Accepted Manuscript

Safe and Appropriate Use of Methadone in Hospice and Palliative Care: Expert
Consensus White Paper

Mary Lynn McPherson, PharmD, MA, MDE, BCPS, CPE, Kathryn A. Walker,
PharmD, BCPS, CPE, Mellar P. Davis, MD FCCP FAAHPM, Eduardo Bruera, M.D.,
Akhila Reddy, MD, Judith Paice, PhD, RN, Kasey Malotte, PharmD, BCPS, Dawn
Kashelle Lockman, PharmD, MA, Charles Wellman, MD, Shelley Salpeter, MD, Nina
M. Bemben, PharmD, BCPS, James B. Ray, PharmD, CPE, Bernard J. Lapointe, MD,
Roger Chou, MD

PII: S0885-3924(18)31114-X
DOI: https://doi.org/10.1016/j.jpainsymman.2018.12.001
Reference: JPS 9984

To appear in: Journal of Pain and Symptom Management

Received Date: 2 August 2018

Revised Date: 28 November 2018
Accepted Date: 1 December 2018

Please cite this article as: McPherson ML, Walker KA, Davis MP, Bruera E, Reddy A, Paice J, Malotte K,
Lockman DK, Wellman C, Salpeter S, Bemben NM, Ray JB, Lapointe BJ, Chou R, Safe and Appropriate
Use of Methadone in Hospice and Palliative Care: Expert Consensus White Paper, Journal of Pain and
Symptom Management (2019), doi: https://doi.org/10.1016/j.jpainsymman.2018.12.001.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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 ACCEPTED MANUSCRIPT

1 Safe and Appropriate Use of Methadone in Hospice and Palliative Care: Expert Consensus

2 White Paper

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4 Mary Lynn McPherson, Kathryn A. Walker, Mellar P. Davis, Eduardo Bruera, Akhila Reddy,

5 Judith A. Paice, Kasey Malotte, Kashelle Lockman, Chuck Wellman, Janet Bull, Shelley Salpeter,

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6 Nina Bemben, James Ray, Bernard LaPointe, Roger Chou

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7

8 Corresponding author:

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9 Mary Lynn McPherson, PharmD, MA, MDE, BCPS, CPE
10 Professor and Executive Director, Advanced Post-Graduate Education in Palliative Care
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11 Department of Pharmacy Practice and Science
12 University of Maryland School of Pharmacy
13 20 N. Pine Street, S405, Baltimore, Maryland 21201
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14 Office 410-706-3682; Cell 443-822-6036; Fax 410-706-4725

15 [email protected]
16
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17 Affiliations and Disclosures (nothing to disclose unless noted):

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18 Mary Lynn McPherson, PharmD, MA, MDE, BCPS, CPE

19 Professor and Executive Director, Advanced Post-Graduate Education in Palliative Care
20 University of Maryland School of Pharmacy
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21 Baltimore, Maryland, USA

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23 Kathryn A. Walker, PharmD, BCPS, CPE
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24 Senior Clinical and Scientific Director of Palliative Care, MedStar Health

25 Associate Professor, University of Maryland School of Pharmacy
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26 Baltimore, Maryland, USA

27
28 Mellar P Davis MD FCCP FAAHPM
29 Geisinger Medical Center
30 Danville, PA, USA
31
32 Eduardo Bruera, M.D.
33 Disclosure: Reports grants from Helsinn Healthcare, outside the submitted work
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34
35 F. T. McGraw Chair in the Treatment of Cancer
36 Professor and Chair of Palliative, Rehabilitation & Integrative Medicine Department
37 The University of Texas MD Anderson Cancer Center
38 Houston, Texas, USA
39

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40 Akhila Reddy, MD
41 Disclosure: (Study drug (levorphanol) provided free of cost by Sentynl Therapeutics INC. No
42 other funding provided.)Associate Professor - Palliative, Rehabilitation & Integrative Medicine

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43 Medical Director, Supportive Care Center
44 The University of Texas | MD Anderson Cancer Center
45 Houston, Texas, USA

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46
47 Judith Paice, PhD, RN
48 Director, Cancer Pain Program; Division, Hematology-Oncology
49 Northwestern University; Feinberg School of Medicine

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50 Chicago, IL, USA
51
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52 Kasey Malotte, PharmD, BCPS
53 Advanced Practice Pharmacist Supportive Care Medicine
54 Cedars-Sinai Medical Center
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55 Los Angeles, CA, USA

56
57 Dawn Kashelle Lockman, PharmD, MA
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58 Clinical Assistant Professor, Hospice & Palliative Care | University of Iowa College of Pharmacy
59 Clinical Pharmacy Specialist | Internal Medicine-Palliative Care Program
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60 Iowa City, IA, USA

61
62 Charles Wellman, MD
Chief Medical Officer, Hospice of the Western Reserve
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63
64 Cleveland, Ohio, USA
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66
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67 Shelley Salpeter, MD
68 Clinical Professor of Medicine
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69 Stanford University School of Medicine, Stanford CA

70 Medical Director, Mission Hospice and Home Care
71 San Mateo, CA, USA
72
73 Nina M. Bemben, PharmD, BCPS
74 Primary Care Pharmacist, Kaiser Permanente
75 San Francisco, CA, USA
76
77 James B. Ray, PharmD, CPE
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78 Disclosure: American College of Surgeons – honorarium for speaking at Clinical Congress

79 meeting; axialHealthcare Scientific Advisory Board – fees for consulting
80 Clinical Associate Professor, University of Iowa College of Pharmacy
81 Clinical Pharmacy Specialist, Supportive and Palliative Care Consult Service, University of Iowa
82 Hospitals and Clinics; Iowa City, IA, USA
83

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84 Bernard J. Lapointe, MD
85 Eric M. Flanders Chair in Palliative Medicine, McGill University
86 Chief Supportive and Palliative Care Division Jewish General Hospital, Montreal, Canada
87

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88 Roger Chou, MD
89 Disclosure: Author on publications from American Pain Society, et al on Methadone Safety, an
opioid review for AHRQ and CDC, and the CDC opioid guidelines.

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90
91 Professor of Medicine, Division of General Internal Medicine and Geriatrics
92 OHSU, USA
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94
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Table 1 – Patient selection for methadone therapy
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95 Table 2 – Precautions and contraindications to methadone therapy
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96 Table 3 – ECG monitoring and action steps

97 Table 4 – Drug therapy modification for patients on stable methadone dose

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98
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99 Word count: 7250

100
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101 Funding: This research did not receive any specific grant from funding agencies in the public,
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102 commercial, or not-for-profit sectors.

