Methadone Pain Management: Physician's guidelines Ontario Canada

M E T H A D O N Efor pain

G U I D E L I N E S

Facilitated by the College of Physicians and Surgeons of OntarioNovember 2004

These guidelines are in effect as of November 2004.This document may be reprinted and distributed in its entirety for non-commercial purposes without permission,

but permission must be obtained to edit its content.

College of Physicians and Surgeons of Ontario80 College Street, Toronto, Ontario, Canada M5G 2E2

Telephone: (416) 967-2661

Table of Contents

Preface/Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Scope and Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

The Pharmacology of Methadone . . . . . . . . . . . . . . . . . . . . . . . . 5

Methadone Maintenance Treatment (MMT) for Opioid Addiction . . . 5

Methadone for Chronic Pain Management . . . . . . . . . . . . . . . . . . 7

Group I: Primary Pain patients . . . . . . . . . . . . . . . . . . . . . . . . 7

Group II: Pain patients with past or active substance dependence . . 7

Group III: Pain patients with concurrent opioid addiction . . . . 8

Using Methadone to Treat Pain . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Assessment Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Treatment Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Informed Consent/Treatment Agreements . . . . . . . . . . . . . . 11

Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Specific Cautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

The Role of Family and Supportive Others . . . . . . . . . . . . . . 12

Misuse/Diversion of Methadone . . . . . . . . . . . . . . . . . . . . . . 13

Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Methadone Dosing in the Management of Pain . . . . . . . . . . . . . 13

Prescribing and Dispensing . . . . . . . . . . . . . . . . . . . . . . . . . 14

General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Methadone Availability . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Opioid Naïve Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Changing to Methadone . . . . . . . . . . . . . . . . . . . . . . . . . 17

Withdrawal Mediated Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

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for painG U I D E L I N E S

Using Methadone to Assess Opioid Responsiveness . . . . . . . . . . 19

Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Optimal Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Vomited Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Missed Doses and Loss of Tolerance . . . . . . . . . . . . . . . . 22

Methadone Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Managing Acute Pain in Patients on Methadone . . . . . . . . . . . . 23

Obtaining a Methadone Exemption . . . . . . . . . . . . . . . . . . . . . . 24

The Pharmacist and Methadone Dispensing for Pain Management . 25

Urine Drug Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Methadone Withdrawal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Therapeutic Taper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Administrative Taper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Managing Patients with Pain and Addictive Disorders . . . . . . . . 33

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Suggested Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Appendix B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Appendix C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Appendix D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Appendix E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Appendix F . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Appendix G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Appendix H . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

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Preface/IntroductionIn the early 1960’s, Dr. Robert Halliday of British Columbia, and later Drs.Vincent Dole and Marie Nyswander of New York, began using methadone inthe treatment of opioid-addicted patients. Methadone, itself a potent opioid, isused to stabilize and maintain opioid-addicted patients due to its slowelimination half-life and less reinforcing character. More recently, methadonehas been ‘rediscovered’ as a potent and unique analgesic for use in themanagement of non-cancer pain.

Although methadone is a versatile drug, it has not been demonstrated to besuperior to morphine as a first-line opioid in the management of any type ofchronic pain, including pain of a neuropathic origin.

Under Canadian legislation, methadone is a prohibited substance that may beprescribed only by physicians who have an exemption permitting them to do so.The term ‘exemption’, as it applies in the context of the prescription ofmethadone, comes from the fact that practitioners who apply to use thisotherwise prohibited substance for the treatment of either pain or opioidaddiction must be exempted from this federal regulation. For practical purposes,the methadone exemption can be thought of as a license to prescribe methadonefor pain management, opioid maintenance, or both indications.

The federal Office of Controlled Substances grants all exemptions to prescribemethadone, under section 56 of the Controlled Drugs and Substances Act. Theprovincial medical authorities (the Colleges of Physicians and Surgeons of eachprovince) have the ability to recommend physicians for an exemption toprescribe methadone for the treatment of opioid dependence. Exemptions toprescribe methadone as an analgesic are granted by the federal authoritieswithout the participation of provincial medical authorities. As of September2004, a total of 182 Ontario physicians have been granted an exemption toprescribe methadone to treat pain and 266 physicians have been granted anexemption to treat opiate dependent individuals under the MethadoneMaintenance Treatment (MMT) Program. Twenty-four physicians have receivedexemptions to prescribe methadone for both indications.

