Drugs (2020) 80:115–130

https://doi.org/10.1007/s40265-019-01234-6

THERAPY IN PRACTICE

Emerging Challenges to the Safe and Effective Use of Methadone

for Cancer‑Related Pain in Paediatric and Adult Patient Populations
Kyle P. Edmonds1,2 · Ila M. Saunders2,3 · Andrew Willeford2,3 · Toluwalase A. Ajayi4 · Rabia S. Atayee1,2,3 

Published online: 9 December 2019

© Springer Nature Switzerland AG 2019

Abstract
Methadone continues to be an important medication for the treatment of paediatric and adult cancer-related pain. Appropriate
patient selection to ensure safe and effective treatment by a team of clinicians who appreciate and are familiar with metha-
done and its unique pharmacology is crucial. Unlike morphine and other more common opioids, methadone is purported to
have involvement with delta-opioid receptor and higher affinity as an N-methyl-d-aspartate-receptor antagonist. Clinically
this gives it the advantage of being effective for both nociceptive and neuropathic pain, but also may be useful in the setting
of tolerance to other opioids. Methadone also comes in multiple available formulations that can be administrated through a
variety of routes beyond the oral route. Challenges with methadone in treating cancer-related pain include drug interactions
specifically as it relates to new targeted cancer therapies. Recent guidelines recommend electrocardiogram monitoring with
methadone and there is potential for additive cardiac toxicity in the oncology setting. Appropriate dosing of methadone for
pain management given age, organ dysfunction, and patients who are on methadone maintenance therapy are also key factors.
This article aims to provide clinicians with evidence and clinical practice guidelines for safe and appropriate use of methadone
including indication, initiation, and monitoring given its complexity for management of pain in the dynamic oncology setting.

Key Points 
Methadone’s unique pharmacodynamic and pharmacoki-
netic features make it a useful analgesic agent when used
by knowledgeable prescribers.
Emerging cancer-directed therapies may present chal-
lenges to the utility and safety profile of methadone.
Methadone’s properties make it uniquely suited to the
treatment of mixed nociceptive-neuropathic pain; the
paediatric setting; and in the management of pain at end-
of-life.
* Rabia S. Atayee
ratayee@health.ucsd.edu
1
Doris A. Howell Palliative Care Teams, University
of California San Diego, La Jolla, CA 92093, USA
2
Skaggs School of Pharmacy and Pharmaceutical Sciences,
University of California San Diego, La Jolla, CA 92093,
USA
3
Department of Pharmacy, University of California San Diego
Health, La Jolla, CA, USA
4
Digital Medicine, Scripps Research Translational Institute,
La Jolla, CA 92037, USA
1 Introduction
1.1 Clinical Impact of Pharmacodynamics
Methadone is a synthetic opioid that often exists as a racemic
mixture. The (R)-enantiomer exerts nearly all the pharmaco-
logical effects of methadone with respect to opioid receptor
activation [1]. While methadone is primarily regarded as a
mu-opioid agonist, it has been shown to interact moderately
with the delta- and minimally with the kappa-opioid recep-
tors [2]. Methadone has been demonstrated to bind the delta-
opioid receptor with affinity similar to that of morphine [2]
and may produce some of its analgesic effects through this
receptor. In contrast to morphine, methadone has been dem-
onstrated to induce delta-opioid receptor desensitisation at
the cellular level [3–5]. This finding is believed to partially
underlie the differences between methadone and morphine
with regards to addiction and tolerance [3–6]. Also unique
to methadone among other opioids is its affinity for the
N-methyl-d-aspartate (NMDA) receptor where it acts as an
antagonist [7, 8]. The NMDA receptor is a glutamatergic
receptor that promotes pain signal transmission through
regulation of calcium influx into neurons [9, 10]. Metha-
done exhibits antinociceptive effects through blockade of
NMDA receptor activation in animal studies [11, 12] and

Vol.:(0123456789)

116
is thought to modulate perception of neuropathic pain in
humans through this pathway [13–15]. Multiple studies have
revealed the NMDA receptor as a critical player in mor-
phine tolerance [16–19]; therefore, increased opioid anal-
gesic effect after converting to methadone (i.e. incomplete
cross-tolerance) requires special attention in finding both an
efficacious and safe dose [20].
1.2 Clinical Impact of Pharmacokinetics
Methadone can be administered orally, sublingually, buc-
cally, intravenously, subcutaneously or intramuscularly.
Following oral administration, methadone is well absorbed
with bioavailability ranging from 36 to 100% [21]. Bioavail-
ability is often in the range of 80–90%; however, given the
broad range, variability, and the risks of methadone, err-
ing on the side of caution is recommended. Upon entering
the plasma, methadone binds to alpha-1-acid glycoprotein
with a bound fraction ranging from 85 to 90% and, due to
its lipophilic nature, is widely distributed into tissues [21].
With respect to metabolism, the opioid is largely bio-trans-
formed through n-demethylation by hepatic and intestinal
CYP3A4 as well as CYP2B6 and CYP2D6 [1, 22]. Given its
enzymatic metabolism, coadministration of methadone with
CYP inducers and inhibitors should be closely monitored.
Furthermore, important pharmacogenomic consequences
exist as shown in studies demonstrating clinically relevant
effects of CYP3A4 and CYP2B6 polymorphisms on metha-
done plasma concentrations and side effects [23–26]. After
intravenous administration, methadone exhibits biexponen-
tial decay with respect to its plasma concentration and has
been shown to have a distribution half-life of roughly 2–4 h
[27]. In contrast, the agent has a longer and more varia-
ble elimination half-life of 8–59 h [21], which reflects the
time to steady-state plasma concentration of approximately
5 days [21]. Although its half-life is long, methadone has
a relatively short duration of analgesia, lasting between 4
and 12 h [20, 28, 29], which is likely related to the initial
rapid decline in plasma concentration during the distribution
phase. This pharmacokinetic property necessitates a need
for more frequent, often twice or thrice, daily dosing. Given
the dichotomy between the elimination half-life and duration
of action, methadone users are at risk for accumulation and
adverse effects, particularly during the first 5 days as steady-
state is achieved [29, 30].
1.3 Impact on the QT Interval
Prolongation of the QT appears to be due to modulation of
the voltage-gated potassium channels of the heart, poten-
tially by the (S)-enantiomer of methadone [31]. Impact on
QT prolongation is impacted by several factors, including
pharmacogenetic variance in the functioning of CYP2B6
K. P. Edmonds et al.
[31, 32]. In one prospective study of adults with can-
cer receiving oral methadone for cancer-related pain at a
median dose of 23 mg, there were no clinically significant
arrhythmias despite the fact that 28% of people had base-
line elevation of their corrected QT-interval [33]. A range of
20–25 mg/day is common dosing for methadone for the indi-
cation of pain [34] and therefore clinical significance of QTc
prolongation and necessity to monitor closely at this dosing
is unknown. A prolonged corrected QT (QTc) interval in
paediatric patients is defined as ≥ 460 ms [35]. In one pro-
spective study focused on the frequency of prolonged QTc
in the paediatric population, the authors found one incident
of significantly prolonged QTc which occurred in a patient
who had a history of prolonged QTc [36]. Similarly, another
study which retrospectively examined frequency and risk
factors of ­QTC showed that hospitalised children on metha-
done exhibited prolonged Q ­ TC more frequently when an
underlying cardiac disease was present. In addition, despite
the prolongation, no episodes of torsades were observed
[37]. It should also be noted that the preservative vehicle in
the intravenous formulation of methadone increases risk for
QTc prolongation [38].
There are two clinical guidelines related to the monitor-
ing of QT interval in those treated with methadone [20, 30].
Repeating the findings and recommendations of these guide-
lines is beyond the scope of this paper. However, the level
of vigilance in obtaining baseline and follow-up ECGs is
best categorised as low, moderate, or high and based on an
interprofessional assessment of the person’s goals of care,
see Table 1 [20].
1.4 Impact on Mortality
The most robust reviews of the risk of mortality are of
adults receiving methadone maintenance therapy (MMT)
for opioid use disorder (OUD) [39]. These reviews dem-
onstrate a nonsignificant trend toward fewer deaths among
those with OUD treated with MMT than those not receiv-
ing methadone [39]. Lower quality evidence found an
association between earlier course in methadone therapy
(recent initiation or shorter duration of treatment) and
methadone-related death [39]. Limited evidence compar-
ing methadone to morphine has not found methadone to
cause more mortality than morphine, although the strength
of the evidence was again low [39]. Cohort studies with
moderate strength of evidence have found that medication-
related deaths involving methadone are more common in
those with other medical comorbidities, overuse of metha-
done, concomitant use of benzodiazepines, and a history
of psychiatric admission [39]. Data on methadone-related
mortality in the treatment of cancer-related pain do not
exist.
Safe Use of Methadone for Cancer-Related Pain
Table 1  Vigilance levels for QT-interval monitoring for those on methadone for pain. Reprinted from McPherson et al. [20], Copyright 2019,
with permission from Elsevier
2 Patient Selection
Similar to selection of any opioid, the assessment of a
methadone candidate who has either not tolerated or not
responded to more routine opioid regimens begins with con-
sideration of their (1) need for a long-acting pain medication
in non-tablet form; (2) pain characteristics; (3) historical
adherence to medication regimens; (4) ability to follow-
up with a prescriber knowledgeable about methadone; (5)
baseline risk for opioid misuse; (6) misunderstandings about
methadone. This assessment is best performed by an inter-
professional team as exemplified by specialist palliative care
teams made up of physicians, advanced practice registered
nurses, nurses, social workers, spiritual care experts, and
clinical pharmacists [40, 41].
In most cases, methadone should be considered for
analgesia in those who are opioid-tolerant and who have
moderate-to-severe neuropathic-or mixed (nociceptive and
neuropathic)-type pain requiring a long-acting opioid [20,
30, 42]. Additionally, in the paediatric population, special
consideration for methadone is given for children who need
a long acting medication but are dependent on feeding tubes
or unable to swallow pills. Methadone is especially attrac-
tive as it is the only long-acting opioid available as a liquid,
117
allowing paediatric palliative care physicians to administer
it to very young patients.
Given the mixed mechanism of action at both opioid and
NMDA receptors, methadone potentially has a special role
to play in those with neuropathic components to their pain
[43]. However, this theoretical role of methadone has only
been demonstrated in limited and low-quality studies of its
efficacy in treating neuropathy [44]. As discussed above,
unique receptor-binding characteristics of methadone may
also provide it with a role to play in those who are demon-
strating true opioid tolerance [16–19] or in those with central
nervous system “wind-up” phenomenon such as allodynia
or hyperalgesia [45, 46]. For these reasons, there are also
those who utilise methadone as a co-analgesic agent, though
a full discussion of that practice is beyond the scope of this
manuscript [20].
Assessment should continue with consideration of the
patient’s historical adherence to medication regimens and
ability to follow-up with a knowledgeable prescriber of
methadone for pain [47]. Follow-up is especially impor-
tant to consider if methadone is being started in the hos-
pital setting [48]. Given the unique characteristics and
risks of methadone, it is critical that the patient can safely
follow medication administration instructions and has a

