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Methadone – Adult/Pediatric/Neonatal – Inpatient/Ambulatory

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Methadone – Adult/Pediatric/Neonatal –
Inpatient/Ambulatory
Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 7
METHODOLOGY ...................................................................................................................... 8
DEFINITIONS: ........................................................................................................................... 8
INTRODUCTION ....................................................................................................................... 8
RECOMMENDATIONS .............................................................................................................. 9
UW HEALTH IMPLEMENTATION ............................................................................................14
REFERENCES .........................................................................................................................15
APPENDIX A ............................................................................................................................18
APPENDIX B ............................................................................................................................19
APPENDIX C ............................................................................................................................20
APPENDIX D ............................................................................................................................21
CPG Contact for Changes: CPG Contact for Content:
Name: Philip Trapskin, PharmD, BCPS Name: Cindy Gaston, PharmD, BCPS
Phone Number: 608-263-1328 Phone Number: 608-265-8161
Email Address: ptrapskin@uwhealth.org Email Address: cgaston@uwhealth.org
Note: Active Table of Contents
Click to follow link
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Guideline Author: Kathryn Hensley, PharmD
Coordinating Team Members:
Cindy Gaston, PharmD, BCPS
Review Individuals/Bodies:
Nathan Rudin, MD; Nalini Sehgal, MD; Scott Hagen, MD; Juan Boriosi, MD; Cindy Gaston, PharmD;
Aaron Steffenhagen, PharmD; Peggy Riley, RN, MN, MPH; Deb Soetenga, RN, CNS; Mike Raschka,
PharmD; Beth Gorski, PharmD; Christi Albert, PharmD; Jamie Limjoco, MD; Laura Konkol, CNS; Emma
Ross, PharmD; Brook Anderson, CNS; Jan Kunz, CNS
Committee Approvals/Dates:
Pharmacy and Therapeutics Committee - April 2015
Release Date: April 2015
Next Review Date: April 2017
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Executive Summary
Guideline Overview
This clinical practice guideline is intended to provide guidance for practitioners wanting to initiate patients
on methadone for chronic pain, provide recommendations related to monitoring patients on methadone,
and to standardize tapers from prolonged opioid infusions in the pediatric and neonatal population.
Target Population
Inpatient and ambulatory adult, pediatric and neonatal patients using methadone for indications other
than methadone maintenance.
Key Practice Recommendations
1. General information
1.1. Renal dosing
1.1.1. Methadone is considered safe to use in patients with renal dysfunction. No dose
adjustments are necessary.1 (Class I, Level B)
1.2. Administration
1.2.1. Enteral
1.2.1.1. Enteral administration of methadone is preferred. (Class I, Level A)
1.2.2. Intravenous
1.2.2.1. If enteral administration is not possible, intravenous administration is the preferred
alternative route.2-4 (Class I, Level A)
1.2.2.2. The recommended IV to PO conversion is 1:2 when switching from intravenous to
oral methadone.4-6 (Class I, Level B)
1.3. Dose conversion in adult patients7,8
1.3.1. Conversion varies based on the total daily dose of oral morphine equivalents.8-10 (Class I,
Level B). Table 1 provides dose conversions based on total daily dose of oral morphine
equivalents.
1.3.2. Patients should have a short acting medication available for use during the conversion
process as methadone may take 7-14 days to reach steady state levels.11 (Class IIa, Level
C)
1.3.3. No specific pediatric dosing conversion is available.
Table I. Converting Adult Patients from Oral Morphine to Oral Methadone
Total Daily
Baseline Oral
Morphine Dose
Daily Oral
Methadone Dose
(as % of total daily
morphine dose)
Conversion ratio
<100 mg 20-30% 3:1
100-300 mg 10-20% 5:1
> 300 mg
Consult with a pain specialist prior to
converting doses or taper current opioid dose
to 300 mg prior to conversion.