Methadone was first synthesized as an analgesic in the 1940’s and during thenext four decades, it was used almost exclusively as a treatment for addiction. Its unique pharmacokinetics were quickly recognized when methadone wascompared to other opioids. It is effective in the treatment of addiction becauseit prevents withdrawal symptoms, diminishes cravings for opioids, and blocks

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the euphoria effect if other opioids are used concurrently. Methadone’s longhalf-life means that it need be taken only once a day to accomplish these goals.

In recent years, interest in using methadone to treat chronic pain has intensified,and there are a number of very good reasons for this. It has excellent analgesicproperties and its long elimination half-life makes it very useful in certain painmanagement situations. Unfortunately, because of the drug’s association withthe treatment of addiction, and the complex pharmacokinetic properties of thedrug, there has been some confusion about its role in managing pain anduncertainties in the practicalities of prescribing the drug for this purpose.

Scope and PurposeThese guidelines are intended to address these uncertainties and facilitate the useof methadone to treat non-cancer pain in a safe and effective manner. Theyreflect a general consensus of practice in Ontario for prescribing methadone inthe treatment of chronic pain. The target users of these guidelines include anyphysician with an exemption to prescribe methadone for pain. The guidelinesare not intended to substitute for sound clinical judgement. In a specificinstance where the individual circumstances of a patient provide clinicaljustification for deviation from these guidelines, a physician may do so.However, it is expected that the physician will balance the risks and benefits tothe patient and document any departure from the guidelines in the patient’smedical record with an indication of the clinical reason(s) for the deviation.Physicians should seek assistance, either formally or informally, in difficult orcomplex cases, from a pain management specialist who is knowledgeable in theuse of methadone. For a complete explanation of the guideline developmentprocess, please see Appendix A.

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The Pharmacology of MethadoneMethadone is a potent full mu and delta opioid agonist with good oralbioavailability, and has a long duration of action. The extended eliminationhalf-life (generally greater than 24 hours) is useful to prevent opioid withdrawalsymptoms in those who are physiologically dependent on opioids. The durationof action with respect to its pain relieving effect is more modest, however,typically six to eight hours, which often necessitates three or four times dailydosing to treat pain. This is in sharp contrast to the once daily dosing patternusually used in the treatment of opioid addiction.

As well, methadone is a non-competitive antagonist at the N-methyl-D-aspartate(NMDA) receptor. There is a great deal of interest in this receptor because it maybe linked to pain processing and spinal neural plasticity, although its exact roleand how it can be manipulated awaits further clarification. Still, it is felt bymany to have a significant effect in treating pain, especially neuropathic pain.

For various reasons, there is significant individual variability in patient responseto methadone, making initiation of therapy and rotation to methadone fromother opioids, at times unpredictable. As such, it does require some special careand knowledge in its use. The use of “equivalency tables” to calculate a dose ofmethadone is unreliable and to be avoided.

Methadone Maintenance Treatment(MMT) for Opioid Addiction In 1996, following program changes made by the Bureau of Drug Surveillance,Health Canada, responsibility for the administration of methadone in thetreatment of opioid dependance was transferred to the provinces. The Collegeentered into a formal partnership with the Ministry of Health and Long-TermCare to provide an office-based methadone maintenance treatment program forpatients with an opioid addiction.

The mandate of the College’s methadone program is to improve the quality andaccessibility of methadone maintenance treatment in Ontario. This isaccomplished in conjunction with the Centre for Addiction and Mental Health(CAMH) and the Ontario College of Pharmacists (OCP). The profile ofmethadone maintenance treatment in Ontario has been enhanced throughoutreach activities and through the recruitment of physicians across the provinceto prescribe methadone for opioid dependence to address excessively longtreatment waiting lists.

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Specific guidelines for MMT1 were revised in October 2001 by the CPSOMethadone Expert Advisory Committee and offer practical information tophysicians who prescribe methadone for the treatment of opioid addiction.