118
safe plan for the management and storage of their metha-
done [20]. Additional considerations may include whether
there are any access barriers to methadone including insur-
ance company formulary restrictions or availability at the
patient’s preferred pharmacy. Given the low cost of most
formulations of methadone, [20] expense is a less com-
mon barrier.
It is best practice to utilise standard opioid safety pre-
cautions with all patients prescribed a new long-acting opi-
oid agent and this is especially important for those being
started on methadone, see Table 2 [49]. A standard protocol
of assessment of baseline risk of opioid misuse [50] can be
determined by using either the Screener and Opioid Assess-
ment for Patients with Pain-Revised (­ SOAPP®-R) or the
Opioid Risk Tool [51–55]. Thus, a protocol for follow-up
and monitoring can be standardised based on level of risk
rather than more subjective criteria [50]. Involvement of spe-
cialists in social work as experts in assessing people in the
context of their lives and relationships can also enrich this
assessment [56–58].
Finally, should methadone be a safe analgesic option, it
is important to assess the patient’s and/or the patient’s car-
egiver’s pre-existing knowledge of methadone, which may
be influenced by pejorative depictions of those using MMT
for opioid use disorder (OUD) [59]. Although descriptions
of the impact of OUD-related stigma acting as a barrier to
methadone analgesia are very limited in the literature, we
find this to be a common concern among our patients. In
our practice, it works best to directly address this concern
by pointing out that some of the same features which make
methadone effective for OUD also make it a safe and effec-
tive analgesic agent.
3 Unique Challenges with Cancer Treatment
Food and Drug Administration (FDA) approval of anti-
cancer therapies has increased dramatically over the last
27 years [60]. The approval of molecular entities such as
tyrosine kinase inhibitors (TKIs) and immune checkpoint
inhibitors (ICIs) has far outpaced approvals for cytotoxic
chemotherapy and hormonal therapy [60, 61]. The approval
of these new agents brings new challenges related to phar-
macokinetic and pharmacodynamic drug interactions in
patients with concomitant pain medications, especially
methadone.
3.1 Pharmacokinetic Drug Interactions
While the majority of oral chemotherapeutic agents are
CYP3A4 substrates and do not impact methadone exposure,
the phosphoinositide-3-kinase (PI3K) inhibitor, idelalisib,
has the potential to dramatically increase the area under the
K. P. Edmonds et al.
curve (AUC) and maximum concentration (Cmax) of sen-
sitive CYP3A4 substrates such as methadone [62, 63]. In
initial pharmacokinetic studies of idelalisib, midazolam, a
major CYP3A4 substrate, was found to have a 2.4- and 5.4-
fold increased Cmax and AUC, respectively, when co-admin-
istered with idelalisib [62, 63]. This clinically significant
drug interaction was further illustrated in a case report by
Bossaer and colleagues in which a patient treated with diaz-
epam (a CYP3A4 substrate), developed altered mental status
and respiratory failure 10 days after idelalisib initiation. The
patient improved clinically once the idelalisib and diazepam
were discontinued [62, 64]. In contrast, the androgen inhibi-
tors enzalutamide and apalutamide significantly decrease the
AUC of sensitive CYP3A4 substrates. In pharmacokinetic
studies, enzalutamide and apalutamide decreased the AUC
of midazolam by 86% and 92%, respectively [65–67]. As
CYP2D6 also plays an important role in methadone metabo-
lism, caution is advised with concurrent use of methadone
with dacomitinib, a strong CYP2D6 inhibitor. In initial phar-
macokinetic studies, dacomitinib increased dextromethor-
phan (a CYP2D6 substrate) Cmax by 9.7-fold and AUC by
9.6-fold [68]. These interactions, especially with common
concomitant medications such as midazolam and diazepam,
are often overlooked in the clinical setting and caution is
advised to providers.
Concomitant administration of idelalisib, dacomi-
tinib, apalutamide, or enzalutamide with methadone
warrant caution. In addition, close monitoring for toxic-
ity and efficacy of methadone is warranted when these
cancer treatments are initiated or discontinued, as metha-
done exposure can be substantially affected. Similarly,
close monitoring may be warranted when methadone is
co-administered with moderate 3A4 and 2D6 inhibitors
and inducers (Table 3). While the use of idelalisib, dac-
omitinib, apalutamide, and enzalutamide is limited in the
very late phases of cancer when methadone is needed, the
clinical implications of these drug interactions are critical
considerations for patient safety.
3.2 Pharmacodynamic Drug Interactions
QTc prolongation occurs at a higher frequency in cancer
patients receiving targeted therapies (i.e. TKIs) compared
to cytotoxic chemotherapy. However, adverse effects such
as diarrhoea, emesis, mucositis, and poor nutrition related to
cytotoxic chemotherapy can also result in electrolyte distur-
bances, which can increase the risk of QTc prolongation [62,
82, 83]. Patients who start methadone while on cancer treat-
ments that can prolong the QTc should have baseline and
follow-up ECGs as recommended by the respective package
insert of each cancer treatment (Table 4) [62, 82, 83]. With
respect to methadone, if the baseline ECG demonstrates
a QTc greater than 450 ms, an alternative to methadone
Safe Use of Methadone for Cancer-Related Pain 119

Table 2  Universal precautions for the prescribing of opioids. Reprinted by permission from Springer Nature: Arthur and Reddy [159]. Also
reprinted by permission from Springer Nature: Arthur and Bruera [160]

Step Precaution Explanation

1 Pain diagnosis and differential
2 Initial screening
3 Informed consent
4 Treatment agreement
5 Opioid therapy ± adjuvant analgesics
6 Subsequent monitoring
7 Pain Outcome assessment
8 Comorbid conditions
9 Specialists referral
10 Documentation
Make an appropriate diagnosis of pain and/or differentials and determine the need for
chronic opioid therapy
Prior to starting opioid therapy, screen all patients using clinical interviews, physical exami-
nation, and risk assessment questionnaires in order to identify those at risk for nonmedical
opioid use: a comprehensive psychological assessment screening is particularly important
Discuss with patient the risks, benefits, adverse effects and alternatives of opioid therapy,
and provide opioid education on safe use, storage, and disposal
Obtain a verbal or written treatment agreement (opioid management plan) outlining patient
obligations, clinician responsibilities, and treatment expectations
Individualize opioid selection and dosing based on prevailing conditions (e.g., patient’s
health status, previous opioid exposure, present contraindications, anticipated complica-
tions); supplement therapy with non-opioid and/or adjuvant analgesics when applicable
At subsequent follow up visits, conduct periodic UDS, utilize PDMP if available, and
observe behavioral patterns to help determine treatment adherence and support therapeutic
decision making
Conduct pre- and periodic post- intervention assessment of pain intensity and functional
level to measure treatment progress and justify the rationale for continual opioid therapy;
use the “ five A’s of pain management outcome assessment; Analgesia, Activity (func-
tion), Adverse effects, Aberrant behavior, and Affect (mood)
Periodically review and address the pain diagnosis and other comorbid medical and psycho-
logic conditions including substance use disorders as these may evolve with time
Consider referral of high risk patients and those with complex opioid regimen to palliative
and pain medicine specialists for co-management
Carefully document all clinical encounters to ensure optimal patient care and minimize any
medicolegal ramifications or regulatory scrutiny

PDMP prescription drug monitoring programs, UDS urine drug screen

may be considered; if baseline QTc is greater than 500 ms,
methadone should not be initiated, and an alternative agent
must be used (Table 1) [20]. Furthermore, concomitant use
of methadone with arsenic trioxide, nilotinib, panobinostat,
and vandetanib should be avoided as these cancer treatments
have black box warnings for QT interval prolongation or
arrhythmias/ECG changes. In order to further minimise the
risk of prolonged QTc, electrolytes should be monitored and
repleted based on the patient’s clinical course and the side-
effect profile of the cancer treatment [82, 83].
While ICIs are not known to prolong the QTc, data
describing cardiotoxic effects of these therapies are emerg-
ing in the literature and may limit the use of QTc prolonging
agents such as methadone. Although the cardiotoxicity of
the ICIs is exceedingly rare (0.2– < 1%), these effects can be
serious and have the potential to be fatal [84]. Cardiotoxic-
ity related to ICIs can present as conduction disease (atrio-
ventricular block), myocarditis (heart failure, ventricular
arrhythmias), coronary artery disease (atherosclerotic plaque
rupture, acute myocardial infarction, coronary vasculitis),
non-inflammatory left-ventricular dysfunction (heart failure,
Takotsubo syndrome), or pericarditis (effusion, tamponade)
[84]. As management of patients with cardiotoxicity sec-
ondary to ICIs is challenging, albeit rare, risks and benefits
should be carefully considered prior to initiating methadone
in this delicate patient population.
4 Dosing of Methadone for Pain
4.1 Initiation and Titration
Although methadone is not commonly used in opioid-naïve
patients, some cancer pain cases may warrant its use under
specialist supervision. In these cases, an initial dose of 1 mg
PO q8h may be considered and titrated up further once the
drug reaches steady-state concentrations [20, 30]. In elderly
patients or those who may be more susceptible to methadone
effects and side effects, an initial lower dose of 2.5 mg every
night at bedtime should be considered with slow and careful
titration to q8h to reflect the pharmacokinetic (PK) proper-
ties of methadone [117]. If elderly patients are unable to
tolerate q8h dosing of methadone, then another opioid may
be more suitable. Although there are weight-based formulas
to initiate methadone, with loading doses, most paediatric
palliative care physicians prefer to use equianalgesic dosing
with dose reduction instead of weight-based formulas to ini-
tiate methadone [35]. This needs to be done cautiously and