Decrease calculated dose of methadone by 25 – 50% based on pain
control, side effects, and patient characteristics.12-14
1.4. Contraindications
1.4.1. Methadone should not be used in patients with a known allergy to methadone, significant
respiratory depression, acute bronchial asthma or paralytic ileus.7 (Class III, Level B)
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1.4.2. Methadone is not recommended for use in patients with baseline QTc ≥500 ms due to
significant increase risk for arrhythmias.11,15 (Class III, Level C)
1.5. Precautions
1.5.1. Use caution when initiating methadone in patients with a baseline QTc between 450 ms and
500 ms.11 (Class IIb, Level B)
1.5.2. Methadone should be initiated cautiously in patients with underlying co-morbidities, such as
sleep apnea, dementia or antecedent constipation which may increase their risk for adverse
effects.11 (Class IIb, Level B)
1.6. Drug interactions
1.6.1. Methadone can interact with many medications, both via metabolism pathways and additive
QTc prolongation.2,9,11,16,17 All patients receiving methadone therapy should have their
medication list reviewed for potential pharmacokinetic and pharmacodynamic drug
interactions. (Class I, Level C)
2. Chronic Pain
2.1. Prior to initiating therapy, evaluate risks and benefits of therapy based on medical and
behavioral factors.11,16,18 (Class I, Level C)
2.2. Indications
2.2.1. Methadone may be used to treat cancer and non-cancer pain, neuropathic pain, and pain
refractory to other opioids.9,16,19 (Class IIa, Level B).
2.2.2. Methadone may be useful in patients with true morphine allergy, those who have
experienced significant adverse effects from other opioids, and patients unable to afford
more expensive long-acting opioids.9,16,19 (Class IIa, Level B).
2.2.3. Methadone may be a good option in persons with a history of substance abuse due to its
lower potential for abuse and the need to treat pain with medications other than those
abused in the past.16 (Level IIb, Class C)
2.2.4. Methadone is useful for weaning pediatric and neonatal patients following prolonged
exposure to opioids.20-23 (Class IIa, Level B)
2.3. Adult dose and titration for chronic pain8,9,11,18
2.3.1. Methadone should be initiated at low doses and titrated slowly. (Level I, Class C)
2.3.2. Non-opioid tolerant
2.3.2.1. The recommended starting dose is 2.5 mg three times daily for most non-opioid
tolerant adult patients.9,11,18 (Class I, Level B)
2.3.2.2. Older patients or those with hepatic impairment might require less frequent
dosing, and a starting dose of 2.5 mg once daily may be sufficient.9 (Class IIa,
Level C)
2.3.2.3. Doses should be increased by no more than 5 mg daily in 5 to 7 day increments.11
(Class IIa, Level B)
2.3.3. Previous opioid use (Class I, Level B)
2.3.3.1. See Table 1 for converting to methadone from other opioids.
2.3.3.2. Doses should be increased by no more than 10 mg per day no more than every 5-
7 days11. (Class IIa, Level B)
2.4. Pediatric dose and titration for chronic pain11
2.4.1. Methadone is not routinely recommended as a first line agent for pain in pediatric
patients.24,25 (Class III, Level B)
2.4.2. Methadone might be considered as a first line agent in specific patient populations.26
(Class IIb, Level C)
2.4.2.1. Patients requiring around-the-clock opioid analgesia but are unable to take
extended release medications
2.4.2.2. Palliative care26
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2.4.3. The recommended starting dose is 0.05 mg/kg every 8 to 12 hours (maximum 2.5
mg/dose). (Class IIa, Level C).
2.4.4. Doses should be increased by no more than 50% of the current methadone dose no sooner
than every 5-7 days11
2.5. Electrocardiogram and QTc monitoring15,27-29
2.5.1. Evaluate patient risk factors for QTc prolongation. (Class I, Level C)
2.5.2. Adult recommendations
2.5.2.1. Obtain a baseline EKG to assess QTc interval prior to initiation of methadone for
patients at risk for QTc prolongation.11,15 (Class I, Level C)
2.5.2.2. For patients with baseline QTc between 450 and 500 ms, alternatives to
methadone should be considered. If benefits to methadone outweigh risks,
evaluate and correct reversible causes of QTc prolongation.11,15 (Class IIb, Level
C).
