as advised
by manufacturers, demonstrates both safety and effectiveness, particularly when conducted
under appropriate supervision in outpatient settings. Interestingly, our observations
indicate that actual dosages of methadone often differ slightly from those obtained
through equianalgesic conversion tables and guidelines. Consequently, physicians should
not solely rely on conversion tables when opting for opioid rotation, but instead
prioritize personalized titration, thorough assessment, and diligent clinical monitoring
during and following the rotation process to mitigate the risk of significant adverse
effects. Additional research is necessary to explore the potential utility of a modified
Morley–Makin approach in facilitating the rotation from other opioids to methadone.