120 K. P. Edmonds et al.

Table 3  Chemotherapeutic agents and potential impact on methadone exposure (adapted from [69, 70])
Chemotherapeutic agent Molecular target/class FDA-approved indication Impact on Impact on liver microsomes
Methadone
exposure

Idelalisib [63] PI3K inhibitor FL, CLL, SLL ↑↑↑ Strong 3A4 inhibitor
Enzalutamide [67] Androgen receptor inhibitor CRPC ↓↓↓ Strong 3A4 inducer
Apalutamide [66] Androgen receptor inhibitor CRPC ↓↓↓ Strong 3A4 inducer
Dacomitinib [68, 71] EGFR inhibitor mNSCLC ↑↑↑ Strong 2D6 inhibitor
Duvelisib [72] PI3 K inhibitor FL, CLL, SLL ↑↑ Moderate 3A4 inhibitor
Crizotinib [73] ALK inhibitor ALK + mNSCLC ↑↑ Moderate 3A4 inhibitor
Ceritinib [74] ALK inhibitor ALK + mNSCLC ↑↑ Moderate 3A4 inhibitor
Imatinib [75] BCR- ABL inhibitor Ph + CML, Ph + ALL, MDS/MPD, ASM, ↑↑ Moderate 3A4 inhibitor
HES/CEL, DFSP, GIST
Nilotinib [76] BCR- ABL inhibitor Ph + CML ↑↑ Moderate 3A4 inhibitor
Ribociclib [77] CDK 4/6 inhibitor mBrCA ↑↑ Moderate 3A4 inhibitor
Bexarotene [78] Retinoid CTCL ↓↓ Moderate 3A4 inducer
Dabrafenib [79] BRAF inhibitor BRAF V600E + melanoma, ATC, ↓↓ Moderate 3A4 inducer
mNSCLC
Lorlatinib [80] ALK inhibitor ALK + mNSCLC ↓↓ Moderate 3A4 inducer
Abiraterone [81] CYP17 inhibitor CRPC, CSPC ↑↑ Moderate 2D6 inhibitor

ALL acute lymphoblastic leukaemia, ALK anaplastic lymphoma kinase, ASM aggressive systemic mastocytosis, ATC​ anaplastic thyroid cancer,
CDK cyclin-dependent kinase, CEL chronic eosinophilic leukaemia, CML chronic myeloid leukaemia, CLL chronic lymphocytic leukaemia,
CRPC castrate resistant prostate cancer, CSPC castrate-sensitive prostate cancer, CTCL cutaneous T cell lymphoma, DFSP dermatofibrosarcoma
protuberans, EGFR epidermal growth factor receptor, FL follicular lymphoma, GIST gastrointestinal stromal tumours, HES hypereosinophilic
syndrome, mBRCA​metastatic breast cancer, mNSCLC metastatic non-small cell lung cancer, MDA/MPS myelodysplastic/myeloproliferative dis-
eases, Ph + Philadelphia chromosome positive, PI3 K phosphoinositide-3-kinase, SLL small lymphocytic lymphoma

only by trained clinicians as there are significant problems
with adult-based conversion tables when used in paediatrics
due to enormous variability within individuals in relative
potency estimates, tolerance development with repetitive
dosing, and the erroneous assumption that relative potency
ratios are irrespective of level of opioid [118].
The tablet or liquid formulation may be used to deliver
these lower doses. Titration of methadone should be done
carefully with close monitoring especially as methadone is
approaching steady-state concentrations in the first 5 days
and even longer in some patients [119–122]. Based on metha-
done’s pharmacokinetic principles, titration should not occur
any sooner than 5 days [29, 30]. In most cases, methadone is
selected for patients who are on another long-acting drug and
need to transition to methadone. Methadone’s high potency,
bioavailability, lack of active metabolites, lower risk of side
effects, and low cost make it an ideal medication to transi-
tion to in the setting of refractory cancer pain [118, 123, 124].
The equianalgesia conversion ratios vary depending on which
method you use. Most of the conversion methods follow simi-
lar trends: as you increase morphine equivalent daily dose
(MEDD), the ratio to methadone is more conservative [34,
125]. For example, in the end-of-life palliative care resource
centre (EPERC) conversion method [126], if the MEDD dose
was between 101 and 300 mg then the conversion ratio to
methadone would be 5:1 and if the MEDD was between 801
and 1000 mg, then the conversion ratio to methadone would be
15:1. These conversion methods are unidirectional and provide
a ratio from morphine to methadone only. The ratio to convert
from morphine back to methadone has been reported in the
range of 1:4–1:5 [127, 128].
Cross titration between morphine or another opioid to
methadone can be completed over various time courses,
some examples cross titration schedules take place over 5,
7, or 9 days [30, 128, 129]. Some clinicians may choose to
stop the other opioid and immediately start methadone. This
would be a good consideration when converting from fen-
tanyl transdermal patch to methadone as it has a similar PK
in its long elimination half-life [29, 30]. In other words, as
transdermal fentanyl is slowly eliminated from the body fol-
lowing discontinuation, methadone simultaneously reaches
steady state. When cross titrating from long-acting morphine
or oxycodone, a common approach is to complete the cross
titration over 3 days [128–130]. Three-day cross-titration
should only be done in a setting where close observation
and dose adjustment of methadone is feasible based on treat-
ment response and adverse effects. Over 3 days, the dose of
the other opioid is decreased by one-third, the dose of the
methadone is increased by one-third, where on day three
the other opioid is at zero, and the methadone is at its target
Table 4  Chemotherapeutic agents and associated QTc prolongation risk [62, 85]
Chemotherapeutic Molecular target/class FDA-approved indication Risk of QTc Requires ECG ECG monitoring recommendation per PI
agent prolongation/ monitoring
TdP per PI

Apalutamide [66] Androgen receptor CRPC Possible No

inhibitor
Arsenic Trioxide Retinoid APL Known Yes BBW: ATO can cause QT interval prolongation and ventricular arrhyth-
(ATO) [86] mia, which can be fatal
ECG prior to ATO administration, then weekly and more frequently for
clinically unstable patients
Bendamustine [87] Alkylating agent NHL and CLL Possible No
Bortezomib [88] Protease inhibitor MM Possible No
Safe Use of Methadone for Cancer-Related Pain

Bosutinib [89] BCR- ABL inhibitor Ph + CML Possible No

Cabozantinib [90] Multi-kinase inhibitor RCC, HCC Possible No
Capecitabine [91] Antimetabolite CRC, mBrCA Possible No
Ceritinib [74] ALK inhibitor ALK + mNSCLC Possible Yesb QTc > 500 ms on at least 2 separate ECGs → withhold until recovery to
baseline or to a QTc < 481 ms, then resume at next lower dosage
QTc > 500 ms or
≥ 60 ms change from baseline with TdP or polymorphic ventricular
tachycardia or signs/symptoms of serious arrhythmia → permanently
discontinue
Cobimetinib [92] MEK inhibitor Melanoma Possible Yesa Monitor ECG prior to initiating treatment and routinely during treatment
Crizotinib [73] ALK inhibitor ALK + mNSCLC Possible Yesb QTc > 500 ms on at least 2 separate ECGs → withhold until recovery to
baseline or to a QTc < 481 ms, then resume at next lower dosage
QTc > 500 ms or
≥ 60 ms change from baseline with TdP or polymorphic ventricular
tachycardia or signs/symptoms of serious arrhythmia → permanently
discontinue
Dabrafenib [79] BRAF inhibitor BRAF V600E + melanoma, Possible No
ATC, mNSCLC
Dasatinib [93] BCR- ABL inhibitor Ph + CML, Possible No
Ph + ALL
Encorafenib [94] BRAF inhibitor BRAF V600E/V600 K + mela- Possible Yesb QTcF > 500 ms and ≤ 60 ms increase from baseline → withhold until
noma QTcF ≤ 500 ms and resume at reduced dose. If more than one recur-
rence, permanently discontinue
QTcF > 500 ms and ≥ 60 ms increase from baseline → permanently DC
Eribulin mesylate [95] Microtubule inhibitor mBrCA Possible Yesb ECG monitoring recommended
5-Fluorouracil [96] Antimetabolite CRC, BrCA, gastric cancer, Possible No
pancreatic cancer
121


Table 4  (continued)
122

Chemotherapeutic Molecular target/class FDA-approved indication Risk of QTc Requires ECG ECG monitoring recommendation per PI
agent prolongation/ monitoring
TdP per PI