2.5.2.3. A repeat EKG should be obtained within 30 days of initiation of methadone.11,15
(Class I, Level C)
2.5.2.4. If QTc on follow-up EKG is between 450 and 500 ms, clinicians should consider
switching to an alternative opioid or decreasing the methadone dose.11 (Class I,
Level C)
2.5.2.5. If QTc on follow-up EKG is ≥500 ms, it is recommended to change methadone to
an alternative opioid or immediately reduce the dose.11 (Class I, Level C)
2.5.2.6. It is reasonable to obtain an EKG prior to initiating medications that may additively
prolong the QTc.11,16 (Class IIa, Level C)
2.5.3. Pediatric recommendations
2.5.3.1. Similar QTc parameters should be applied for children being treated with
methadone long-term due to the potential for risks associated with prolonged
QTc.11 (Class IIb, Level C)
2.5.3.2. It is reasonable to obtain an EKG prior to initiation of methadone for weaning
prolonged opioid infusions.(Class IIb, Level C)
3. Prolonged Opioid Infusion Tapers in Pediatric Patients
3.1. Methadone may be used to facilitate weaning and prevent withdrawal symptoms in critically ill
children exposed to prolonged infusions of opioid.23,30-32 (Class IIa, Level B)
3.2. Taper20,21,33 (Class IIa, Level C)
Table 2. Methadone Taper for Patients Receiving Opioid Infusion for 5-10 Days
Step Day Methadone dose (oral)
(max: 5 mg/dose) Opioid Infusion
1
1
0.1 mg/kg every 6 h x 48 h Decrease by 25% every 6 hours after 1st dose
2 Off on day 2
2 3 0.1 mg/kg every 8 h x 24 h
3 4 0.1 mg/kg every 12 h x 24 h
4 5 0.08 mg/kg every 12 h x 24 h
5 6 0.06 mg/kg every 12 h x 24 h
6 7 0.03 mg/kg every 12 h x 24 h
7 8 0.03 mg/kg every 24 h x 24 h
8 9 Discontinue methadone
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Table 3. Methadone Taper for Patients Receiving Opioid Infusion for ≥10 Days or Cumulative
Fentanyl Dose of 2.5mg/kg (or equivalent)
Step Day Methadone dose (oral)
(max: 5 mg/dose) Opioid Infusion
1
1
0.1 mg/kg every 6 h x 48 h Decrease by 25% every 6 hours after 1st dose
2 Off on day 2
2
3
0.1 mg/kg every 8 h x 48 h
4
3
5
0.1 mg/kg every 12 h x 48 h
6
4
7
0.08 mg/kg every 12 h x 48 h
8
5
9
0.06 mg/kg every 12 h x 48 h
10
6
11
0.03 mg/kg every 12 h x 48 h
12
7 13 0.03 mg/kg every 24 h x 24 h
8 14 Discontinue methadone
3.3. Withdrawal symptoms
3.3.1. Assessment
3.3.1.1. The Withdrawal Assessment Tool-1 (WAT-1) can be useful in assessing opioid
withdrawal in at-risk pediatric patients (Appendix C).21,34,35 (Class I, Level B)
3.3.1.2. A WAT-1 score of >3 predicts opioid withdrawal with 87% sensitivity and 88%
specificity.21,34 Rescue doses of opioid should be provided for patients with WAT-1
scores ≥3. (Class I, Level C)
3.3.2. Treatment of withdrawal symptoms
3.3.2.1. Intermittent rescue doses of 0.1 – 0.3 mg/kg/dose oral morphine (max dose 5 mg)
every 1-2 hours prn may be used for breakthrough withdrawal symptoms.30 (Class
IIa, Level C)
4. Neonatal Abstinence Syndrome (in utero exposure)
4.1. Morphine is the most commonly recommended first line agent for treatment of neonatal
abstinence syndrome from in utero opioid exposure.33,36 (Class IIa, Level C)
4.2. Methadone may be used in place of morphine in patients unable to tolerate morphine.33,36 (Class
IIa, Level C)
4.3. The modified Finnegan scoring system should be used to assess withdrawal in neonates
(Appendix D).33,36 (Class I, Level C)
Companion Documents
Methadone Pain Care Fast Facts
Withdrawal Assessment Tool (WAT-1)
State Behavioral Scale (SBS)
Pertinent UWHC Policies & Procedures
Policy 8.56 Pediatric Sedation Policy
Patient Resources:
Opioid Medicine for Chronic Pain HFFY 7716
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Scope
Disease/Condition(s):
Guidance for the use of methadone in chronic cancer and non-cancer pain, neuropathic pain and for
tapering prolonged opioid infusions, in UW Health adult, pediatric and neonatal patients. Methadone use
as part of an addiction treatment program is not included. Additional information on Methadone Clinics
can be found by following this link:
https://uconnect.wisc.edu/clinical/references/medication-use-manual/operations-for-specific-medications/
resources/name-31928-en.file
Clinical Specialty:
ξ Primary Care Providers
ξ Pharmacists
ξ Palliative Care Providers
ξ Pediatric and Neonatal Critical Care Providers
ξ Pain Management Providers
Intended Users:
Prescribing providers, pharmacists and nurses
CPG objective(s):
To improve the safety of methadone prescribing and monitoring for UW Health patients.