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103

104
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105 ABSTRACT

106 Methadone has several unique characteristics that make it an attractive option for pain

107 relief in serious illness, but the safety of methadone has been called into question after reports

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108 of a disproportionate increase in opioid-induced deaths in recent years. The American Pain

109 Society (APS), College on Problems of Drug Dependence, and the Heart Rhythm Society

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110 collaborated to issue guidelines on best practices to maximize methadone safety and efficacy,

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111 but guidelines for the end-of-life scenario have not yet been developed. A panel of 15

112 interprofessional hospice and palliative care experts from the US and Canada convened in

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113 February 2015 to evaluate the APS methadone recommendations for applicability in the
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114 hospice and palliative care setting. The goal was to develop guidelines for safe and effective

115 management of methadone therapy in hospice and palliative care. This article represents the
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116 consensus opinion of the hospice and palliative care experts for methadone use at end of life,
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117 including guidance on appropriate candidates for methadone, detail in dosing, titration, and
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118 monitoring of patients’ response to methadone therapy.

119
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120 Keywords: methadone, hospice, palliative care, medication safety, arrhythmias

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122
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123 Introduction

124 Methadone hydrochloride is a synthetic mu-opioid agonist, and N-methyl-D-aspartate

125 receptor antagonist used for the treatment of pain and substance use disorder.1 Methadone

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126 has several unique characteristics that make it an attractive option for pain relief in serious

127 illness, including long duration of action, availability of multiple dosage formulations (tablet,

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128 oral solution, highly concentrated oral solution, intravenous), high oral bioavailability, low cost,

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129 lack of pharmacologically active metabolites, and perceived enhanced effectiveness in difficult

130 pain syndromes. Although methadone is considered a valuable analgesic, the safety of

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131 methadone has been called into question after reports of a disproportionate increase in the of
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132 opioid-related death rate in recent years.2

133 In 2014 the American Pain Society (APS), College on Problems of Drug Dependence, and
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134 the Heart Rhythm Society collaborated to issue guidelines on best practices to maximize
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135 methadone safety and efficacy.3 This guidance is valuable in many practice settings that focus
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136 on populations with anticipated long-term survival where safety is a significant concern. The

137 level of monitoring suggested by those authors may not fully reflect the risk versus benefit in an
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138 end-of-life scenario where goals of care have shifted, as 52with patients with anticipated

139 shorter survival who need rapid pain relief, in whom the utility of aggressive monitoring is
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140 questionable.
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141 In preparation for preparing this document, a systematic search of the methadone

142 literature was performed (Pubmed/Medline), and relevant articles were culled and forwarded

143 to a panel of 15 interprofessional hospice and palliative care (HPC) experts from Canada and the

144 US for review. Subsequently, an all-day consensus-building meeting was held with all 15
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145 panelists in February 2015 to consider the APS methadone recommendations and their

146 application to hospice and palliative care. The purpose was to develop guidance for hospice and

147 palliative care practitioners to help maximize benefit and minimize risks of methadone therapy

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148 in patients with serious illness. Hospice or palliative care for methadone maintenance

149 treatment program patients was considered beyond the scope of this article. The group

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150 consisted of eight physicians, six pharmacists, and one nurse. Consensus was achieved among

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151 the group after several draft iterations.

152

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153 Appropriate and Inappropriate Candidates for Methadone
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154 The HPC consensus group considered criteria for palliative patients who are appropriate

155 or inappropriate candidates for methadone therapy. As noted in the APS guidelines, clinicians
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156 should “perform an individualized medical and behavioral risk evaluation to assess risks and
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157 benefits of methadone” to determine the appropriateness of methadone for an individual

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158 patient.3 However, the risk-benefit consideration in patients with a serious illness is different

159 from a chronic pain or substance use disorder population. Patients with serious illnesses
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160 experience multiple transitions in care, potentially to a less experienced clinician. They may

161 experience rapid disease progression resulting in pain escalation and may not be in a highly
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162 monitored environment. Potentially appropriate and inappropriate candidates for opioid
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163 therapy, with special consideration for methadone are described in the HPC recommendations

164 (Table 1).

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166 Risk Assessment Before Starting Methadone Therapy

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167 A baseline risk assessment for therapy must be conducted after the patient is

168 determined to be an acceptable candidate for methadone. This assessment is individualized to

169 account for the patient's situation, prognosis, pain severity, previous use opioids, and other

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170 variables. Precautions and contraindications to opioid therapy in general, and methadone

171 specifically, are shown in Table 2.

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172 A targeted history and physical examination should include the patient’s age, diagnosis,

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173 pain assessment, average daily opioid use, past medical history, prognosis, medication history,

174 risk of drug diversion, and personal or family history of alcoholism or substance abuse disorder.

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175 The patient’s cognitive status, ability to adhere to the treatment plan, and ability to swallow
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176 dosage formulations should be assessed. Community dwelling patients who do not have a

177 competent caregiver and do not have sufficient mental acuity to take methadone as directed
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178 should not be started on methadone. Comprehensive medication reconciliation is essential

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179 because numerous pharmacokinetic and pharmacodynamic drug interactions are associated
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180 with methadone (see Interacting Medications section). .

181
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182 History of Liver Disease

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183 Methadone does not have a high hepatic extraction ratio because it has an oral
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184 bioavailability of 80% and therefore low first pass hepatic clearance. Liver disease reduces

185 hepatic extraction but does not influence methadone bioavailability to any appreciable degree.

186 Methadone is highly bound to alpha-1 acid glycoprotein, which is reduced in liver disease.4 This
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187 influences methadone distribution and unbound serum concentration, potentially contributing

188 to interpatient variability with methadone dosing.4-7

189 Methadone metabolism is highly dependent on multiple phase 1 enzymes (mixed

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190 function oxidases), which are impaired or diminished as the liver fails, as in cirrhosis.

191 Methadone clearance will not be further impaired with hepatorenal syndrome because

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192 methadone metabolites are pharmacologically inactive. Methadone should be used with

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193 caution in advanced liver disease (Child–Pugh class C) due to impaired metabolism and

194 increased free drug availability.8,9 Practitioners should consider lower doses and allow extra

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195 time between methadone dosage increases (for example, wait 10-14 days instead of 5-7 days)
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196 in patients with severe (Child-Pugh class C) liver disease because it will take longer to achieve a

197 steady-state serum concentration.

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198 In general, methadone should be avoided in the setting of severe, acute hepatic
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199 impairment, although there are no specific recommendations for methadone dosing in these
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200 patients. Decreased cytochrome enzyme activity should be expected, which prolongs the

201 metabolism of methadone.