Gilteritinib [97] FLT3 inhibitor AML Possible Yes Obtain ECG prior to initiation of treatment with gilteritinib, on days
8 and 15 of cycle 1, and prior to the start of the next two subsequent
cycles
QTc > 500 ms → resume a reduced dose when QTc interval is within
30 ms of baseline or ≤ 480 ms
QTc interval increased by > 30 ms on day 8 of cycle 1 → confirm with
ECG on day 9 and if confirmed, consider dose reduction
Glasdegib [98] Hedgehog pathway AML Possible Yes Avoid concomitant use of QT-prolonging drugs
inhibitor Monitor ECG prior to treatment initiation, ~ 1 week after initiation, and
once monthly × 2 months. Repeat ECG if abnormal.
QTc interval
prolongation on at least 2 separate ECGs
 480–500 ms → assess electrolyte and replete PRN, review and adjust
concomitant QTc prolonging medications
 > 500 ms → DC glasdegib and resume at a reduced dose once QTc
interval returns to within 30 ms of baseline ≤ 480 ms; monitor ECGs at
least weekly for 2 weeks following resolution of QTc prolongation.
QTc interval prolongation with life-threatening arrhythmia → DC
glasdegib
Inotuzumab ozo- CD22-directed ADC ALL Possible Yes Monitor ECG prior to initiating treatment, after initiation of any drug
gamicin [99] known to prolong QTc, and periodically monitor as clinically indicated
during treatment
Ivosidenib [100] IDH-1 inhibitor AML Possible Yes Avoid concomitant use of QT-prolonging drugs
Monitor ECGs at least once weekly for the first 3 weeks of therapy and
then at least once monthly for the duration of therapy
QTc 480–500 ms → DC ivosidenib and resume once QTc interval
is ≤ 480 ms; monitor ECGs at least weekly for 2 weeks following reso-
lution of QTc prolongation
 > 500 ms → DC ivosidenib and resume at a reduced dose once QTc
interval returns to within 30 ms of baseline ≤ 480 ms; monitor ECGs at
least weekly for 2 weeks following resolution of QTc prolongation.
QTc interval prolongation with life-threatening arrhythmia → DC
ivosidenib
Lapatinib [101] HER2 inhibitor mBrCA Possible Yesb Monitor the ECG in patients who have or may develop prolongation of
QTc during treatment
Lenvatinib [102] Multi-kinase inhibitor Thyroid cancer Possible Yesb Monitor the ECG in patients who have or may develop prolongation of
QTc during treatment
QTc ≥ 500 ms or > 60 ms increase from baseline → withhold lenvatinib
until QTc ≤ 480 ms or baseline and resume at a reduced dose
Midostaurin [103] FLT3 inhibitor FLT3 + AML, SM Possible Noc
K. P. Edmonds et al.
Table 4  (continued)
Chemotherapeutic Molecular target/class FDA-approved indication Risk of QTc Requires ECG ECG monitoring recommendation per PI
agent prolongation/ monitoring
TdP per PI

Nilotinib [76] BCR-ABL inhibitor Ph + CML Possible Yes BBW: Nilotinib prolongs the QT interval
Monitor ECG prior to treatment initiation, 1 week after initiation, and
periodically thereafter, and following any dose adjustments
QTc > 480 ms →
DC nilotinib, monitor and replete electrolytes; resume nilotinib within
2 weeks if if QTcF returns to > 450 ms and within 20 ms of baseline
If QTcF is 450–480 ms after 2 weeks, reduce dose per PI
DC nilotinib if, following dose-reduction, QTcF
> 480 ms
Safe Use of Methadone for Cancer-Related Pain

Osimertinib [104] EGFR inhibitor EGFR T790 M + mNSCLC Possible Yesb Monitor the ECG in patients who have or may develop prolongation of
QTc during treatment
QTc > 500 ms on 2 separate ECGs → DC osimertinib and resume at a
reduced dose once QTc is < 481 ms or recovery to baseline if baseline
is ≥ 481 ms
Oxaliplatin [105] Platinum agent CRC​ Known [106] No
Panobinostat [107] HDAC inhibitor MM Possible Yes BBW: severe and fatal cardiac ischemic events, severe arrhythmias, and
ECG changes have occurred in patients receiving panobinostat
Avoid concomitant use of QT-prolonging drugs
Monitor the ECG prior to the start of therapy and repeat periodically
during treatment as clinically indicated.
Verify that the QTcF is < 450 ms prior to initiation of treatment
If during treatment, the QTcF is ≥ 480 ms → DC panobinostat and cor-
rect any electrolyte abnormalities
If QT prolongation does not resolve, permanently DC
Pazopanib [108] Multi-kinase inhibitor RCC, sarcoma Possible Yes Use with caution in patients at higher risk of developing QT interval
prolongation
Baseline and periodic monitoring of ECGs should be performed
Ribociclib [77] CDK4/6 inhibitor mBrCA Possible Yes Avoid concomitant use of QT-prolonging drugs
Monitor ECGs prior to initiation of treatment.
Repeat ECGs at ~ day 14 of cycle 1 and ~ day 1 of cycle 2 and as clini-
cally indicated
Sorafenib [109] Multi-kinase inhibitor RCC, HCC, thyroid cancer Possible Yesb Monitor ECG and if QTc is > 500 ms or ≥ 60 ms from baseline → DC
sorafenib, correct electrolyte abnormalities and use medical judgement
prior to resuming
Sunitinib [110] Multi-kinase inhibitor RCC, GIST, pNET Possible Yesb Periodic monitoring with on-treatment ECGs should be considered
Tamoxifen [111] Estrogen agonist/ ER + BrCA Known [112] No
antagonist
123


Table 4  (continued)
124

Chemotherapeutic Molecular target/class FDA-approved indication Risk of QTc Requires ECG ECG monitoring recommendation per PI
agent prolongation/ monitoring
TdP per PI

Tipiracil and Trifluri- Nucleoside metabolic CRC, gastric or GEJ cancer Possible No
dine [113] inhibitor and thymi-
dine phosphorylase
inhibitor
Vandetanib [114] VEGF inhibitor Thyroid cancer Known Yes BBW for QTc prologation and TdP
Monitor ECG at baseline, 2–4 weeks and 8–12 weeks after starting treat-
ment and every 3 months thereafter
QTcF > 500 ms → Resume at a reduced
dose when the QTcF returns to < 450 ms.
Monitor ECGs more frequently in patients who experience diarrhoea
Following any dose reduction for QT prolongation or any dose interrup-
tion > 2 weeks, conduct QT assessments as described above
QTcF > 500 ms → DC vandetanib until the QTcF < 450 ms and then
resume at a reduced dose
Vemurafenib [115] BRAF inhibitor BRAF V600E + melanoma, Possible Yes Prior to and following treatment initiation or after dose modification of
ECD for QTc prolongation, evaluate ECG after 15 days, monthly during the
first 3 months, and then every 3 months thereafter or more often as
clinically indicated
QTc ≥ 500 ms → DC vemurafenib and resume at a reduced dose once
QTc ≤ 500
QTc > 500 ms and increased > 60 ms from baseline after controlling
cardiac risk factors → permanently DC vemurafenib
Vorinostat [116] HDAC inhibitor CTCL Possible No

ADC antibody drug conjugate, ALL acute lymphoblastic leukaemia, ALK anaplastic lymphoma kinase, APL acute promyelocytic leukaemia, ATC​anaplastic thyroid cancer, BrCA breast cancer,
CDK cyclin-dependent kinase, CML chronic myeloid leukaemia, CLL chronic lymphocytic leukaemia, CRPC castrate resistant prostate cancer, CRC​ colorectal cancer, CTCL cutaneous T-cell
lymphoma, DC discontinue, ECD Erdeim Chester Disease, ECG electrocardiogram, EGFR epidermal growth factor, ER oestrogen receptor, GEJ gastroesophageal junction, GIST gastrointes-
tinal stromal tumour, HDAC histone deacetylase, mBRCA​ metastatic breast cancer, MEK mitogen-activated protein kinase, MM multiple myeloma, ms milliseconds, mNSCLC metastatic non-
small cell lung cancer, SM systemic mastocytosis, NHL non-Hodgkins lymphoma, Ph + Philadelphia chromosome positive, PI package insert, pNET pancreatic neuroendocrine tumours, QTcF
Corrected QT interval, Fridericia, RCC​renal cell carcinoma, TdP torsade de Pointes, VEGF vascular endothelial growth factor
a
 When administered with vemurafenib
b
 Monitor patients who already have or who are at significant risk of developing QTc prolongation (i.e. congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval,
including Class Ia and III antiarrhythmics, and electrolyte abnormalities)
c
 Consider interval assessments of QT by ECG if midostaurin is taken concurrently with medications that can prolong the QT interval
K. P. Edmonds et al.
Safe Use of Methadone for Cancer-Related Pain
dose. Cross titration can be over a longer period as needed
per clinical situation as long as careful monitoring is contin-
ued during titration period and beyond [128, 129].
4.2 Methadone Maintenance Treatment (MMT)
and Cancer‑related Pain
It can be pharmacologically challenging to address cancer
pain in patients who are receiving methadone maintenance
treatment (MMT) [131]. Although non-pharmacological
approaches and non-opioid analgesia should be considered
in managing pain in patients receiving MMT, moderate-to-
severe cancer pain requires opioid therapy [131, 132]. The
clinician managing the patient’s pain should initiate contact
with the methadone clinic and continue the dialogue, espe-
cially if a methadone dose change or use of any other opi-
oids are warranted [133]. In the case of acute pain, patients
should be continued on their methadone without dose modi-
fication and a short-acting opioid medication should be used
on an as-needed basis for the acute pain [133, 134]. Given
the history of intravenous heroin abuse, oral or sublingual
formulations of methadone should be used as long as the
patient is able to swallow and is able to absorb the medica-
tion through the oral mucosa or gastrointestinal (GI) tract,
even in the setting of severe pain. Intravenous short-acting
opioid should only be considered if patients are unable to
swallow, use sublingual or do not have an intact GI tract. In
the setting of chronic cancer pain, the recommendation is for
patients to be on both a long- and short-acting opioids. In
patients who are on MMT, the methadone can serve as the
long-acting regimen [131, 135]. As mentioned prior in the
pharmacology section, methadone needs to be administered
every 8 h to optimally provide continuous analgesic effects
versus MMT, which is usually administered once a day. The
MMT daily dose can be divided into three doses and admin-
istered every 8 h. For example, if the total daily MMT dose
is 110 mg then the methadone can be given as 35 mg, 40 mg,
35 mg separated by 8 h. If the patient’s chronic cancer pain
improves or resolves, then the patient can be converted back
to MMT daily dose for ease of direct observation of therapy
administration at methadone clinics. In some clinical cases
every 12-h dosing frequency may also be adequate for anal-
gesic effects. As there is no evidence to guide the practice
of dividing MMT doses other than the analgesic half-life
data, others have found that continuing the MMT with the
addition of a non-methadone long-acting opioid formulation
to be better tolerated by patients.
4.3 Methadone Considerations in Renal
and Hepatic Dysfunction
Methadone is extensively metabolised by the liver and
excreted predominantly through a faecal, non-renal route
125
[48, 136]. In the setting of renal failure, methadone is
excreted entirely through the faecal route [137]. These
pharmacodynamic variables lend methadone to be a useful
medication in the setting of renal failure and offer an advan-
tage to other opioids, as all other opioids are predominantly
excreted via the renal route [138]. The reliance of methadone
on hepatic metabolism warrants caution in dosing and titra-
tion in the setting of advance liver disease [20, 139, 140].
Although there are no specific published recommendations,
methadone should not be considered first line in the setting
of severe or end-stage liver disease as metabolism may be
delayed and may impact its efficacy tolerability, or toxicity.
Additionally, the risk of acute encephalopathy in end-stage
liver disease makes long-acting opioids, including metha-
done, a less appropriate approach [141–143]. It is highly
recommended that practitioners who are familiar with its
use and who can monitor closely use methadone cautiously.
Collaborating with hepatology colleagues may be useful if
methadone is used in liver dysfunction.
5 Place in Therapy Take‑home Points
5.1 Adult Setting
The complex properties of methadone necessitate a thought-
ful approach to selecting patients in whom it will be both
effective and safe. In well-chosen patients, it is a beneficial
second- or third-line opioid analgesic when employed by
prescribers with extensive knowledge of its unique risks,
pharmacokinetics, and pharmacodynamics [20, 42, 129,
144, 145]. Although there are those who advocate for use of
methadone as a first-line analgesic for cancer-related pain,
these highly patient-specific scenarios are best considered
by specialists in palliative care or pain and are beyond the
scope of this article [20, 42, 118, 124, 144, 146].
5.2 Paediatric Setting
Methadone is an excellent opioid choice in advanced pae-
diatric pain management and paediatric palliative care but
remains significantly under-utilised [118]. Methadone is a
particularly useful long-acting pain medication in the pae-
diatric population because of its inexpensiveness and liquid
formulation [35, 118, 147, 148]. Given methadone can be
dosed based on body surface area in children, the drug is
preferred over fentanyl patches particularly in children who
cannot reliably or are unable to swallow pills in general due
to feeding tube dependence. Most of the studies for metha-
done are centred around paediatric cancer-related pain but
its utility is more far-reaching [149–151]. Regardless, even
within the oncology population, it is often used a second- or
third-line agent after other long-acting opioids have been