For pediatric patients undergoing tapers, the goal is to improve safety by standardizing care and minimize
significant withdrawal symptoms following long-term use of opioid infusions.
Target Population:
Adult, pediatric and neonatal inpatient and ambulatory patients.
Major Outcomes Considered:
The major outcomes considered in this guideline are the safe and appropriate use of methadone for all
indications other than opioid addiction maintenance. Appropriate use is measured through careful patient
selection and dosing and safety is measured by prevention of adverse effects such as severe respiratory
depression and cardiac events.
Guideline Metrics:
ξ Time to wean off opioid infusions, duration of methadone tapers, withdrawal symptoms with opioid
taper
ξ Appropriate dose conversion and titration
ξ Appropriate QTc monitoring
ξ Appropriate monitoring of significant drug interactions
ξ Adverse drug reaction reports for methadone
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Methodology
A modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system
developed by the American Heart Association and the American College of Cardiology Foundation has
been used to assess the Quality and Strength of the evidence in this Clinical Practice Guideline.
(Appendix A).37
A literature search conducted in PubMed was completed using the search terms: “methadone”, “pain”,
“chronic pain”, “cancer”, “non-cancer”, “dose conversion”, “pediatrics” and “opioid tapers”. Identified
articles had reference lists reviewed to identify other resources.
Method of Guideline Validation:
A multidisciplinary workgroup of clinical experts provided evidence-based input and developed a
consensus for recommendations.
Definitions:
Opioid tolerant (adults): Patients taking at least 60 mg oral morphine or equivalent per day for 1 week or
longer.38
Opioid tolerant (pediatrics): There is no standard definition of opioid-tolerance in pediatric patients.
Children exposed to less than 3 days of opioids are unlikely to develop tolerance.21 Cumulative doses
>2.5 mg/kg of fentanyl or a duration of fentanyl infusion >9 days are 100% predictive of opioid
withdrawal.39
Introduction
Methadone is indicated for the treatment of moderate to severe pain unresponsive to non-opioid
analgesics and is an alternative to other, more expensive, long-acting opioids. Methadone may be used
for the treatment of chronic cancer, noncancer and neuropathic pain, as well as in patients who have
developed tolerance to, or side effects from, other opioids.2,9,11,19,40 Additionally, methadone’s long half-life
and excellent oral bioavailability make it a useful medication for preventing withdrawal syndromes in
pediatric patients who have been exposed to prolonged opioid infusions.20,23,32
Despite its utility, methadone has been associated with significant morbidity and mortality. Opioid-related
overdose deaths more than tripled between 1999 and 2006, rising from 4,000 to 13,800, a majority of
which were attributed to methadone.41 In the mid-2000’s, methadone for any indication represented less
than 5% of the opioid prescriptions in the United States but was responsible for a third of all opioid-related
deaths.41 This data prompted the FDA to issue a safety warning in 2006 notifying professionals of the risk
of death and life-threatening adverse events such as respiratory arrest and cardiac arrhythmias.42 The
rate of fatal overdoses associated with methadone increased more than fivefold from 1999 to 2009,
peaking in 2007 at a rate of 1.8 deaths per 100,000 persons.43 This increase in methadone-related deaths
is associated with an increase in methadone use for pain.44 Despite a slow decline in the rate of overdose
deaths, the death rate associated with methadone remains disproportionately greater than that for any
other opioid.27,43
Methadone has unique pharmacokinetic and pharmacodynamic properties that contribute to this
increased risk of overdose and death. Unlike most other opioids, methadone’s relative potency increases
with escalating opioid doses, leading to a non-linear model of dose conversion.8,10,16,40 Methadone also
has a long and variable half-life, typically ranging from 15-60 hours, but with high inter-patient variability,