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202

203 History of Substance Use Disorder

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204 Individuals in hospice and palliative care settings with a history of substance use
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205 disorder are likely at higher risk for overdose and other adverse events when prescribed

206 methadone (or any opioid).10 Risk mitigation strategies should be implemented. Ideally the

207 patient should be co-managed by an addiction specialist.Active use of an illicit substance is a

208 contraindication to methadone therapy. While controversial in advanced illness, most

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209 practitioners would agree the professional obligation to treat pain is contingent on the patient’s

210 adherence to the plan of care and abstinence from use of illicit substances that may increase

211 risk of methadone overdose or adverse event.

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212

213 History of Disordered Breathing

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214 Several studies have shown that methadone has been associated with central and

obstructive sleep apnea,11-17 which often goes undetected by practitioners. There is little

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215

216 correlation between the methadone dose and development of sleep apnea, but a study of

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217 individuals on chronic methadone reported a 30% rate of central sleep apnea by
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218 polysomnography.18 In that study, antidepressants played a role in potentiating methadone-

219 related sleep apnea and methadone was associated with reduced responsiveness to PCO2 and
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220 a wide awake alveolar-arterial oxygen gradient. A second study found sleep-disordered
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221 breathing in 75% of individuals who received stable doses of opioids for at least 6 months.16
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222 There was a direct relationship between methadone and the apnea-hypopnea index, which was

223 not found with other scheduled opioids. Benzodiazepines had an additive effect on the
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224 breathing disorders associated with methadone.

225 There are no guidelines for the management of sleep disorders associated with
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226 methadone. Traditional treatments with continuous positive airway pressure and bi-level
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227 positive airway pressure are often not effective.19 Avoidance of methadone is the safest option

228 for individuals with central or obstructive sleep apnea. Concurrent use of methadone and

229 benzodiazepines should be avoided unless the benefit clearly outweighs the risk.7,20-22

230
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231 History of Cardiovascular Disease

232 Risk of cardiac death on methadone is reversible by stopping the drug because

233 methadone does not have a direct adverse effect on the myocardium. .23 A history of heart

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234 failure has been associated with an increased risk of a prolonged QTc interval with methadone

235 use. Patients with heart failure in a palliative care program had an odds ratio of 11.9 (95% CI,

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236 3.7 to 38.2) of having a prolonged QTC interval on methadone.24 The authors of that

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237 retrospective study did not define congestive heart failure, and therefore it is not clear

238 whether this finding was based on echocardiographic criteria and reduction of ejection fraction

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239 or impaired diastolic dysfunction or on clinical presentation or history. However, congestive
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240 heart failure was an independent risk factor when correcting for methadone dose.

241 Congestive heart failure was one of the three independent risk factors for prolonged
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242 QTc interval in a separate study of patients on methadone maintenance,.25 A large

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243 epidemiological pharmacovigilance study conducted by addiction specialists found that

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244 individuals with cardiac disease were at significant risk for QTc prolongation on methadone.26

245 The percentage of patients with arrhythmia and coronary artery disease could not be
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246 determined. Similarly, a population base nested case-control study of persons receiving

247 methadone found that heart disease, defined as coronary artery disease or arrhythmia, was
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248 associated with 5.3-fold (95% CI 2.0-14.0) greater odds of opioid-related death. 10 In that
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249 study, individuals were relatively young (median age 42 years) and on methadone MAT.10

250 In patients with cancer pain the median age is likely to be higher, with a greater

251 prevalence of coronary artery disease and arrhythmia, potentially increasing the absolute risk

252 of opioid-related death due to methadone. The SAMSHA guidelines recommend ECG
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253 monitoring for patients with a history of heart disease, pre-existing arrhythmia, or unexplained

254 syncope.27 These recommendations for ECG interval monitoring are largely based on expert

255 opinion and need prospective validation. There are no randomized trials of ECG interval

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256 monitoring for cardiac risk in patients on methadone that validate its benefits in reducing

257 mortality.28

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258 Individuals with heart failure have a greater incidence of sleep disordered breathing.29.

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259 Methadone will worsen this and may cause nocturnal arrhythmias and hypoxia leading to

260 sudden deaths unrelated to the QTc interval. The use of adaptive servoventilation in this group

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261 of patients actually increases mortality.30
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262

263 Prolonged QTc Syndrome

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264 Pre-existing (prior to initiating methadone) QTc prolongation is relatively common and is

usually asymptomatic.27,31,32
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265
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266 Many QTc-prolonging drugs commonly used in palliative medicine (such as haloperidol,

267 olanzapine, ondansetron, tricyclic antidepressants, and citalopram) may potentiate the
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268 repolarization caused by methadone. . The APS guidelines3 recommend reconsideration of

269 methadone use with a QTc interval between 450 and 500 ms and avoidance of methadone with
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270 a QTc above 500 ms. There is no consensus about the safe or clinically important upper limit or
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271 amount of change of the QTC interval in response to drug exposure,particularly in patients with

272 serious illness. Considerations relevant to this population include the availability of ECG

273 monitoring, prognosis, type of pain, and anticipated methadone total daily dose. Guidance from
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274 the HPC consensus group on ECG monitoring and action steps is shown in Table 3. Individuals

275 who elect comfort measures may decline ECG monitoring.

276

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277 Interacting Medications

278 Drug interactions with methadone can manifest as opioid-receptor mediated adverse

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279 effects, such as sedation or respiratory failure, or non-opioid receptor mediated adverse

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280 effects, including QTc prolongation, TdP, and sudden cardiac death. Drug interactions can result

281 in an additive pharmacodynamic effects, such as increased risk of sedation and sleep-

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282 disordered breathing when using lorazepam (and other benzodiazepines) and methadone
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283 together 16 The Food and Drug Administration Adverse Event Reporting System (FAERS)

284 reported that 3.4% of methadone-induced harm was due to QTc prolongation and TdP
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285 combined, with a mean of 3.5 cases reported monthly.30 Adding methadone to regimens
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286 containing other QTc interval-prolonging drugs increases the risk of QTc prolongation and TdP,
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287 especially with patients with multiple risk factors. 33 The most commonly reported concomitant

288 medications were HIV antiretroviral medications, lorazepam, morphine, trimethoprim, and
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289 ceftriaxone accounting for ~42% of the drug-interactions.34 Most risk assessment has been

290 extrapolated using case studies and pharmacokinetic modeling, which is the best guidance
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291 currently available to determine risk.35 A complete list of medications that can prolong the QTc
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292 interval is available at https://crediblemeds.org/. Table 1 online highlights common

293 pharmacodynamic drug interactions with methadone.