126
exhausted. This is due in large part to the fact that most
paediatricians are not experienced or trained on how to use
methadone to treat pain, and there are few paediatric pallia-
tive care providers [35].
5.3 End‑of‑Life Setting
For those people who have transitioned to active dying [152],
are no longer able to safely swallow medications, and who
are on methadone for pain, decisions about next steps should
be based on estimate of prognosis [153–157]. For those with
a prognosis of hours-to-days, the methadone already in their
system will continue to provide basal analgesia until death.
As such, it is sufficient to provide frequently available doses
of short-acting opioids for acute pain or breathlessness. In
those with a prognosis of days-to-weeks, alternative basal
analgesia should be considered either via buccal, sublingual,
intravenous or subcutaneous methadone; rotation to a fenta-
nyl patch; or through the use of other agents [158].
5.4 Cancer Survivorship
For those who have achieved sustained remission or cure of
their cancer, an appropriate, personalised taper of cancer-
pain–directed analgesics becomes important. If pain persists,
it may have changed character (i.e. neuropathy as a result of
cancer-directed therapies) and require a re-evaluation of the
analgesia regimen. It is also possible that the pain subsides
or resolves altogether. As such, there is not a single goal of
tapering off methadone. All non-opioid co-analgesics should
be maximised as appropriate and evaluation with chronic
pain specialists is advised.
6 Conclusion
Methadone is a complicated medication with novel analgesic
properties that, when deployed by experienced prescribers,
can result in cost-effective and clinically significant anal-
gesia. Patient selection and monitoring should be based on
a number of factors including the patient’s goals of care.
Emerging anti-cancer therapies add to the complex risk/ben-
efit analysis [61] for initiation and monitoring of methadone
for analgesia.
Funding  This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
References
1. Eap CB, Buclin T, Baumann P. Interindividual variability
of the clinical pharmacokinetics of methadone: implications
K. P. Edmonds et al.
for the treatment of opioid dependence. Clin Pharmacokinet.
2002;41(14):1153–93. https​://doi.org/10.2165/00003​088-20024​
1140-00003​.
2. Kristensen K, Christensen CB, Christrup LL. The mu1, mu2,
delta, kappa opioid receptor binding profiles of methadone ste-
reoisomers and morphine. Life Sci. 1995;56(2):PL45–50. https​
://doi.org/10.1016/0024-3205(94)00426​-s.
3. Liu JG, Liao XP, Gong ZH, Qin BY. Methadone-induced desen-
sitization of the delta-opioid receptor is mediated by uncoupling
of receptor from G protein. Eur J Pharmacol. 1999;374(2):301–8.
https​://doi.org/10.1016/s0014​-2999(99)00322​-2.
4. Bot G, Blake AD, Li S, Reisine T. Opioid regulation of the
mouse delta-opioid receptor expressed in human embryonic
kidney 293 cells. Mol Pharmacol. 1997;52(2):272–81. https​://
doi.org/10.1124/mol.52.2.272.
5. Liu JG, Liao XP, Gong ZH, Qin BY. The difference between
methadone and morphine in regulation of delta-opioid receptors
underlies the antagonistic effect of methadone on morphine-
mediated cellular actions. Eur J Pharmacol. 1999;373(2–3):233–
9. https​://doi.org/10.1016/s0014​-2999(99)00270​-8.
6. Berger AC, Whistler JL. How to design an opioid drug that
causes reduced tolerance and dependence. Ann Neurol.
2010;67(5):559–69. https​://doi.org/10.1002/ana.22002​.
7. Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone,
methadone and pethidine are non-competitive N-methyl-d-as-
partate (NMDA) antagonists in the rat cortex and spinal cord.
Neurosci Lett. 1995;187(3):165–8. https:​ //doi.org/10.1016/0304-
3940(95)11364​-3.
8. Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of
methadone bind to the non-competitive site on the N-methyl-
d-aspartate (NMDA) receptor in rat forebrain and spinal cord.
Neurosci Lett. 1997;223(1):5–8. https​://doi.org/10.1016/s0304​
-3940(97)13391​-2.
9. Vyklicky V, Korinek M, Smejkalova T, Balik A, Krausova
B, Kaniakova M, et  al. Structure, function, and pharmacol-
ogy of NMDA receptor channels. Physiol Res. 2014;63(Suppl
1):S191–203.
10. Methadone-associated overdose deaths: Factors contributing to
increased deaths and efforts to prevent them. General Account-
ability Office. 2016. https​://perma​.cc/9B6M-BWYA​. Accessed
10 Oct 2016.
11. Shimoyama N, Shimoyama M, Elliott KJ, Inturrisi CE. d-Metha-
done is antinociceptive in the rat formalin test. J Pharmacol Exp
Ther. 1997;283(2):648–52.
12. Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance
and N-methyl-d-aspartate-induced hyperalgesia. J Pharmacol
Exp Ther. 1999;289(2):1048–53.
13. Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK.
Low-dose methadone has an analgesic effect in neuropathic pain:
a double-blind randomized controlled crossover trial. Palliat
Med. 2003;17(7):576–87. https​://doi.org/10.1191/02692​16303​
pm815​oa.
14. Altier N, Dion D, Boulanger A, Choiniere M. Management of
chronic neuropathic pain with methadone: a review of 13 cases.
Clin J Pain. 2005;21(4):364–9.
15. Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment
of neuropathic pain. Pain Res Manag. 2003;8(3):149–54. https​://
doi.org/10.1155/2003/23671​8.
16. Trujillo KA, Akil H. Inhibition of morphine tolerance and
dependence by the NMDA receptor antagonist MK-801. Science.
1991;251(4989):85–7. https​://doi.org/10.1126/scien​ce.18247​28.
17. Price DD, Mayer DJ, Mao J, Caruso FS. NMDA-receptor antago-
nists and opioid receptor interactions as related to analgesia and
tolerance. J Pain Symptom Manag. 2000;19(1 Suppl):S7–11.
18. Popik P, Kozela E, Danysz W. Clinically available NMDA recep-
tor antagonists memantine and dextromethorphan reverse existing
Safe Use of Methadone for Cancer-Related Pain
tolerance to the antinociceptive effects of morphine in mice. Nau-
nyn Schmiedebergs Arch Pharmacol. 2000;361(4):425–32. https​
://doi.org/10.1007/s0021​09900​205.
19. Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS. Effects of
NMDA receptor antagonists on inhibition of morphine tol-
erance in rats: binding at mu-opioid receptors. Eur J Phar-
macol. 1996;297(1–2):27–33. https​://doi.org/10.1016/0014-
2999(95)00728​-8.
20. McPherson ML, Walker KA, Davis MP, Bruera E, Reddy A,
Paice J, et al. Safe and appropriate use of methadone in hospice
and palliative care: expert consensus white paper. J Pain Symp-
tom Manag. 2019;57(3):635–45. https​://doi.org/10.1016/j.jpain​
symma​n.2018.12.001 (e4).
21. Dolophine (methadone) [package insert]. Columbus: Roxane
Laboratories; 2006.
22. Gadel S, Friedel C, Kharasch ED. Differences in metha-
done metabolism by CYP2B6 variants. Drug Metab Dispos.
2015;43(7):994–1001. https:​ //doi.org/10.1124/dmd.115.064352​ .
23. Chen CH, Wang SC, Tsou HH, Ho IK, Tian JN, Yu CJ, et al.
Genetic polymorphisms in CYP3A4 are associated with with-
drawal symptoms and adverse reactions in methadone main-
tenance patients. Pharmacogenomics. 2011;12(10):1397–406.
https​://doi.org/10.2217/pgs.11.103.
24. Kharasch ED, Regina KJ, Blood J, Friedel C. Methadone phar-
macogenetics: CYP2B6 polymorphisms determine plasma
concentrations, clearance, and metabolism. Anesthesiology.
2015;123(5):1142–53. https:​ //doi.org/10.1097/ALN.000000​ 0000​
00086​7.
25. Somogyi AA, Barratt DT, Ali RL, Coller JK. Pharmacogenom-
ics of methadone maintenance treatment. Pharmacogenomics.
2014;15(7):1007–27. https​://doi.org/10.2217/pgs.14.56.
26. Victorri-Vigneau C, Verstuyft C, Bouquie R, Laforgue EJ, Har-
douin JB, Leboucher J, et al. Relevance of CYP2B6 and CYP2D6
genotypes to methadone pharmacokinetics and response in the
OPAL study. Br J Clin Pharmacol. 2019;85(7):1538–43. https​://
doi.org/10.1111/bcp.13936​.
27. Meresaar U, Nilsson MI, Holmstrand J, Anggard E. Single dose
pharmacokinetics and bioavailability of methadone in man
studied with a stable isotope method. Eur J Clin Pharmacol.
1981;20(6):473–8.
28. Por tenoy RK. Treatment of cancer pain. Lancet.
2011;377(9784):2236–47. https ​ : //doi.org/10.1016/S0140​
-6736(11)60236​-5.
29. Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J
Pain. 2002;18(4 Suppl):S3–13.
30. Chou R, Cruciani RA, Fiellin DA, Compton P, Farrar JT,
Haigney MC, et al. Methadone safety: a clinical practice guide-
line from the American Pain Society and College on Problems
of Drug Dependence, in collaboration with the Heart Rhythm
Society. J Pain Off J Am Pain Soc. 2014;15(4):321–37. https​://
doi.org/10.1016/j.jpain​.2014.01.494.
31. Ansermot N, Albayrak O, Schlapfer J, Crettol S, Croquette-
Krokar M, Bourquin M, et al. Substitution of (R, S)-metha-
done by (R)-methadone: impact on QTc interval. Arch Intern
Med. 2010;170(6):529–36. https​://doi.org/10.1001/archi​ntern​
med.2010.26.
32. Turpeinen M, Zanger UM. Cytochrome P450 2B6: function,
genetics, and clinical relevance. Drug Metabol Drug Interact.
2012;27(4):185–97. https​://doi.org/10.1515/dmdi-2012-0027.
33. Reddy S, Hui D, El Osta B, de la Cruz M, Walker P, Palmer
JL, et al. The effect of oral methadone on the QTc interval in
advanced cancer patients: a prospective pilot study. J Palliat Med.
2010;13(1):33–8. https​://doi.org/10.1089/jpm.2009.0184.
34. Karimian P, Atayee RS, Ajayi TA, Edmonds KP. Methadone
dose selection for treatment of pain compared with consensus
127
recommendations. J Palliat Med. 2017;20(12):1385–8. https​://
doi.org/10.1089/jpm.2017.0089.
35. Madden K, Liu D, Bruera E. Attitudes, beliefs, and practices
of paediatric palliative care physicians regarding the use of
methadone in children with advanced cancer. J Pain Symptom
Manag. 2019;57(2):260–5. https:​ //doi.org/10.1016/j.jpains​ ymma​
n.2018.11.009.
36. Madden K, Jo E, Williams JL, Liu D, Bruera E. QTc interval
prolongation in paediatric and young adult patients on methadone
for cancer related pain. J Pain Symptom Manag. 2019. https​://
doi.org/10.1016/j.jpain​symma​n.2019.05.021.
37. Schwinghammer AJ, Wilson MD, Hall BA. Corrected QT inter-
val prolongation in hospitalized paediatric patients receiving
methadone. Pediatr Crit Care Med. 2018;19(8):e403–8. https​://
doi.org/10.1097/PCC.00000​00000​00160​1.
38. Kornick CA, Kilborn MJ, Santiago-Palma J, Schulman G, Thaler
HT, Keefe DL, et al. QTc interval prolongation associated with
intravenous methadone. Pain. 2003;105(3):499–506. https​://doi.
org/10.1016/s0304​-3959(03)00205​-7.
39. Chou R, Weimer MB, Dana T. Methadone overdose and cardiac
arrhythmia potential: findings from a review of the evidence for
an American Pain Society and College on Problems of Drug
Dependence clinical practice guideline. J Pain Off J Am Pain Soc.
2014;15(4):338–65. https:​ //doi.org/10.1016/j.jpain.​ 2014.01.495.
40. Ahluwalia SC, Chen C, Raaen L, Motala A, Walling AM,
Chamberlin M, et  al. A systematic review in support of the
national consensus project clinical practice guidelines for qual-
ity palliative care, fourth edition. J Pain Symptom Manag.
2018;56(6):831–70. https ​ : //doi.org/10.1016/j.jpain ​ s ymma​
n.2018.09.008.
41. Atayee RS, Sam AM, Edmonds KP. Patterns of palliative care
pharmacist interventions and outcomes as part of inpatient pal-
liative care consult service. J Palliat Med. 2018;21(12):1761–7.
https​://doi.org/10.1089/jpm.2018.0093.
42. Nicholson AB, Watson GR, Derry S, Wiffen PJ. Methadone for
cancer pain. Cochrane Database Syst Rev. 2017;2:CD003971.
https​://doi.org/10.1002/14651​858.cd003​971.pub4.
43. Haumann J, Geurts JW, van Kuijk SM, Kremer B, Joosten EA,
van den Beuken-van Everdingen MH. Methadone is superior
to fentanyl in treating neuropathic pain in patients with head-
and-neck cancer. Eur J Cancer. 2016;65:121–9. https​://doi.
org/10.1016/j.ejca.2016.06.025.
44. McNicol ED, Ferguson MC, Schumann R. Methadone for
neuropathic pain in adults. Cochrane Database Syst Rev.
2017;5:CD012499. https:​ //doi.org/10.1002/146518​ 58.cd0124​ 99.
pub2.
45. Eide PK. Wind-up and the NMDA receptor complex from a
clinical perspective. Eur J Pain. 2000;4(1):5–15. https​://doi.
org/10.1053/eujp.1999.0154.
46. Chalker C, O’Neill H, Cranfield F. Efficacy of low-dose and/or
adjuvant methadone in palliative medicine. BMJ Support Palliat
Care. 2019. https​://doi.org/10.1136/bmjsp​care-2018-00169​5.
47. Nguyen LM, Rhondali W, De la Cruz M, Hui D, Palmer L,
Kang DH, et al. Frequency and predictors of patient deviation
from prescribed opioids and barriers to opioid pain manage-
ment in patients with advanced cancer. J Pain Symptom Manag.
2013;45(3):506–16. https ​ : //doi.org/10.1016/j.jpain ​ s ymma​
n.2012.02.023.
48. Atayee RS, Hur GH, Karimian P, Hollenbach KA, Edmonds KP.
Methadone inpatient and discharge prescribing patterns for pain
at an academic health system. J Palliat Med. 2017;20(2):184–92.
https​://doi.org/10.1089/jpm.2016.0267.
49. Leidig E, Noller F, Mentzel H. Noninvasive, continuous moni-
toring of artificial respiration in premature and newborn infants
by the constant measurement of respiratory minute volume,