It is important to remember that the MMT program is well structured andregulated. Patients who meet the criteria for opioid addiction are eligible toobtain a prescription for methadone from a methadone-exempted medicalpractitioner who is in good standing with the College at the time of application;has completed a minimum of eight hours of approved training; and hasobserved, for two full days, a physician in an office-based setting with anexemption to prescribe methadone for the treatment of opioid addiction. Thesepatients are registered in a central database at the College as methadonemaintenance treatment patients. Initially, patients are monitored closely both forsigns of relapse and to encourage any behavioural changes made as a result oftreatment. Patient responsibility with the drug is extremely limited in the earlyphase of treatment. Patients are required to attend daily at a pharmacy wheretheir ingestion of this dose is witnessed. As patients become more stable, in partas evidenced by appropriate urine drug screen results, they are given moreresponsibility with daily doses of methadone. This graduated responsibility withthe drug is commonly referred to as a “carry” or “take-home” dose. Clearly, earlyin treatment, the ‘locus of control’ as defined by the degree of self controlexperienced by the patient (compared to that which the system applies to helpachieve stability) with respect to his or her responsibility to safely manage his orher use of methadone is largely external to the MMT patient. This graduallymoves towards a more shared responsibility as evidence of stability, throughongoing treatment, mounts. This helps to limit the potential for drug misuse,especially diversion.

‘Locus of control’2 is in fact a theoretical construct designed to assess a person’sperceived control over his or her behaviour3. For the purpose of theseguidelines, ‘locus of control’ refers to the degree to which patients are able tocontrol their use of medications, as compared to external controls placed onthem by the health care system.

The pharmacist also plays an integral part in the MMT program. The pharmacydispenses a once-daily unit dose of methadone, usually mixed into 100 ml of anorange flavoured drink. Two important points here are that methadone is notdispensed in a stock solution of fixed concentration and it is mixed with someform of flavouring to reduce the risk of parenteral administration. This is arequirement of the methadone guidelines for the treatment of opioid addiction.

In contrast, a formal program does not exist for the use of methadone in thetreatment of chronic pain at the physician and pharmacy levels, and methadone

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1. College of Physicians ofSurgeons of Ontario, Centrefor Addiction and MentalHealth, Ontario College ofPharmacists. MethadoneMaintenance Guidelines, 2nd ed 2001.

2. Rotter, J. 1996. Generalizedexpectancies for internal versusexternal control of reinforce-ment. Psychol Monograph80:1-28.

3. The American Heritage®

Stedman’s Medical Dictionary© 2002, 2001, 1995,Houghton Mifflin Company.

is regulated no differently at the patient level than any other opioid. As such,patients might attempt to access methadone for the treatment of addictionthrough the less structured pain management field. Fewer rules and regulations,and less apparent stigma may all contribute to a patient’s desire to accessmethadone outside the traditional methadone maintenance paradigm. Thismakes it all the more important for those contemplating prescribing methadonefor pain management to understand its use in the field of addiction medicine.

Increased availability of methadone through pain management channels mayserve to undermine the methadone maintenance program if physicians remainnaïve to the dual role of this drug.

Methadone for Chronic Pain ManagementMethadone may have a particularly unique role in pain management on thebasis of its activity at the NMDA receptor. As well, its long half-life may helpstabilize patients who experience fluctuations in their opioid drug levels and whoare developing withdrawal symptoms between doses (also referred to as“withdrawal mediated pain”). It may be particularly useful for the small butimportant subgroup of pain patients who suffer from addictive disorders, as wellas chronic pain.

It is, in fact, this effectiveness in both managing pain and opioid addictivedisorders which leads naturally to the division of patients into three broadgroups4:

Group I: Primary Pain patientsPain patients with no identified risk factors for addiction beyond the generalpopulation. In general, it should be remembered that addictive disorders arepresent in approximately 10% of the general population.5 Methadone would beused as any other opioid, with attention given to its unique pharmacokineticsand the need for careful titration of dose (see below).

Group II: Pain patients with past or active substance dependencePain patients who have either a past or active history of drug (a substance otherthan opioids) or alcohol dependence, including problematic use of prescriptiondrugs or abuse as diagnosed in the DSM-IV (see Appendix D). Other factors,such as a family history of drug or alcohol problems also increase risk.

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4. Gourlay, D., Heit, HA.,Almarhezi, A. (March 2005).Universal Precautions in PainManagement: A rationalapproach to management ofchronic pain. Pain Medicine(6):2.

5. Savage, SR. Long-term opioidtherapy: assessment of conse-quences and risks. J. PainSymptom Manage. 1996.11:275-286.

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Family history should go back a minimum of two generations to credibly assessrisk since alcohol and other drug problems often skip generations. Past drug usehistories other than opioids are also significant as risk factors.