294 Numerous cytochrome P450 enzymes are involved in methadone metabolism; major

295 enzymes include CYP2B6, CYP2C19, CYP3A4, and CYP2D6.36-38 Of these enzymes, CYP2B6 is
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296 primarily responsible for methadone levels and clearance.37-41 Methadone is also a weak

297 substrate for CYP2C8 and CYP2C9.37,38 Medications that inhibit CYP2C19 and CYP2C8 contribute

298 to an increased risk of respiratory depression and mu-opioid receptor mediated side effects,

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299 while medications that inhibit CYP3A4, CYP2B6 or CYP2D6 contribute to increased risk of TdP

300 and respiratory depression.37,38 An example of non medication interaction is cigarette smoking,

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301 which can induce CYP2B6.42 Smoking cessation returns CYP2B6 to normal levels, causing a

higher concentration of methadone.43 Pharmacogenetics complicate methadone

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302

303 pharmacokinetics because genetic polymorphisms result in a range of variable phenotypes

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304 from poor to ultra-rapid metabolizers. CYP2B6 has been associated with numerous allelic
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305 variants, including 16 variants that result in no or reduced CYP2B6 expression and/or activity,

306 higher methadone levels, and prolonged elimination.44 CYP2B6 polymorphisms occurs in a
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307 variable ethnic distribution.36,40,45,46

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308 The panel made these recommendations a comprehensive patient-specific risk

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309 evaluation and routine review of medication regimens to assess:

310 • Initiation or discontinuation of medications that may impact methadone levels (Table 4).
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311 • Initiation or discontinuation of medications that may have additive clinical effects to

312 methadone, such as sedation, disordered breathing, and QTc interval prolongation.
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313
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314 Methadone Dosing Considerations

315 Dosing in Opioid Naïve (Non-Opioid Tolerant) Patients

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316 Patients generally begin methadone therapy by converting from a different opioid,

317 however in the hands of experienced practitioners, it may be considered in opioid-naïve

318 patients with moderately severe pain. The European Association for Palliative Care (EAPC)

recommends that methadone may be used as a step III opioid under these circumstances.47

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319

320 According to the APS guideline, the initial dose of methadone in opioid-naïve patients should

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321 not exceed 7.5 mg oral methadone daily in the management of pain (e.g., 2.5 mg by mouth

three times daily).3 Those guidelines also include patients receiving up to 40-60 mg per day of

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323 oral morphine equivalents. Salpeter demonstrated that the use of low-dose methadone

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324 (median dose titrated to 5 mg per day) in both home-based hospice patients and hospitalized
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325 patients provided excellent pain control.48,49

326 The HPC consensus group largely agreed with the APS recommendation, explicitly
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327 recommending a dosage range of 2 to 7.5 mg oral methadone per day. This specifically allows
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328 for very low dose methadone such as 1 mg by mouth twice daily as a starting dose. The APS and
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329 HPC guidelines agree that the dose should not be increased before 5-7 days and should not be

330 increased by more than 5 mg/day. Methadone has a long and unpredictable half-life of
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331 elimination (ranges from 5-130 hours, with a mean of 20-35 hours50). Allowing 5-7 days before

332 adjusting the dose allows for most patients to achieve steady-state, but this may take longer in
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333 some patient populations.

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334

335 Dosing in Opioid-Tolerant Patients

336 When switching from other opioids to methadone, the HPC guidelines suggest the

337 following conversions, which take into account the potential for incomplete cross-tolerance and
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338 are based on expert consensus, given variability in published methadone dose conversion

339 ratios:

340 • < 60 mg oral morphine per day or equivalent (OME) – refer to opioid-naïve dosing

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341 • 60-199 mg OME and patient < 65 years of age – 10:1 conversion (10 mg OME:1 mg oral

342 methadone)

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343 • > 200 mg OME and/or patient > 65 years of age – 20:1 conversion (20 mg OME:1 mg oral

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344 methadone)

345 Additionally, the APS and HPC guidelines recommend converting to a methadone dose no

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346 greater than 30-40 mg per day regardless of the previous opioid dose.3 The dose should not be
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347 increased before 5-7 days and should not be increased by more than 5 mg/day up to 30-40

348 mg/day, then can be increased by 10 mg/day (after 5-7 days). For clinicians experienced in
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349 using methadone, a more aggressive titration method has been employed and may be feasible
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350 in a closely monitored environment.

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351

352 Switching from Opioid Addiction Methadone Maintenance Therapy to Methadone Analgesia
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353 Methadone is is dosed once daily when used as an opioid agonist therapy to treat those

354 recovering from SUDbecause it blocks opioid craving for 24-36 hours.51,52Methadone is
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355 generally dosed two or three times daily for pain because the duration of analgesia ranges from
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356 6 to 12 hours.53 Methadone maintenance patients require more frequent dosing to manage

357 pain and may need a higher dose because of a high level of opioid tolerance.54 If the patient is

358 unable to continue receiving care from the methadone maintenance clinic (e.g., a patient

359 admitted to hospice), a common clinical strategy is to administer the total daily dose in three
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360 divided doses and titrate the dose up as needed. It is important to advise the methadone clinic

361 that the patient is no longer able to return and to clearly document in the medical record that

362 the methadone is being used for pain management and to maintain abstinence.

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363

364 Methadone as an Adjuvant Analgesic

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365 Patients with a serious illness may experience opioid dosage escalation due to a variety

366 of potential reasons including disease progression, tolerance to the analgesic effects of opioid

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367 therapy, or development of opioid-induced hyperalgesia.55 In cases of poorly responsive

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368 neuropathic pain, or with the development of tolerance or opioid-induced hyperalgesia, use of
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369 an N-methyl-D-aspartate receptor antagonist such as methadone may be beneficial,56 although

370 evidence is sparse and not of high quality. This may be a particularly useful strategy in cases
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371 where the patient’s life expectancy is shorter than the time to steady-state. Courtemanche and
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372 colleagues57 evaluated the impact on pain control in 146 cancer pain patients receiving chronic
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373 opioid therapy. The median oral morphine dose was 120 mg per day, and a median dose of 3

374 mg oral methadone was added to the medication regimen. Results showed that 72 of the 146
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375 patients (49.3%) had at least a 30% reduction in pain intensity, with a median time of 7 days to

376 first significant response.

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377 Wallace and colleagues58 evaluated the addition of oral methadone to the opioid
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378 regimen of 20 cancer patients in an outpatient palliative care clinic. The mean daily routine oral

379 morphine equivalent was 338 ± 217.8 mg/day at initiation of the study, and 332 ± 191 mg/day

380 at evaluation (1-month evaluation or closest available Edmonton Symptom Assessment Scale).

381 The mean dose of methadone at initiation was 4.4 ± 1.4 mg/day, and 15.5 ± 5.9 mg/day at
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382 evaluation. Eight patients (40%) achieved a decrease in pain score of two or more points at 1

383 month, and an additional 7 (35%) had a decrease in pain score of two or more points at the

384 closest available point in time. Additional research is needed in this area to determine optimal

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385 strategies for using methadone as an adjuvant.