there have been reports of a half-life as long as 120 hours.11 The average half-life in children ranges from
4-62 hours.17,23 This long half-life means most patients do not reach steady state levels for 7 to 14 days.11
If initial doses are too high or increased too fast, this long and variable half-life can lead to accumulation
with repeated dosing and subsequent life-threatening respiratory depression and death.9,11,19 In addition
to serious respiratory adverse effects, methadone has been associated with QTc prolongation and
serious cardiac arrhythmias, including Torsades de Pointes.11,15,27-29,45
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Careful patient selection and complete understanding of the risks associated with methadone allows the
medication to be used safely in a variety of patient populations due to its many advantages. Methadone is
a purely synthetic opioid that acts as a mu- and delta-opioid receptor agonist and N-methyl-D-aspartate
(NMDA) receptor antagonist.7,9,16,19 This antagonism is unique to methadone and can provide additional
therapeutic benefit. NMDA antagonism can produce central sensitization and may help prevent the
development of tolerance, making it useful in patients experiencing hyperalgesia to other opioids.9,46 This
receptor activity also makes methadone an option for treatment of neuropathic pain.47-49 Additional
benefits of methadone include its excellent oral bioavailability, lack of known active metabolites,
prolonged analgesic effects lasting from 6-12 hours, and its ability to be safely used in patients with renal
dysfunction or true allergy to morphine and other opioids. 9,11,16,19 Methadone’s use in children to facilitate
weaning has the benefit of preventing withdrawal symptoms and faster discontinuation of IV opioid
infusions.23
Recommendations
1. General information
1.1. Renal dosing
1.1.1. Methadone is considered safe to use in patients with renal dysfunction. No dose
adjustments are necessary.1 (Class I, Level B)
1.1.2. Methadone is not dialyzed and no dose adjustments are necessary in dialysis patients.1
(Class I, Level C)
1.2. Administration
1.2.1. Enteral
1.2.1.1. Enteral administration of methadone is preferred. (Class I, Level A)
1.2.1.2. Methadone is available as tablets and solution for enteral use.2-4
1.2.1.3. Bioavailability of methadone via gastric route is approximately 70-80%.2,4,7,11,49
1.2.2. Intravenous
1.2.2.1. If enteral administration is not possible, intravenous administration is the
preferred alternative route.2-4 (Class I, Level A)
1.2.2.2. The recommended IV to PO conversion is 1:2 when switching from intravenous
to oral methadone.4-6 (Class I, Level B)
1.2.2.3. Methadone is not recommended for use in patient-controlled analgesia. (Class
III, Level C)
1.2.3. The following routes of administration are available with limited evidence and are not
recommended for routine use. (Class III, Level B)
1.2.3.1. Rectal – If no other route is available the oral solution of methadone can be
administered rectally4 Bioavailability of rectal administration is approximately 76%
and mean duration of action is approximately 10 hours
1.2.3.2. Sublingual – One case report demonstrates efficacy with concentrated oral
solution given sublingually.50
1.2.3.3. Intramuscular – The injectable solution of methadone can be administered IM
with deltoid injections providing better analgesia and higher peak plasma
concentrations.3,4
1.2.3.4. Subcutaneous – Methadone may be administered subcutaneously but is often
associated with local irritation.2
1.3. Methadone is not routinely recommended for use in acute pain. (Class III, Level C)
1.3.1. In select patient populations when administration long acting enteral opioid via feeling
tube is required, methadone could be considered. An inpatient pain consult is
recommended. . (Class IIb, Level C)
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1.4. Dose conversion in adult patients7,8
1.4.1. Conversion varies based on the total daily dose of oral morphine equivalents.8-10 (Class I,
Level B). Table 1 provides dose conversions based on total daily dose of oral morphine
equivalents.