Although nicotine dependency is acknowledged as a risk factor, its weight mustbe appropriately considered.

This population of patients is more complicated and needs clearer boundarysetting around prescribed medications. Most clinicians would endorse the use ofcarefully set boundaries for the use of opioids, beyond what might be normallyused with patients without identified risk (Group I). Although these patientswould not meet the criteria for methadone maintenance therapy, they often haverisk factors and/or behavioural issues that might move the clinician to includemuch of the structure developed within MMT programs in managing theirchronic pain. There must be a balance between safety and risk of drug misuse onthe one hand, and patient convenience and drug effectiveness on the otherhand. In most cases, unit dosing, the standard dispensing of each doseindividually, will not be suitable for the treatment of chronic pain.

Group III: Pain patients with concurrent opioidaddictionPatients with an opioid addiction who would otherwise qualify for methadonemaintenance under the CPSO Methadone Maintenance Treatment guidelinesand are suffering from concurrent pain problems. These patients can, andoften do, require pain management and some will benefit from the use ofchronic opioids. It is the expectation of the College that practitioners willfollow the MMT guidelines as much as possible, while managing the patient’spain.

It is important to appreciate that the use of methadone for the treatment ofopioid responsive pain will, by necessity, require increased responsibility for thisdrug by persons who might not be behaviourally stable. Although painmanagement often necessitates that subsequent doses of the drug be takenthroughout the day, it is still important early in therapy to dispense these dosesdaily, with the ingestion of the first dose of the day being witnessed by apharmacist or other responsible third party.

Applying the CPSO office-based MMT guidelines to the first witnessed dose ofeach day can still encourage graduated responsibility with this drug. After twomonths on the program, with evidence of increased stability with respect toillicit drug use, the patient can be given one full day’s methadone (normallythree unit doses) for each month of sustained abstinence from the misuse ofillicit or prescription medication.

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It is important to recognize the primary nature and severity of opioid addiction,when this is the case. Accordingly, where possible, this group of patients shouldbe registered with the CPSO in the methadone maintenance program. Patientsin this group are ideally managed by, or in consultation with, an addictionmedicine specialist knowledgeable in the use of methadone as maintenancetherapy for opioid addiction. Due to resource limitations, however, the idealmay not always be available.

Using Methadone to Treat PainIt should be noted that these guidelines are not designed to assess who should begiven a trial of methadone for pain management, but rather, once the decisionhas been made to use a trial of methadone for pain management, how to do itsafely. Nevertheless, the principles of sound practice in pain management shouldbe followed. The reader is referred to the Evidence-Based Recommendations forMedical Management of Chronic Non-Malignant Pain6 available from the Collegewebsite at www.cpso.on.ca. Some general principles to consider and documentin the management of chronic pain patients follow.

Assessment PhaseThe assessment of patients with chronic pain should follow the principles ofsound medical practice. The workup includes taking a history, conducting asystems review and a relevant physical examination, and ordering pertinentinvestigations. Special attention is usually expected in certain areas, such as thepatient’s previous therapies and concomitant illness, especially the presence ofpast or present substance dependence or abuse. Some helpful points to considerinclude the following:

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6. College of Physicians andSurgeons of Ontario. Evidence-BasedRecommendations for MedicalManagement of Chronic Non-Malignant Pain. November2000.

Table 1. Patient Categories for Methadone Management for Pain

Group I II IIIFeatures Pain patients with no identified

risk factors for addictionbeyond that expected in thegeneral population.

Pain patients who have either apast or active history of drug (to asubstance other than opioids) oralcohol dependence, includingproblematic use of prescriptiondrugs or abuse as diagnosed inthe DSM-IV.

Patients with an opioid addictionwho would otherwise qualify formethadone maintenance treat-ment under the CPSO MMTguidelines and are suffering fromconcurrent pain problems.

1. History of the pain problem;2. Previous therapies and outcomes;3. Psychosocial issues and their impact on the pain experience;4. Coexisting illnesses;5. Presence of addiction risks and/or problem medication use;6. Investigations (i.e., x-ray, CT, ultrasound);7. Previous consultations and referral to specialists.