386

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387 Methadone and Alternate Routes of Administration

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388 Methadone is commonly administered orally, but palliative care patients often require

389 alternate routes of administration. Methadone can be administered through several different

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390 routes, allowing clinicians to conveniently maintain long acting analgesia for patients unable to
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391 swallow. Methadone is highly lipophilic and has an oral bioavailability of 80%, making

392 sublingual administration oral concentrated solution (10 mg/mL) is a common well tolerated
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393 first-line alternative with absorption rates of 35% to 75% depending on pH.59,60 61 Dosing may
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394 be modified to limit the volume of liquid administered. For example, volumes in excess of 1.5
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395 ml may be divided into both buccal cavities, or smaller doses may be administered more

396 frequently. The lipophilicity of methadone is also conducive to effective rectal administration,
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397 but this is not commonly done in practice.62 Intravenous methadone requires decreasing the

398 dose by 50% (oral: parenteral ratio, 2:1), which is conservative considering the 80%
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399 bioavailability. Conversion from parenteral to oral methadone should be 1:1.3 (parenteral:
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400 oral), based on clinical practice and oral bioavailability.63 The risk of QTc prolongation is greater

401 with parental methadone due to the inclusion of the solvent chlorobutanol. Therefore

402 additional electrocardiographic monitoring should be considered in this setting. Solvent-free

403 parenteral preparations are extremely expensive and are generally reserved for neuraxial use.64
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404 Subcutaneous administration of methadone has been reported in a few small studies.65-67

405 Although subcutaneous administration is generally well tolerated in volumes less than 3

406 ml/hour, there are risks of local toxicity (such as erythema and induration).65-67 The risks can be

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407 mitigated using concurrent infusions of dexamethasone or hyaluronidase, frequent injection

408 site changes, flushing the site with normal saline, and limiting dose.65-67. Spinal methadone

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409 rapidly distributes to systemic circulation and has little to offer in advantages over oral or

parenteral methadone.68,69

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410

411

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412 Patient Monitoring
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413 A systematic approach is necessary to monitor patients on methadone for adverse

414 effects and response to therapy. Patients on methadone should be monitored for therapeutic
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415 response, adverse reactions, home environment oversight accountability, and outcomes of risk
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416 mitigation strategies as appropriate.

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417 Recommendations exist to advise clinicians on ECG monitoring in chronic pain patients

418 and in managing opioid addiction. However, the risk-benefit profile differs in patients with
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419 serious illness. The HPC consensus group recommended additional considerations to account

420 for the proarrhythmic risks associated with monitoring methadone use in patients with serious
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421 illness (Table 3). Three categories of monitoring vigilance were identified based on the patient’s
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422 goals of care (curative versus comfort) and the role of methadone (first line or second line).

423 • High level of vigilance (patients using methadone as first-line therapy, with curative

424 goals of care): ECG monitoring per APS guidelines is indicated.3

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425 • Moderate level of vigilance (patients using methadone as first-line therapy with

426 comfort-based goals of care and patients using methadone as second-line therapy with

427 curative goals of care)

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428 Low level of vigilance (patients using methadone as second-line therapy with comfort-

429 based goals of care).

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430 Immediately after initiation or titration of methadone, intensive monitoring for opioid-

related side effects such as sedation should be carried out for a minimum of 5-7 days.70-73 This

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431

432 interval may need to be increased to 10-14 days in older adults or in patients where it will likely

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433 take longer to achieve steady-state (for example, in liver disease) due to the long and
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434 unpredictable elimination half-life of methadone. One commonly overlooked monitoring

435 indicatoris the initiation or cessation of medications that interact with methadone, such as
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436 antidepressants, anti-infective agents, or amiodarone. The entire caregiving team should be
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437 educated and involved in the monitoring process, supported by protocols and guidelines to
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438 facilitate comprehensive monitoring including standard assessment scales. A sample protocol is

439 shown in Table 2 Online. If the patient is in a home setting, the panel recommends daily in
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440 person assessments by the clinical team for toxicity and therapeutic response. If there is a

441 dependable caregiver in the home and in-person visits are not possible or practical, it can be
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442 acceptable to communicate daily during the intensive monitoring phase. With symptoms of
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443 overdose, methadone doses should be held until the patient is assessed by a clinician to ensure

444 that symptoms of overdose are not misinterpreted as signs that the patient is actively dying

445 (e.g., change in arousal, breathing pattern changes). Low-dose naloxone may be administered,

446 but care should be taken to avoid full opioid reversal and reoccurrence of pain.
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447 Employing risk mitigation strategies is an essential component of universal precautions

448 when opioids are prescribed for chronic pain. Patients with serious illness may also suffer from

449 concomitant substance use disorder or they may misuse or divert opioids. Treatment

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450 agreements and urine drug testing (UDT) are not always practical strategies for patients in the

451 terminal phase of serious illness. Useful strategies include using a locked medication storage

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452 box, designating one caregiver to administer medications, and using an alternate route of

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453 administration as well as those listed above. If UDT is warranted in a palliative care setting, one

454 that is able to detect synthetic opioids (enzyme-mediated immunoassay is not useful in

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455 detecting methadone for that reason) should be ordered, such as gas chromatography/mass
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456 spectrometry (GC/MS), liquid chromatography tandem mass spectrometry (LC/MS/MS), or

457 high-performance liquid chromatography (HPLC) UDT. 74-76 These tests can distinguish drugs
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458 from the same class (such as methadone versus oxycodone) as well as metabolites, including
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459 the primary metabolite of methadone 2-ethylidene-1,5-dimethyl1-3,3-diphenylpyrrolidine

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460 (EDDP).77,78 The provider should be aware of substances that can cause false positive results,

461 such as quetiapine and diphenhydramine.79-82 Although methadone is included in prescription

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462 drug monitoring programs (PDMPs) when prescribed for pain, PDMPs do not typically include

463 methadone when provided for an addiction treatment program. Federal facilities such as
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464 Veterans Affairs Administration) are not currently required to submit data, but many
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465 participate voluntarily..