128
oxygen consumption and carbon dioxide release. Klin Padiatr.
1986;198(4):321–5. https​://doi.org/10.1055/s-2008-10338​80.
50. Ma JD, Horton JM, Hwang M, Atayee RS, Roeland EJ. A single-
center, retrospective analysis evaluating the utilization of the opi-
oid risk tool in opioid-treated cancer patients. J Pain Palliat Care
Pharmacother. 2014;28(1):4–9. https​://doi.org/10.3109/15360​
288.2013.86964​7.
51. Chou R, Fanciullo GJ, Fine PG, Miaskowski C, Passik SD,
Portenoy RK. Opioids for chronic noncancer pain: predic-
tion and identification of aberrant drug-related behaviors:
a review of the evidence for an American Pain Society and
American Academy of Pain Medicine clinical practice guide-
line. J Pain Off J Am Pain Soc. 2009;10(2):131–46. https​://doi.
org/10.1016/j.jpain​.2008.10.009.
52. Kaye AD, Jones MR, Kaye AM, Ripoll JG, Galan V, Beakley
BD, et al. Prescription opioid abuse in chronic pain: an updated
review of opioid abuse predictors and strategies to curb opioid
abuse: part 1. Pain Physician. 2017;20(2S):S93–109.
53. Kaye AD, Jones MR, Kaye AM, Ripoll JG, Jones DE, Galan
V, et al. Prescription opioid abuse in chronic pain: an updated
review of opioid abuse predictors and strategies to curb opioid
abuse (part 2). Pain Physician. 2017;20(2S):S111–33.
54. Garcia C, Lefkowits C, Pelkofski E, Blackhall L, Duska LR.
Prospective screening with the validated opioid risk tool dem-
onstrates gynecologic oncology patients are at low risk for
opioid misuse. Gynecol Oncol. 2017;147(2):456–9. https​://doi.
org/10.1016/j.ygyno​.2017.08.008.
55. Clark MR, Hurley RW, Adams MCB. Re-assessing the validity of
the opioid risk tool in a tertiary academic pain management center
population. Pain Med. 2018. https​://doi.org/10.1093/pm/pnx332​ .
56. Shier ML, Graham JR, Keogh JM. Social work and the emerg-
ing opioid epidemic: a literature review. Br J Soc Work. 2019.
https​://doi.org/10.1093/bjsw/bcy12​7.
57. Reid MC, Eccleston C, Pillemer K. Management of chronic
pain in older adults. BMJ. 2015;350:h532. https ​ : //doi.
org/10.1136/bmj.h532.
58. Loeser JD, Schatman ME. Chronic pain management
in medical education: a disastrous omission. Postgrad
Med. 2017;129(3):332–5. https ​ : //doi.org/10.1080/00325​
481.2017.12976​68.
59. Shah S, Diwan S. Methadone: does stigma play a role as
a barrier to treatment of chronic pain? Pain Physician.
2010;13(3):289–93.
60. Beaver JA, Howie LJ, Pelosof L, Kim T, Liu J, Goldberg KB,
et al. A 25-year experience of us food and drug administration
accelerated approval of malignant hematology and oncology
drugs and biologics: a review. JAMA Oncol. 2018;4(6):849–56.
https​://doi.org/10.1001/jamao​ncol.2017.5618.
61. Harvey RD. Managing drug interactions with oral anticancer
agents: signals, noise, and echoes. J Oncol Pract. 2019;15(2):91–
2. https​://doi.org/10.1200/JOP.18.00721​.
62. Rogala BG, Charpentier MM, Nguyen MK, Landolf KM, Hamad
L, Gaertner KM. Oral anticancer therapy: management of drug
interactions. J Oncol Pract. 2019;15(2):81–90. https​: //doi.
org/10.1200/JOP.18.00483​.
63. ZYDELIG® (idelalisib) [package insert]. Foster City: Gilead Sci-
ences; 2014.
64. Bossaer JB, Chakraborty K. Drug interaction between idelalisib
and diazepam resulting in altered mental status and respiratory
failure. J Oncol Pharm Pract. 2017;23(6):470–2. https​://doi.
org/10.1177/10781​55216​65370​5.
65. Hong JH. Pharmacokinetic/pharmacodynamic drug evaluation
of enzalutamide for treating prostate cancer. Expert Opin Drug
Metab Toxicol. 2018;14(3):361–9. https:​ //doi.org/10.1080/17425​
255.2018.14402​88.
K. P. Edmonds et al.
66. ERLEADATM (apalutamide) [package insert]. Horsham: Janssen
Pharmaceutical Companies; 2018.
67. XTANDI® (enzalutamide) [package insert. Northbrook: Astellas
Pharma; 2012.
68. VIZIMPRO® (dacomitinib) [package insert]. New York: Pfizer;
2018.
69. Administration UFD. Drug development and drug interactions:
table of substrates, inhibitors and inducers. Table 3-2: examples
of clinical inhibitors for P450-mediated metabolisms (for con-
comitant use clinical DDI studies and/or drug labeling). 2016.
https​://perma​.cc/YM3X-TXRA.
70. Conde-Estevez D. Targeted cancer therapy: interactions with
other medicines. Clin Transl Oncol. 2017;19(1):21–30. https​
://doi.org/10.1007/s1209​4-016-1509-x.
71. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR,
et al. DrugBank 5.0: a major update to the DrugBank database
for 2018. Nucleic Acids Res. 2018;46(D1):D1074–82. https​://
doi.org/10.1093/nar/gkx10​37.
72. COPIKTRA (duvelisib) [package insert]. Needham: Verastem
Inc; 2018.
73. XALKORI® (crizotinib) [package insert]. New York: Pfizer
Labs; 2016.
74. ZYKADIA™ (ceritinib) [package insert]. East Hanover:
Novartis Pharmaceuticals Corporation; 2014.
75. GLEEVEC (imatinib mesylate) [package insert]. East Hanover:
Novartis Pharmaceuticals Corporation; 2017.
76. TASIGNA ® (nilotinib) [package insert]. East Hanover:
Novartis Pharmaceuticals Corporation; 2018.
77. KISQALI ® (ribociclib) [package insert]. East Hanover:
Novartis Pharmaceuticals Corporation; 2018.
78. TARGRETIN® (bexarotene) [package insert]. St. Petersburg:
Catalent Pharma Solutions LLC; 2015.
79. TAFINLAR (dabrafenib) [package insert]. Research Triangle
Park: GlaxoSmithKline; 2014.
80. LORBRENA® (lorlatinib) [package insert]. New York: Pfizer
Labs; 2018.
81. ZYTIGA® (abiraterone acetate) [package insert]. Horsham:
Janssen Biotech, Inc; 2019.
82. Naing A, Veasey-Rodrigues H, Hong DS, Fu S, Falchook GS,
Wheler JJ, et al. Electrocardiograms (ECGs) in phase I anti-
cancer drug development: the MD Anderson Cancer Center
experience with 8518 ECGs. Ann Oncol. 2012;23(11):2960–3.
https​://doi.org/10.1093/annon​c/mds13​0.
83. Porta-Sanchez A, Gilbert C, Spears D, Amir E, Chan J, Nan-
thakumar K, et al. Incidence, diagnosis, and management of
QT prolongation induced by cancer therapies: a systematic
review. J Am Heart Assoc. 2017. https​: //doi.org/10.1161/
jaha.117.00772​4.
84. Lyon AR, Yousaf N, Battisti NML, Moslehi J, Larkin J.
Immune checkpoint inhibitors and cardiovascular toxicity.
Lancet Oncol. 2018;19(9):e447–58. https​://doi.org/10.1016/
S1470​-2045(18)30457​-1.
85. Woosley RL, Heise CW, Gallo T, et al: QTdrugs list. https​://
www.credi​bleme​ds.org/. Accessed 11 June 2019.
86. TRISENOX® (arsenic trioxide) [package insert]. North Wales:
Teva Pharmaceuticals USA, Inc; 2019.
87. TREANDA® (bendamustine hydrochloride) [package insert].
Frazer: Cephalon, Inc; 2008.
88. VELCADE ® (bortezomib) [package insert]. Cambridge: Mil-
lennium Pharmaceuticals, Inc; 2014.
89. BOSULIF ® (bosutinib) [package insert]. New York: Pfizer
Labs; 2012.
90. CABOMETYX™ (cabozantinib) [package insert]. South San
Francisco: Exelixis, Inc; 2016.
91. XELODA (capecitabine) [package insert]. South San Fran-
cisco: Genentech USA, Inc; 2015.