In general, it should be remembered that addiction is present in approximately10% of the general population. The true prevalence of addiction within thechronic pain population is, at the present time unknown, but it is unlikely to beless than that observed in the general population. As such, the likelihood thatpain and addiction can coexist in the same patient is not insignificant. Thediagnosis of addiction is most commonly made prospectively, over time. Even aprevious problem with drug or alcohol use does not, in itself, preclude asuccessful trial of opioids. While a past history of substance abuse is important,and may increase risk for problematic use of prescription medications in thefuture, it does not absolutely contraindicate their use.

By setting reasonable boundaries for the patient to remain within, it is possibleto assess aberrant behaviour in the context of an emerging diagnosis of anaddictive disorder. In general, the diagnosis of an addictive disorder is madeprospectively, over time.

A specific diagnosis should be formulated, if possible; it may be possible only totreat the most likely mechanism of pain (i.e., nociceptive, neuropathic).

Some measurement tool to assess function and pain (such as a visual analog ornumerical scale) is often very helpful, and can be utilized over time to documentthe efficacy of treatments employed.

Treatment PhaseThis section deals with general considerations in the ongoing management of painwith methadone. Specific dosing issues are dealt with later in the guidelines. A treatment plan is always part of prudent medical practice and its development is particularly useful in the management of chronic pain.

Geographic considerations may have an impact on the practitioner’s ability tosafely treat a patient with methadone. Given the regulatory peculiarities of thisdrug, as well as unique safety concerns, prescriptions to patients who live outsideof a physician’s geographical catchment area may be problematic. Each casemust be considered carefully, and in light of both patient and prescriber safety.In general, prescriptions for infrequently seen patients are to be avoided.

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It is not recommended to initiate patients on methadone who are geographicallyremote unless adequate local medical support and supervision is available. Apreviously agreed upon plan for transfer of care back to the referring physiciancan be useful to prevent overloading the limited resources of secondary ortertiary consultative care.

Informed Consent/Treatment AgreementsInformed consent should include a discussion of tolerance and withdrawal, aswell as side effects and an outline of expectations. The likelihood of physicaldependence and the possibility of developing true addiction, no matter howsmall, should be discussed carefully.

Treatment agreements (sometimes unwisely referred to as treatment contracts)can be very helpful in documenting discussion of the above issues, and may beused to tighten boundaries for patients at risk for drug misuse. While it may notalways be necessary to have a signed, written agreement, this can be an effectivemeans of accurately documenting this important part of the medical record. Infact, it has been suggested that a “tripartite treatment agreement” can help tobring the pain specialist and primary care doctors together to improvecommunication, thus improving patient care7.

Treatment agreements should include consent for communicating with allindividuals involved in the patient’s care (refer to Appendix E for an example ofa treatment agreement).

MonitoringOpioid therapy in general, and methadone therapy in particular, requires carefuland ongoing assessment to reduce risk and improve outcomes. Practitionersshould follow up with patients frequently, documenting treatment outcomes,the effectiveness of opioid therapy, along with discussions of side effects. As well,ongoing monitoring for problem drug use should be part of each follow-upassessment. Interval dispensing and careful adherence to boundaries are essentialcomponents of a safe treatment program. Assessment of the “5-As” should beperformed and documented in the chart at frequent intervals.

The 5-As refers to the assessment of analgesia (effectiveness), adverse effects,aberrant behaviour, activity8, and affect. The 5-As should be assessed regularlyand recorded in the chart as evidence of a successful trial of therapy. (Affectadded by E. Covington9).

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7. Fishman, SM., Mahajan, G.,Jung, SW., et al. 2002. The trilateral opioid contract:Bridging the pain clinic andthe primary care physicianthrough the opioid contract. J. Pain Symptom Management24:335-344.

8. Passik, SD., Weinreb, HJ.,2000. Managing chronic non-malignant pain: Overcomingobstacles to the use of opioids.Advances in Therapy17(2):70-83.

9. Covington, E. Oct. 2001.Lawful Opioid Prescribing andPrevention of Diversion;Dannemiller EducationFoundation, CD ROM.

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Specific CautionsPatients should be cautioned about sedation/impairment of psychomotorfunction during the titration phase of methadone initiation. Methadone can belethal to someone naïve to opioid use — proper and secure storage must bediscussed. Specific advice regarding the safe storage and use of this drug isexpected as part of the treatment plan and should be revisited periodically, asappropriate, during the course of treatment. A locked box to securely store thedrug is strongly recommended to reduce the risk of accidental ingestion of apotentially fatal dose of medication by an opioid naïve or intolerant individual.