1.4.2. Patients should have a short acting medication available for use during the conversion
process as methadone may take 7-14 days to reach steady state levels.11 (Class IIa,
Level C)
1.4.3. No specific pediatric dosing conversion is available.
Table I. Converting Adult Patients from Oral Morphine to Oral Methadone
Total Daily
Baseline Oral
Morphine Dose
Daily Oral
Methadone Dose
(as % of total daily
morphine dose)
Conversion ratio
<100 mg 20-30% 3:1
100-300 mg 10-20% 5:1
> 300 mg Consult with a pain specialist prior to
converting doses or taper current opioid dose
to 300 mg prior to conversion.
Decrease calculated dose of methadone by 25 – 50% based on pain
control, side effects, and patient characteristics.12-14
Modified from Methadone package insert and Toombs et al 20057,9,40
1.5. Contraindications
1.5.1. Methadone should not be used in patients with a known allergy to methadone, significant
respiratory depression, acute bronchial asthma or paralytic ileus.7 (Class III, Level B)
1.5.2. Methadone is not recommended for use in patients with baseline QTc ≥500 ms due to
significant increase risk for arrhythmias.11,15 (Class III, Level C)
1.6. Precautions
1.6.1. Use caution when initiating methadone in patients with a baseline QTc between 450 ms
and 500 ms.11 (Class IIb, Level B)
1.6.2. Methadone should be initiated cautiously in patients with underlying co-morbidities, such
as sleep apnea, dementia or antecedent constipation which may increase their risk for
adverse effects.11 (Class IIb, Level B)
1.7. Drug interactions
1.7.1. Methadone can interact with many medications, both via metabolism pathways and
additive QTc prolongation risks.2,9,11,16,17 All patients receiving methadone therapy should
have their medication list reviewed for potential pharmacokinetic and pharmacodynamic
drug interactions. (Class I, Level C)
1.7.1.1. Electronic resources such as Micromedex® or Lexi Comp© may be used to run
drug interaction reports to assess safety of medication combinations.
1.7.1.2. Caution should be used when initiating any medication that may increase risk of
side effects from methadone.
2. Chronic Pain
2.1. Prior to initiation therapy evaluate risk and benefits of therapy based on medical and behavioral
factors.11,16,18 (Class I, Level C)
2.2. Indications
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2.2.1. Methadone may be used to treat cancer and non-cancer pain, neuropathic pain, and pain
refractory to other opioids.9,16,19 (Class IIa, Level B).
2.2.2. Methadone may be useful in patients with true morphine allergy, those who have
experienced significant adverse effects from other opioids, and patients unable to afford
more expensive long-acting opioids.9,16,19 (Class IIa, Level B).
2.2.3. Methadone may be a good option in persons with a history of substance abuse due to its
lower potential for abuse and need to treat pain with medications other than those
abused in the past.16 (Level IIb, Class C)
2.2.4. Methadone is useful for weaning pediatric and neonatal patients following prolonged
exposure to opioids.20-23 (Class IIa, Level B)
2.3. Adult dose and titration for chronic pain8,9,11,18
2.3.1. Methadone should be initiated at low doses and titrated slowly (Level I, Class C)
2.3.2. Due to the long half-life, the full analgesic effects of methadone may not be apparent for
1-2 weeks.11,16,49 Patients should be cautioned not to self-titrate doses if pain relief is
inadequate. (Level I, Class C)
2.3.3. Non-opioid tolerant
2.3.3.1. The recommended starting dose is 2.5 mg three times daily for most non-opioid
tolerant adult patients.9,11,18 (Class I, Level B)
2.3.3.2. Older patients or those with hepatic impairment might require less frequent
dosing and a starting dose of 2.5 mg once daily may be sufficient.9 (Class IIa,
Level C)
2.3.3.3. Doses should be increased by no more than 5 mg daily in 5 to 7 day
increments.11 (Class IIa, Level B)
2.3.4. Previous opioid use (Class I, Level B)
2.3.4.1. See Table 1 for converting to methadone from other opioids
2.3.4.2. Doses should be increased by no more than 10 mg per day no more than every
5-7 days11. (Class IIa, Level B)
2.3.5. As needed dosing of methadone is not recommended.11,18 (Class III, Level C)
2.4. Pediatric dose and titration for chronic pain11
2.4.1. Methadone is not routinely recommended as a first line agent for pain in pediatric
patients.24,25 (Class III, Level B)
2.4.2. Methadone might be considered as a first line agent in specific patient populations.26
(Class IIb, Level C)
2.4.2.1. Patients requiring around-the-clock opioid analgesia, but unable to take
extended release medications
2.4.2.2. Palliative care26
2.4.3. The recommended starting dose is 0.05 mg/kg every 8 to 12 hours (maximum 2.5
mg/dose). (Class IIa, Level C).