Safe Use of Methadone for Cancer-Related Pain
92. COTELLIC (cobimetinib) [package insert]. South San Fran-
cisco: Genentech USA, Inc; 2015.
93. SPRYCEL® (dasatinib) [package insert]. Princeton: Bristol-
Myers Squibb Company; 2010.
94. BRAFTOVI™ (encorafenib) [package insert]. Boulder: Array
BioPharma Inc; 2018.
95. HALAVEN™ (eribulin mesylate) [package insert]. Woodcliff
Lake: Eisai Inc; 2010.
96. FLUOROURACIL injection [package insert]. Irvine: Spectrum
Pharmaceuticals, Inc; 2016.
97. XOSPATA​® (gilteritinib) [package insert]. Northbrook: Astellas
Pharma US, Inc; 2018.
98. DAURISMOTM (glasdegib) [package insert]. New York: Pfizer
Labs; 2018.
99. BESPONSA (inotuzumab ozogamicin) [package insert]. Phila-
delphia: Wyeth Pharmaceuticals, Inc; 2017.
100. TIBSOVO® (ivosidenib tablets) [package insert]. Cambridge,
MA: Agios Pharmaceuticals, Inc; 2018.
101. TYKERB (lapatinib) [package insert]. East Hanover: Novartis
Pharmaceuticals Corporation: 2018.
102. LENVIMA (lenvatinib) [package insert]. Woodcliff Lake: Eisai
Inc; 2015.
103. RYDAPT ® (midostaurin) [package insert]. East Hanover:
Novartis Pharmaceuticals Corporation; 2017.
104. TAGRISSO® (osimertinib) [package insert]. Wilmington: Astra-
Zeneca Pharmaceuticals LP; 2018.
105. ELOXATIN (oxaliplatin) [package insert]. Bridgewater: Sanofi-
aventis U.S. LLC; 2011.
106. Hancox JC, Caves RE, Choisy SC, James AF. QT interval prolon-
gation and torsades de pointes with oxaliplatin. Ther Adv Drug
Saf. 2016;7(6):261–3. https:​ //doi.org/10.1177/204209​ 86166​ 6608​
1.
107. FARYDAK® (panobinostat) [package insert]. East Hanover, NJ:
Novartis Pharmaceuticals Corporation; 2015.
108. VOTRIENT (pazopanib) [package insert]. Research Triangle
Park: GlaxoSmithKline; 2012.
109. NEXAVAR (sorafenib) [package insert]. Wayne: Bayer Health-
Care Pharmaceuticals Inc; 2010.
110. SUTENT® (sunitinib malate) [package insert]. New York: Pfizer
Labs; 2011.
111. SOLTAMOX® (tamoxifen citrate) [package insert]. Raleigh:
Midatech Pharma US Inc; 2018.
112. Duan J, Tao J, Zhai M, Li C, Zhou N, Lv J, et al. Anticancer
drugs-related QTc prolongation, torsade de pointes and sudden
death: current evidence and future research perspectives. Onco-
target. 2018;9(39):25738–49. https:​ //doi.org/10.18632/​ oncota​ rget​
.25008​.
113. LONSURF (trifluridine and tipiracil) [package insert]. Princeton:
Taiho Oncology, Inc; 2015.
114. CAPRELSA® (vandetanib) [package insert]. Wilmington: Astra-
Zeneca Pharmaceuticals LP; 2014.
115. ZELBORAF® (vemurafenib) [package insert]. South San Fran-
cisco: Genentech USA, Inc; 2017.
116. ZOLINZA® (vorinostat) [package insert]. Whitehouse Station:
Merck & Co., Inc; 2018.
117. van Ojik AL, Jansen PA, Brouwers JR, van Roon EN. Treat-
ment of chronic pain in older people: evidence-based choice of
strong-acting opioids. Drugs Aging. 2012;29(8):615–25. https​://
doi.org/10.2165/11632​620-00000​0000-00000​.
118. Friedrichsdorf SJ. From tramadol to methadone: opioids in the
treatment of pain and dyspnea in paediatric palliative care. Clin
J Pain. 2019;35(6):501–8. https​://doi.org/10.1097/AJP.00000​
00000​00070​4.
119. Farese RV. Phospholipid signaling systems in insulin action.
Am J Med. 1988;85(5A):36–43. https​://doi.org/10.1016/0002-
9343(88)90396​-8.
129
120. Baxter LE Sr, Campbell A, Deshields M, Levounis P, Martin JA,
McNicholas L, et al. Safe methadone induction and stabilization:
report of an expert panel. J Addict Med. 2013;7(6):377–86. https​
://doi.org/10.1097/01.ADM.00004​35321​.39251​.d7.
121. Buster MC, van Brussel GH, van den Brink W. An increase
in overdose mortality during the first 2 weeks after entering
or re-entering methadone treatment in Amsterdam. Addiction.
2002;97(8):993–1001.
122. Zador DA, Sunjic SD. Methadone-related deaths and mortality
rate during induction into methadone maintenance, New South
Wales, 1996. Drug Alcohol Rev. 2002;21(2):131–6. https​://doi.
org/10.1080/09595​23022​01390​28.
123. Parsons HA, de la Cruz M, El Osta B, Li Z, Calderon B, Palmer
JL, et al. Methadone initiation and rotation in the outpatient set-
ting for patients with cancer pain. Cancer. 2010;116(2):520–8.
https​://doi.org/10.1002/cncr.24754​.
124. Madden K, Park M, Liu D, Bruera E. Practices, attitudes, and
beliefs of palliative care physicians regarding the use of metha-
done and other long-acting opioids in children with advanced
cancer. J Palliat Med. 2018;21(10):1408–13. https ​ : //doi.
org/10.1089/jpm.2017.0670.
125. Toombs JD, Kral LA. Methadone treatment for pain states. Am
Fam Physician. 2005;71(7):1353–8.
126. Gazelle G, Fine PG. Methadone for the treatment of pain #75.
J Palliat Med. 2003;6(4):620–1. https​://doi.org/10.1089/10966​
21037​68253​740.
127. Walker PW, Palla S, Pei BL, Kaur G, Zhang K, Hanohano J,
et al. Switching from methadone to a different opioid: what is
the equianalgesic dose ratio? J Palliat Med. 2008;11(8):1103–8.
https​://doi.org/10.1089/jpm.2007.0285.
128. Mercadante S, Casuccio A, Calderone L. Rapid switching from
morphine to methadone in cancer patients with poor response
to morphine. J Clin Oncol. 1999;17(10):3307–12. https​://doi.
org/10.1200/JCO.1999.17.10.3307.
129. Mercadante S, Casuccio A, Fulfaro F, Groff L, Boffi R, Villari P,
et al. Switching from morphine to methadone to improve anal-
gesia and tolerability in cancer patients: a prospective study. J
Clin Oncol. 2001;19(11):2898–904. https​://doi.org/10.1200/
JCO.2001.19.11.2898.
130. Davies D, DeVlaming D, Haines C. Methadone analgesia
for children with advanced cancer. Pediatr Blood Cancer.
2008;51(3):393–7. https​://doi.org/10.1002/pbc.21584​.
131. Eyler EC. Chronic and acute pain and pain manage-
ment for patients in methadone maintenance treatment.
Am J Addict. 2013;22(1):75–83. https ​ : //doi.org/10.111
1/j.1521-0391.2013.00308​.x.
132. Carr DB, Goudas LC. Acute pain. Lancet. 1999;353(9169):2051–
8. https​://doi.org/10.1016/S0140​-6736(99)03313​-9.
133. Alford DP, Compton P, Samet JH. Acute pain management for
patients receiving maintenance methadone or buprenorphine
therapy. Ann Intern Med. 2006;144(2):127–34. https​://doi.
org/10.7326/0003-4819-144-2-20060​1170-00010​.
134. Mehta V, Langford RM. Acute pain management for opioid
dependent patients. Anaesthesia. 2006;61(3):269–76. https​://
doi.org/10.1111/j.1365-2044.2005.04503​.x.
135. Blinderman CD, Sekine R, Zhang B, Nillson M, Shaiova L.
Methadone as an analgesic for patients with chronic pain in
methadone maintenance treatment programs (MMTPs). J Opioid
Manag. 2009;5(2):107–14.
136. Kreek MJ, Bencsath FA, Fanizza A, Field FH. Effects of liver
disease on fecal excretion of methadone and its unconjugated
metabolites in maintenance patients. Quantitation by direct probe
chemical ionization mass spectrometry. Biomed Mass Spectrom.
1983;10(10):544–9. https​://doi.org/10.1002/bms.12001​01003​.