Sedatives, other non-prescribed opioids, and alcohol must be used with extremecaution, if at all.

In the absence of other sedating drugs, chronic, stable opioid use has not beenshown to adversely affect cognitive function or limit the performance ofcomplex motor tasks such as operating a motor vehicle10. The most commoncause of sedation in patients on stable doses of opioids is the effect of concurrentsedative use such as benzodiazepines and alcohol.

The Role of Family and Supportive OthersFamily members are always affected when their loved one is ill and they areoften involved in the long-term management of a family member with chronicpain. They may provide information on symptoms, response to treatment, andoverall patient status, which the patient may be unable or unwilling to give. Thisinformation may be extremely helpful when treating chronic pain or addiction,particularly in situations where elements of both conditions coexist.

Physicians should utilize all resources available, and when the patient has givenexplicit consent, family members can supply collateral information, which maybe crucial to treatment decisions. The family may also provide support andpractical advice in the long-term management of chronic pain disorders.

In some cases, family members and significant others may be unable to provide asafe and supportive environment to assist in the often complex pharmacotherapyseen in chronic pain management. Although tempting, it may be unwise to tryto enlist a significant other in the daily control of prescription medications.Where possible, objective support from knowledgeable professionals such asnurses/pharmacists should be employed.

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10. Zacny, J. A review of theeffects of opioids on psychomo-tor and cognitive functioning inhumans. Experimental andClinical Psychopharmacology.1995. 3(4):432-466.

Misuse/Diversion of MethadoneAny concerns about misuse or diversion of methadone should be followed upcarefully. Consultation, and at times joint management with other healthprofessionals knowledgeable in addiction treatment, can be very helpful,although not always readily available.

Urine drug screening is becoming a more widely accepted practice in themanagement of chronic pain with opioids. It should be presented to the patientas an adjunct to treatment rather than as a monitoring tool. Testing must bepatient-centred and not designed to “catch” patients who might have chronicpain, as well as an underlying substance use disorder. Having either conditiondoes not rule out the other. Refer to Appendix F and/or the Monograph UrineDrug Testing in Primary Care11, available at www.familydocs.org/UDT.pdf andthe reference guide www.familydocs.org/UDT_RefCard.pdf.

All laboratory results should be used to open a dialogue with the patient toassist, where necessary, in healthy change. It is important when using urine drugtesting to use the results carefully. An unexpected result should be checked withthe testing laboratory and with the patient before any decision is made tochange the patient’s care. In particular, the absence of a prescribed medicationshould not be seen as proof of drug diversion. Other reasons for a negative testfor a prescribed medication include laboratory error, limits of technology, or thepatient overusing the drug and running out in advance of the test.

DocumentationThe importance of accurate and complete documentation cannot be overemphasized. The medical record must clearly reflect the decision-making processthat resulted in any given medical outcome. Even if the result was less thanoptimum, thorough records will protect both the doctor’s and the patient’sinterests.

Remember, good records demonstrate that a service was provided to the patientand establish that the service provided was medically necessary.

Methadone Dosing in the Management of PainThe initial titration of methadone begins after the medical assessment has beencompleted and the decision for a trial of methadone as therapy for pain has beenmade.

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11. Heit, HA., Gourlay, D. March2004. Urine Drug Testing inPain Medicine. Journal of Painand Symptom Management,27(3)

Prescribing and Dispensing

General ConsiderationsAs mentioned earlier, under Canadian legislation, methadone is a prohibitedsubstance that may be prescribed only by physicians who have an exemptionpermitting them to do so. The term ‘exemption’, as it applies in the context ofthe prescription of methadone, comes from the fact that practitioners who applyto use this otherwise prohibited substance for the treatment of either pain oropioid addiction must be exempted from this federal regulation. For practicalpurposes, the methadone exemption can be thought of as a license to prescribemethadone for pain management, opioid maintenance, or both indications.

Methadone is available in tablets or as a powder, which is dissolved into asolution by the pharmacist prior to dispensing, or as a commercially preparedsolution. Methadone maintenance therapy patients are dispensed each dose ofmethadone individually, diluted in orange juice or another suitable vehicle, apractice sometimes called unit dosing. In contrast, patients being treated forpain with methadone usually have their drug dispensed as a concentratedsolution, which is then measured out by the patient for each dose prescribed. It is important to realize that the controlling factor in pain management is leftlargely to the patients themselves. The need for multiple daily dosing, andtitration-to-effect within any given day, necessitates the patient taking thedominant role in dosing. In the MMT population, the locus of control,especially early on in therapy, is largely external to the patient and the dominantrole in dosing stays with the prescribing physician.