2.4.4. Doses should be increased by no more than 50% of the current methadone dose no
sooner than every 5-7 days11
2.5. Electrocardiogram and QTc monitoring15,27-29
2.5.1. Evaluate patient risk factors for QTc prolongation. (Class I, Level C)
Risk factors include:11,45,51
ξ Electrolyte abnormalities
ξ Structural heart disease
ξ Genetic predisposition
ξ Concomitant use of other QTc prolonging drugs
ξ Escalating doses of methadone, especially ≥100mg/day
ξ Use of intravenous methadone
2.5.2. Adult recommendations
2.5.2.1. Obtain a baseline EKG to assess QTc interval prior to initiation of methadone for
patients at risk for QTc prolongation.11,15 (Class I, Level C)
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2.5.2.2. Recommend against initiation of methadone if baseline QTc >500ms11,15 (Class
IIII, Level C)
2.5.2.3. For patients with baseline QTc between 450 and 500 ms, alternatives to
methadone should be considered. If benefits to methadone outweigh risks,
evaluate and correct reversible causes of QTc prolongation.11,15 (Class IIb, Level
C).
2.5.2.4. A repeat EKG should be obtained within 30 days of initiation of methadone.11,15
(Class I, Level C)
2.5.2.5. If QTc on follow-up EKG is between 450 and 500 ms, clinicians should consider
switching to an alternative opioid or decreasing the methadone dose.11 (Class I,
Level C)
2.5.2.6. If QTc on follow-up EKG is ≥500 ms, it is recommended to change methadone to
an alternative opioid or immediately reduce the dose.11 (Class I, Level C)
2.5.2.7. It is reasonable to obtain an EKG prior to initiating medications that may
additively prolong the QTc.11,16 (Class IIa, Level C)
2.5.3. Pediatric recommendations
2.5.3.1. Similar QTc parameters should be applied for children being treated with
methadone long-term due to the potential for risks associated with prolonged
QTc.11 (Class IIb, Level C)
2.5.3.2. It is reasonable to obtain an EKG prior to initiation of methadone for weaning
prolonged opioid infusions.(Class IIb, Level C)
3. Prolonged Opioid Infusion Tapers in Pediatric Patients
3.1. Methadone may be used to facilitate weaning and prevent withdrawal symptoms in critically ill
children exposed to prolonged infusions of opioid.23,30-32 (Class IIa, Level B)
3.2. Taper20,21,33 (Class IIa, Level C)
Table 2. Methadone Taper for Patients Receiving Opioid Infusion for 5-10 Days
Step Day Methadone dose (oral)
(max: 5 mg/dose) Opioid Infusion
1
1 0.1 mg/kg every 6 h x 48 h Decrease by 25% every 6 hours after 1st dose
2 Off on day 2
2 3 0.1 mg/kg every 8 h x 24 h
3 4 0.1 mg/kg every 12 h x 24 h
4 5 0.08 mg/kg every 12 h x 24 h
5 6 0.06 mg/kg every 12 h x 24 h
6 7 0.03 mg/kg every 12 h x 24 h
7 8 0.03 mg/kg every 24 h x 24 h
8 9 Discontinue methadone
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Table 3. Methadone Taper for Patients Receiving Opioid Infusion for ≥10 Days or Cumulative
Fentanyl Dose of 2.5mg/kg (or equivalent)
Step Day Methadone dose (oral)
(max: 5 mg/dose) Opioid Infusion
1
1
0.1 mg/kg every 6 h x 48 h Decrease by 25% every 6 hours after 1st dose
2 Off on day 2
2
3
0.1 mg/kg every 8 h x 48 h
4
3
5
0.1 mg/kg every 12 h x 48 h
6
4
7
0.08 mg/kg every 12 h x 48 h
8
5
9
0.06 mg/kg every 12 h x 48 h
10
6
11
0.03 mg/kg every 12 h x 48 h
12
8 13 0.03 mg/kg every 24 h x 24 h
9 14 Discontinue methadone
3.3. Hold methadone dose and contact prescriber if patient has a State Behavior Scale (SBS) score
of -1 or lower (Appendix B)52. If a patient is too sedated at a specific step, it is reasonable to
move on to the next step of the taper at the discretion of the provider and resume weaning from
there. (Class IIa, Level C)
3.4. Withdrawal symptoms
3.4.1. Assessment
3.4.1.1. The Withdrawal Assessment Tool-1 (WAT-1) can be useful in assessing opioid