466

467 Patient, Family and Caregiver Education

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468 The panel emphasized the importance of an informed patient and caregiver as the most
83
469 important factors for safe use of methadone. Written and oral education should be provided

470 including all key elements of methadone education can be found in Table 3, online:84

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471 Caregivers should have an action plan, which in some settings may include use of

472 naloxone, for findings of concern such as pinpoint pupils and sedation, confusion, or change in

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473 arousal. This plan typically includes calling the hospice or palliative providers immediately and

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474 holding doses of methadone until symptoms resolve. Patients should be advised not to abruptly

475 stop taking methadone because this may provoke withdrawal symptoms. Hospice and palliative

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476 providers should be engaged in closely monitoring patients for 3-5 days after methadone
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477 initiation or with dose increases because most methadone overdose deaths occur during this

478 period.70-73 As with all opioids, patients and families must be warned to avoid alcohol and
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479 sedatives, without talking to their health care provider. It is also important to provide
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480 information about safe storage and disposal.85 The patient and the caregivers must be
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481 instructed to store opioids out of plain sight and preferably in a lock box. Particularly in patients

482 with limited life expectancy or those with unused methadone, the HPC consensus group
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483 recommends addressing methods of safe disposal such as taking it to medication take-back

484 programs, flushing down the toilet, mixing with unpalatable substances (such as coffee
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485 grounds, cat litter) and disposing in the trash, or other recommended methods from the U. S.
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486 Food and Drug Administration.27 Counseling must be provided against sharing medication with

487 others because of risk of overdose.

488

489 Conclusion
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490 Methadone can be a valuable opioid in the hospice and palliative care provider’s

491 armamentarium to treat pain in serious illness. However, it is critically important that health

492 care providers be informed about the unique pharmacokinetic and pharmacodynamic

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493 properties of methadone. Careful consideration of appropriate candidates for methadone and

494 attention to detail in dosing and monitoring the patient’s response to therapy are essential

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495 components of care. The consensus group was able to develop guidance for hospice and

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496 palliative care practitioners that aim to maximize benefit and minimize risks of methadone

497 therapy in patients with serious illness, with an appropriate degree of patient monitoring.

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498
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499
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500

501 Acknowledgement: The authors gratefully acknowledge the contributions of Lyn Camire, MA,

502 ELS, of MedStar Union Memorial Hospital for editorial support.

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503

504

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505 REFERENCES
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684 hospices. J Palliat Med 2013;16:237-242.

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685 76. Tan PD, Barclay JS, Blackhall LJ. Do palliative care clinics screen for substance abuse and
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694 urine drug screen in a patient treated with quetiapine. Acta Clin Croat 2012;51:269-272.

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697 82. Rogers SC, Pruitt CW, Crouch DJ, Caravati EM. Rapid urine drug screens: diphenhydramine

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700 deviation from prescribed opioids and barriers to opioid pain management in patients

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702 84. Oosten AW, Oldenmenger WH, Mathijssen RH, van der Rijt CC. A systematic review of

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704 pain: a call for the use of standardized outcome measures. J Pain 2015;16:935-946.
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705 85. Reddy A, De la Cruz M, Rodriguez EM, et al. Patterns of storage, use, and disposal of
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706 opioids among cancer outpatients. Oncologist 2014;19:780-785.

707

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Table 1. Patient Selection for Methadone Therapy

Potentially Appropriate Candidates for Potentially Inappropriate Candidates for

Methadone in HPC Methadone in HPC

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• Moderate to severe pain (especially as • Patient lives alone, or poor cognitive

a second line opioid choice) functioning, without a responsible

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• Pain refractory to other opioids caregiver

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• True phenanthrene (e.g., morphine) • Lack of knowledgeable practitioner on

allergy transfer

• Significant renal impairment

U • History of opioid/medication
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• Need for a long-acting opioid nonadherence

•
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(particularly as an oral concentrate History of substance misuse or SUD

solution) (patient or family)

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• High opioid tolerance • Multiple risk factors for methadone

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• Poorly controlled opioid-induced toxicity (e.g., clinical instability,

adverse effects with other opioids multiple transitions in care, history of

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• History of dysphagia, inability to transplant)

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swallow, or feeding tube placement. • History of QTc prolongation or at high

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risk for such

• Prognosis less than projected time to

methadone steady state (i.e., 5-7 days)

• Obstructive or central sleep apnea

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• Determined to be medically

inappropriate after risk assessment

(see next section)

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Table 2. Precautions and Contraindications to Methadone Therapy

Risk Factor Precaution Contraindication Applies to all Applies

opioid including specifically to

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methadone methadone

Impaired liver function x x

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or liver failure

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Acute or unstable liver X X (precaution) X

injury/damage (avoid use) (contraindicated)

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Active illicit drug use or x X (overall risk) X (additional risk
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misuse (cocaine, of QTc

amphetamines, prolongation)
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ephedrine, heroin,
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opioids)
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Congenital QTc x (buprenorphine X

syndrome (patient or and methadone

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family) only)

Structural heart disease x X

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(congenital heart
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defects, history of

endocarditis or heart

failure)*
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Methadone in Hospice and Palliative Care

Electrolyte x X

abnormalities, or at risk

for same (e.g.,

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hypokalemia,

hypomagnesemia)

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Disordered breathing x x

SC
syndromes

Paralytic ileus x x

U
*See ECG monitoring section.
AN
M
D
TE
C EP
AC
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Methadone in Hospice and Palliative Care

Table 3. ECG Monitoring and Action Steps

Level of Goals of Care Methadone Baseline ECG Follow-Up ECG

PT
Vigilance Role

RI
High Curative, life- First Line Obtain baseline ECG: Obtain ECG within 2-4 weeks:

• •

SC
prolonging Positive risk factors* Positive risk factors

• Prior QTC > 450 ms • Prior ECG with QTc > 450

U
• ms

AN
History suggestive of prior

ventricular arrhythmia • History of syncope

M
Consider baseline ECG: Obtain additional ECG:

D
• No risk factors • TDD methadone reaches

•
TE
QTc < 450 ms in previous year 30-40 mg
EP
Recommendation: • TDD methadone reaches
C

• QTc > 500 ms – do not use 100 mg

AC

methadone • New risk factors or

• QTc 450-499 ms – consider signs/symptoms suggesting

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Methadone in Hospice and Palliative Care

alternate opioid (or correct arrhythmia

reversible causes of QTc Recommendation:

PT
prolongation and reassess) • QTc > 500 ms – switch to

RI
alternative opioid or reduce

SC
methadone dose

• QTc 450-499 ms – consider

U
switching to alternative

AN
opioid or reduce

M
methadone dose

D
Moderate Curative, life- Second Line • Discuss risks and benefit with • Re-initiate discussion of

prolonging
TE
patient/family in light of goals of risks/benefits if goals of
EP
Comfort First Line care care change
C

measures only • Routine baseline ECG monitoring • Routine follow-up ECG

AC

not recommended; may consider monitoring not

ECG depending on patient’s risk recommended; may

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Methadone in Hospice and Palliative Care

status, wishes and goals of care consider ECG depending on

(e.g., curative) patient’s risk status, wishes

PT
• Document informed consent if no and goals of care

RI
ECG Document informed

SC
If ECG obtained, follow consent if no ECG

recommendations above • If ECG obtained, follow

U
recommendations above

AN
Low Comfort Second line • No ECG unless compelling • No ECG unless compelling

M
measures only indication indication

D
• If ECG obtained, follow • If ECG obtained, follow

TE
recommendations above recommendations above
C EP

*Clinical risk assessment is always indicated and may alter recommendation for ECG monitoring. Risk factors include hypokalemia,
AC

hypomagnesemia, impaired liver function, structural heart disease (congenital heart defects, history of endocarditis or heart failure),

and genetic predisposition including patient or family history of congenital QTc syndrome, use of QTc-prolonging medications.3
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Methadone in Hospice and Palliative Care