130
137. Kreek MJ, Schecter AJ, Gutjahr CL, Hecht M. Methadone use
in patients with chronic renal disease. Drug Alcohol Depend.
1980;5(3):197–205.
138. Mallappallil M, Sabu J, Friedman EA, Salifu M. What do we
know about opioids and the kidney? Int J Mol Sci. 2017. https​://
doi.org/10.3390/ijms1​80102​23.
139. Davis M. Cholestasis and endogenous opioids: liver disease
and exogenous opioid pharmacokinetics. Clin Pharmacokinet.
2007;46(10):825–50. https​://doi.org/10.2165/00003​088-20074​
6100-00002​.
140. Novick DM, Kreek MJ, Fanizza AM, Yancovitz SR, Gelb AM,
Stenger RJ. Methadone disposition in patients with chronic
liver disease. Clin Pharmacol Ther. 1981;30(3):353–62. https​
://doi.org/10.1038/clpt.1981.172.
141. Chandok N, Watt KD. Pain management in the cirrhotic patient:
the clinical challenge. Mayo Clin Proc. 2010;85(5):451–8.
https​://doi.org/10.4065/mcp.2009.0534.
142. Oliverio C, Malone N, Rosielle DA. Opoid use in liver fail-
ure #260. J Palliat Med. 2012;15(12):1389–91. https​: //doi.
org/10.1089/jpm.2012.9543.
143. Potosek J, Curry M, Buss M, Chittenden E. Integration of pal-
liative care in end-stage liver disease and liver transplantation.
J Palliat Med. 2014;17(11):1271–7. https​://doi.org/10.1089/
jpm.2013.0167.
144. Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney
C, et  al. Methadone versus morphine as a first-line strong
opioid for cancer pain: a randomized, double-blind study. J
Clin Oncol. 2004;22(1):185–92. https​: //doi.org/10.1200/
JCO.2004.03.172.
145. Ripamonti C, Groff L, Brunelli C, Polastri D, Stavrakis A,
De Conno F. Switching from morphine to oral methadone in
treating cancer pain: what is the equianalgesic dose ratio? J
Clin Oncol. 1998;16(10):3216–21. https​://doi.org/10.1200/
JCO.1998.16.10.3216.
146. Madden K, Mills S, Dibaj S, Williams JL, Liu D, Bruera E.
Methadone as the initial long-acting opioid in children with
advanced cancer. J Palliat Med. 2018;21(9):1317–21. https​://
doi.org/10.1089/jpm.2017.0712.
147. Habashy C, Springer E, Hall EA, Anghelescu DL. Methadone
for pain management in children with cancer. Paediatr Drugs.
2018;20(5):409–16. https:​ //doi.org/10.1007/s40272​ -018-0304-2.
148. LeBlanc Z, Vance C, Payne J, Zhang J, Hilliard L, Lebensburger
JD, et al. Management of severe chronic pain with methadone in
paediatric patients with sickle cell disease. Pediatr Blood Cancer.
2018;65(8):e27084. https​://doi.org/10.1002/pbc.27084​.
149. Horst J, Frei-Jones M, Deych E, Shannon W, Kharasch ED.
Pharmacokinetics and analgesic effects of methadone in chil-
dren and adults with sickle cell disease. Pediatr Blood Cancer.
2016;63(12):2123–30. https​://doi.org/10.1002/pbc.26207​.
K. P. Edmonds et al.
150. Busse J, Gottlieb D, Ferreras K, Bain J, Schechter W. Phar-
macological management of severe neuropathic pain in a case
of eosinophilic meningitis related to angiostrongylus canton-
ensis. Case Rep Anesthesiol. 2018;2018:5038272. https​://doi.
org/10.1155/2018/50382​72.
151. Yazde Puleio ML, Gomez KV, Majdalani A, Pigliapoco V, Santos
Chocler G. Opioid treatment for mixed pain in paediatric patients
assisted by the Palliative Care team. Five years of experience.
Arch Argent Pediatr. 2018;116(1):62–4. https​://doi.org/10.5546/
aap.2018.eng.62.
152. Hui D, Nooruddin Z, Didwaniya N, Dev R, De La Cruz M, Kim
SH, et al. Concepts and definitions for “actively dying,” “end of
life,” “terminally ill,” “terminal care,” and “transition of care”: a
systematic review. J Pain Symptom Manag. 2014;47(1):77–89.
https​://doi.org/10.1016/j.jpain​symma​n.2013.02.021.
153. Zimmerman KO, Hornik CP, Ku L, Watt K, Laughon MM,
Bidegain M, et al. Sedatives and analgesics given to infants
in neonatal intensive care units at the end of life. J Pedi-
atr. 2015;167(2):299–304. https ​ : //doi.org/10.1016/j.jpeds​
.2015.04.059.
154. Hui D, dos Santos R, Chisholm G, Bansal S, Silva TB, Kilgore
K, et al. Clinical signs of impending death in cancer patients.
Oncologist. 2014;19(6):681–7. https​://doi.org/10.1634/theon​
colog​ist.2013-0457.
155. Hui D, Dos Santos R, Chisholm G, Bansal S, Souza Crovador C,
Bruera E. Bedside clinical signs associated with impending death
in patients with advanced cancer: preliminary findings of a pro-
spective, longitudinal cohort study. Cancer. 2015;121(6):960–7.
https​://doi.org/10.1002/cncr.29048​.
156. Zhang J, Zhang C, Li Q, Zhang J, Gu X, Zhao W, et al. C-Reac-
tive protein/albumin ratio is an independent prognostic predictor
of survival in advanced cancer patients receiving palliative care.
J Palliat Med. 2019. https​://doi.org/10.1089/jpm.2019.0102.
157. Miyamoto T, Fujitani M, Fukuyama H, Hatanaka S, Koizumi Y,
Kawabata A. The C-reactive protein/albumin ratio is useful for
predicting short-term survival in cancer and noncancer patients.
J Palliat Med. 2019;22(5):532–7. https ​ : //doi.org/10.1089/
jpm.2018.0404.
158. Blinderman CD, Billings JA. Comfort care for patients dying in
the hospital. N Engl J Med. 2015;373(26):2549–61. https​://doi.
org/10.1056/NEJMr​a1411​746.
159. Arthur J, Reddy A. Opioid prescribing in an opioid crisis: What
basic skills should an oncologist have regarding opioid therapy?
Curr Treat Options Oncol. 2019;20(5):39.
160. Arthur J, Bruera E. Balancing opioid analgesia with the risk
of nonmedical opioid use in patients with cancer. Nat Rev Clin
Oncol. 2018;16(4):213–26.