withdrawal in at-risk pediatric patients (Appendix C).21,34,35 (Class I, Level B)
3.4.1.2. A WAT-1 score of >3 predicts opioid withdrawal with 87% sensitivity and 88%
specificity.21,34 Rescue doses of opioid should be provided for patients with WAT-
1 scores ≥3. (Class I, Level C)
3.4.1.3. Scoring should be done at least every 12 hours, or more frequently based on
patient condition.
3.4.1.4. Patients should be re-scored after receiving rescue doses of morphine to assess
response to treatment. (Class I, Level C) 34
3.4.2. Treatment of withdrawal symptoms
3.4.2.1. Intermittent rescue doses of 0.1 – 0.3 mg/kg/dose oral morphine (max dose 5
mg) every 1-2 hours prn may be used for breakthrough withdrawal symptoms.30
(Class IIa, Level C)
3.4.2.2. Rescue doses of morphine may be reduced near the end of the taper. (Class IIa,
Level C)
3.4.2.3. If a patient requires ≥3 rescue doses of morphine in a 24 hour period, they
should remain at the current step in the taper until they no longer require frequent
rescue doses. (Class I, Level C)
4. Neonatal Abstinence Syndrome (in utero exposure)
4.1. Morphine is the most commonly recommended first line agent for treatment of neonatal
abstinence syndrome from in utero opioid exposure.33,36 (Class IIa, Level C)
4.1.1. Starting morphine doses of 0.04mg/kg/dose every 3-4 hours are preferred. (Class I,
Level C)
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14
4.2. Methadone may be used in place of morphine in patients unable to tolerate morphine.33,36 (Class
IIa, Level C)
4.2.1. A typical starting dose of methadone for NAS is 0.05-0.1mg/kg/dose every 12 hours.36
(Class IIa, Level C)
4.2.2. Initial dose reduction by 10-20% weekly has been shown to be successful.33 (Class IIb,
Level C)
4.3. The modified Finnegan scoring system should be used to assess withdrawal in neonates
(Appendix D).33,36 (Class I, Level C)
UW Health Implementation
Potential Benefits:
The benefits of implementation of this guideline include improved safety and appropriateness of
prescribing and monitoring methadone. It will also provide a standardized approach to weaning patients
exposed to prolonged infusions of opioids in the pediatric intensive care unit.
Potential Harms:
While it is anticipated that the overall safety and appropriateness of methadone prescribing and
monitoring will be improved after guideline implementation, there are risks of QTc prolongation and
serious respiratory depression associated with methadone. Patient specific risk factors must be evaluated
prior to initiation of methadone and a risk-benefit discussion should take place between the prescriber
and patient.
Implementation Plan/Tools
Practitioner education will be completed. The guideline will be posted on UConnect and linked to all
methadone orders in HealthLink. An order set for the pediatric methadone tapers will be created to
operationalize guideline recommendations.
Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and treatment of
patients. This Clinical Practice Guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that
some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely
establish the only appropriate approach to a problem.
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15
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Appendix A
Modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE)37
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Appendix B
State Behavior Scale52
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Appendix C
Withdrawal Assessment Tool – 1 (WAT – 1)34
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Appendix D
Modified Finnegan’s Neonatal Abstinence Scoring Tool33
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