PT
RI
U SC
AN
M
D
TE
C EP
AC
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Methadone in Hospice and Palliative Care

Table 4. Drug Therapy Modification for Patients on Stable Methadone Dose

Recommendation

Desired Modification

PT
Initiating an inducer Monitor carefully for increased pain or withdrawal symptoms.

RI
Provide breakthrough opioid for pain.

SC
Discontinuing an inducer Empirically reduce methadone dose by 25%-33%, monitor carefully

and use generous breakthrough. (consensus recommendation)

Initiating an inhibitor
U
Empirically reduce methadone dose by 25% and monitor carefully.
AN
Discontinuing an inhibitor Monitor carefully for increased pain or withdrawal symptoms.
M

Provide breakthrough opioid for pain.

D
TE
C EP
AC
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Methadone in Hospice and Palliative Care

Table 1 - Online. Medications with Potential to Impact Methadone Levelsa

Drug Net effect Effect on major metabolic enzymes Effect on minor metabolic enzymes Effect on

PT
on QTc

methadone intervalb/

RI
level TdPc

SC
reported

U
with

AN
concomitant

M
methadone

use

D
TE
CYP2B6 CYP2C19 CYP3A4 CYP2D6 CYP2C9 CYP2C8

Anti-Infectives
EP
Amprenavir ↑ ↓↓↓
C

Atazanavir --d ↓↓↓ Possiblec

AC

Azithromycin Riskc

Bocepravir ↑ ↓↓↓
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Methadone in Hospice and Palliative Care

Ciprofloxacin ↑ ↓ Riskc

Clarithromycin ↑ ↓↓↓ Riskc

PT
Cobicistat --e ↓↓↓ ↓

Delavirdine ↑ ↓ ↓↓↓

RI
Efavirenz ↓ ↑↑

SC
Erythromycin ↑ ↓↓ Riskc

U
Fluconazole ↑ ↓↓↓ ↓↓ ↓↓ Risk

AN
Nevirapine ↓ ↑↑↑

M
Efavirenz ↓ ↑ ↓↓ ↑↑ ↓↓ ↓↓

D
Isavuconazonium
↑ ↓ ↓↓ ↓

TE
sulfate

Isoniazid ↑ ↓↓ ↓ ↓↓ ↓
EP
Itraconazole ↑ ↓↓↓ Conditionalc
C

Ketoconazole ↑ ↓ ↓↓ ↓↓↓ ↓↓ ↓↓ ↓ Conditional

AC

Levofloxacin Riskc

Posaconazole ↑ ↓↓↓ Conditional

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Methadone in Hospice and Palliative Care

Ritonavir ↓ ↑↑↑ ↓↑ ↓↓↓ ↓↓ ↓↑ ↓↓ Conditionalc

Rifampin ↓ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑

PT
Saquinavir ↓e ↓ ↓↓↓ ↓ ↓ Possible

RI
Terbinafine ↑ ↓↓↓

SC
Tipranavir ↓e ↓↓↓

U
AN
Voriconazole ↑ ↓↓ ↓↓ ↓↓↓ ↓↓ Conditionalb

M
Central Nervous System

D
Alprazolam ↑ ↓

Amitriptyline
TE Conditional
EP
Aripipazole Possible
C
AC

Asenapine ↑ ↓ Possible

Buprenorphine ↑ ↓↓ ↓↓
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Methadone in Hospice and Palliative Care

Bupropion ↑ ↓↓↓

Carbamazepine ↓ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑

PT
Chlorpromazine ↑ ↓↓ Risk

RI
Citalopram ↑ ↓ ↓ ↓ Risk

SC
Clomipramine ↑ ↓↓ Possible

U
AN
Clozapine Possible

M
Cocaine ↑ ↓↓↓ Riskc

D
Desipramine ↑ ↓↓ ↓↓ Possible

Dexmedetomidine TE Possible
EP
Diazepam ↑ ↓
C
AC

Doxepin Possiblec

Droperidol Riskc
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Methadone in Hospice and Palliative Care

Duloxetine ↑ ↓↓

Escitalopram ↑ ↓ Risk

PT
Fluoxetine ↑ ↓ ↓↓ ↓↓↓ ↓ Conditionalc

RI
Fluvoxamine ↑ ↓ ↓↓↓ ↓ ↓ ↓ Conditionalc

SC
Haloperidol ↑ ↓↓ Risk

U
AN
Imipramine Possible

M
Midazolam ↑ ↓ ↓

D
Mirtazapine Possible

Modafinil ↓ ↑ TE↓↓ ↑↑ ↓
EP
Nefazodone ↑ ↓ ↓↓↓ ↓ ↓
C
AC

Nortriptyline Possible

Olanzapine Possible
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Paroxetine ↑ ↓↓ ↓ ↓↓↓ ↓ Conditionalc

Phenytoin ↓ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑

PT
Phenobarbital ↓ ↑↑↑ ↑↑↑ ↑↑↑ ↑↑↑

RI
Primidone ↓ ↑↑↑ ↑↑↑ ↑↑↑

SC
Quetiapine Conditionalc

U
AN
Risperidone Possible

M
Sertraline ↑ ↓↓ ↓↓ ↓ ↓↓ ↓ ↓ Conditionalc

D
Thioridazine Risk

Tizanidine TE Possible
EP
Trazodone Conditional
C
AC

Venlafaxine Possible

Ziprasidone Conditionalc
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Cardiovascular

Amiodarone ↑ ↓ ↓ ↓↓ ↓↓ Riskc

PT
Clopidogrel ↑ ↓↓ ↓ ↓↓↓

RI
Diltiazem ↑ ↓↓ ↓ ↓

SC
Furosemide Conditionalc

U
AN
Hydrochlorothiazide Conditional

M
Indapamide Conditional

D
Nicardipine ↑ ↓↓ ↓ ↓↓ ↓↓↓ Possible

Nifedipine ↑
TE ↓ ↓ ↓
EP
Ticlopidine ↑ ↓↓ ↓↓↓ ↓↓ ↓
C
AC

Torsemide Conditional

Verapamil ↑ ↓↓ ↓ ↓
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Methadone in Hospice and Palliative Care

Chemotherapeutics

Abiraterone ↑ ↓↓ ↓↓ ↓↓ ↓

PT
Anastrozole ↑ ↓ ↓

RI
Doxorubicin ↑ ↓↓ ↓

SC
Imatinib ↑ ↓↓ ↓ ↓

U
AN
Endocrine

Estradiol ↓ ↑ ↑

M
Gastrointestinal

D
TE
Cimetidine ↑ EP↓↓ ↓ ↓↓ ↓

Esomeprazole ↑ ↓↓
C

Lansoprazole ↑ ↓ ↓ ↓
AC

Omeprazole ↑ ↓↓ ↓ ↓↓

Pantoprazole ↑ ↓ Conditional
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Ranitidine ↑ ↓

Famotidine Conditional

PT
Anti-Emetics

RI
Aprepitant ↑ ↓ ↓↓ ↑↑↑

SC
Dolasetron Possible

U
AN
Granisetron Possible

M
Metoclopramide Conditional

D
Ondansetron Riskc

Other
TE
EP
Celecoxib ↑ ↓↓ ↓↓
C

Chlorpheniramine ↑ ↓
AC

Cinacalcet ↑ ↓↓↓
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Clemastine ↑ ↓

Cyclosporine ↑ ↓ ↓

PT
Darifenacin ↑ ↓↓

RI
Dexamethasone =/↓ ↑ ↑ ↑ ↑

SC
Diphenhydramine ↑ ↓↓ Conditional

U
AN
Grapefruit juice ↑ ↓↓↓

M
Hydroxyzine ↑ ↓ Conditional

D
St. John’s Wort

(hypericum ↓
TE ↑↑ ↑↑↑
EP
perforatum)
C
AC

a
The table describes the major CYP450 enzyme interactions and identifies those with QTc risk. ↑, inducer; relative strength weak, ↑,

moderate, ↑↑, or strong↑↑↑. ↓, inhibitor; relative strength weak, ↓, moderate, ↓↓, strong, ↓↓↓. A weak inhibitor causes a > 1.25-fold

but < 2-fold increase in the plasma AUC values or 20-50% decrease in clearance. A moderate inhibitor causes a > 2-fold increase in
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Methadone in Hospice and Palliative Care

plasma AUC values or 50% to 80% decrease in clearance. A strong inhibitor causes a > 5-fold increase in plasma AUC values or more

than 80% decrease in clearance. (FDA) Classification of inducers is not as clearly defined due to a history of methodological

PT
variability in the pharmaceutical industry.90-92 Therefore, literature was reviewed for each medication and the consensus qualifier

was used to define weak, moderate, or strong effect using relative induction score, if available.93 QTc risk definitions: Risk,

RI
substantial evidence supports the conclusion that these drugs prolong the QTc interval are clearly associated with a risk of TdP, even

SC
when taken as directed in official labeling; Possible, substantial evidence supports the conclusion that these drugs can cause QTc

U
interval prolongation but there is insufficient evidence that these drugs, when used as directed in official labeling, are associated

AN
with a risk of causing TdP; Conditional, substantial evidence supports the conclusion that these drugs are associated with a risk of

M
TdP but only under certain conditions (e.g,. excessive dose, hypokalemia, or congenital long QTc interval or by causing a drug-drug

D
interaction that results in excessive QTc interval prolongation).94

TE
b
Definitions from CredibleMeds.org.95
EP
c
Evidence reports TdP with concomitant methadone use.
d
No effect on methadone levels.96
C
AC

e
Boosted with ritonavir: net effect is lower levels.
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Methadone in Hospice and Palliative Care

Table 2 – Online - Suggested Methadone Monitoring Protocol

Monitoring Parameter Day 0a Day 1 Day 2 Day 3 Day 4 Day 5b

Therapeutic Effectiveness

PT
Pain rating (0-10) – Best in past 24 hours

RI
Pain rating (0-10) – Worst in past 24 hours

SC
Pain rating (0-10) – Average in past 24 hours

No. of doses of opioid for breakthrough pain

U
AN
Able to perform ADLs?

Potential Toxicity (New or Worsening): RAPS

M

R – RR; respirations slowed or

D

irregular/apnea, snoring (assess respirations

TE

for 60 seconds)
EP

A – altered mental status or vision (e.g.,

hallucinations or nightmares)
C

P – pupils, palpitations/lightheadedness
AC

S – sedation scale rating

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Methadone in Hospice and Palliative Care

General opioid adverse effects (constipation,

nausea, urinary retention, itching, dry mouth,

myoclonus (drug-induced movement

PT
disorder)

Additional monitoring (as appropriate):

RI
Changes in other prescription and

SC
nonprescription medications

U
Prescription drug monitoring program update
AN
Patient’s ability to swallow
M

Informal caregiver reliability / living situation

D

Substance misuse and chemical coping risk

(patient and family)

TE

Risk mitigation strategies as appropriate

EP

(urine drug screens, opioid agreement, pill

count, etc.)
C
AC

a
Day 0, patient status before first dose of methadone. Day 1, patient status 24 hours after

beginning methadone, and so on.

b
Continue as needed.
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Methadone in Hospice and Palliative Care

Table 3 – Online – Elements of Methadone Education

• The importance of taking methadone exactly as prescribed and reporting any changes in

other medications immediately

PT
The need for communication about changes in patient’s home and psychosocial

situation

RI
• Understanding of opioid-related side effects and risks, especially those that may be

SC
more specific to methadone (e.g., QTc prolongation)

o Allergic reaction to methadone may manifest as troubled breathing, itching, and

U
hives and requires immediate medical attention.
AN
o Constipation is a very common and easily preventable side effect. It is important

to use the prescribed prophylactic bowel regimen to prevent opioid-induced

M

constipation.
D

o Nausea and vomiting may accompany opioid use, especially in the first few days
TE

or weeks of initiation of methadone. An antiemetic may be prescribed for use in

case of nausea and vomiting.

EP

o Mild sedation may accompany initiation or up-titration of methadone. This effect

usually resolves within a few days.

C

o Symptoms suggestive of arrhythmia may include palpitations, lightheadedness,

AC

and syncope.

o Opioid-induced neurotoxicity (excessive sedation, confusion, myoclonus, and

hallucination), vivid dreams, and respiratory depression may occur. The patient
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Methadone in Hospice and Palliative Care

should be instructed to stop methadone dosing and seek medical help

immediately.

PT
RI
U SC
AN
M
D
TE
C EP
AC
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PT
RI
USC
AN
M
D
TE
C EP
AC