Unlike MMT, there are no specific rules governing the use of methadone in thetreatment of pain. The notion of carry medication or take-home medication isan artificial construct that has been found to be useful in the safe and effectivetreatment of persons suffering from opioid addiction.

The controlling factor in pain management, unlike in MMT, must reside largelywith the patient.

Methadone AvailabilityAs of the writing of this document, a tablet form of methadone has recentlybeen approved for use in Canada; because of the increased risk of diversion,patient selection will be crucial to the safe use of this form of the drug. At thepresent time, due to peculiarities in the approved product monograph for thecommercially available forms of methadone (Metadol® liquid/methadonetablets), prescribers are advised to carefully read Health Canada’s approvedproduct inserts.

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In the management of pain, oral methadone is generally used in a multiple dailydosing fashion, usually three-times-daily. Although methadone has recently beenmade available in a tablet form, a uniform concentration of 5 or 10 mg/ml as asolution is currently the preferred form.

Common concentrations for methadone solution are 5 mg/ml (compounded bythe pharmacist) or more recently, as a commercially prepared 1mg/ml or 10mg/ml stock solution. For patient safety, a graduated oral syringe must be used tomeasure out individual doses, which should be specified on the prescription. “Useas directed” is strongly discouraged without some limits being stated on the order.

Once daily dosing of methadone is not normally adequate for the treatment ofpain. The duration of action of methadone when prescribed as an analgesic isshorter than the duration of action when prescribed as maintenance therapy ofopioid addiction.

When prescribing methadone in tablet/capsule form, care should be exercised toselect patients with low risk of drug diversion/misuse.

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Table 2. Methadone Dosing Options Available

Form ClinicalIndication

AvailableDoses Pro Con

Unit DoseLiquid

Group III,

Unstable GroupII

Variable concentra-tion in 100 ml vol-ume

Safest for physician to titrate.

Large volume has reducedabuse liability.

Easiest to control in unstablepatient.

Difficult to give 3 doses perday beyond 1 week at a time.

Difficult for patient to titratedose.

Bitter taste, and limited shelf-life due to flavoured additive.

LiquidConcentrate

(*1mg/ml,5mg/ml,*10mg/ml inaqueous)

Group I, HighlyStable Group II

Specific stock con-centration

Easiest form for patient totitrate up and down, easilystored, a familiar form to bothpatients and pharmacists.

If compounded with flavouredcrystals, may reduce parenter-al abuse liability.

Storage/handling of drug canbe difficult.

Pure aqueous form easiest toabuse via injection.

Tablets Group I 1, 5, 10, 25 mg Easy form for patient to use.

Easily stored and transported.

A familiar form for patients.

Can be easily abused, divert-ed/trafficked.

Easily converted to parenteralroute for abuse.

Higher cost.

*commercially available

Unfortunately, not all pharmacists choose to dispense methadone, even thoughat the present time, there are no specific regulations that limit their ability tostock and dispense this drug. In some locations, pharmacy staff may only befamiliar with the use of methadone in the treatment of opioid addiction. It isimportant to clarify treatment goals with the pharmacist and to discuss anyconcerns they may have related to dispensing methadone for the treatment ofchronic pain.

Opioid Naïve Patients(May also apply to patients on relatively small doses of opioids or who have beenusing opioids erratically for whatever reason)

The initial prescription generally does not exceed 15-30 mg/day for the first threedays, but may be as low as 1-2 mg every 12 hours in older or debilitated patients.

Prescription Example:Methadone solution X mg/mlTake X mg (Y ml) PO every 4 hours, to a maximum of 30 mg daily (6 ml) forthree days, then as directed to a maximum of 45 mg/day divided in three timesdaily doses. M: yyy ml

It is important that the quantity of drug to be dispensed is unambiguously statedin the order. Since the concentration of stock solution has been specified, it issufficient to state the volume of stock solution alone to be dispensed. For addedsecurity, it may be useful to also specify the volume to be dispensed written inwords. On the directions to the patient, the dose or range of dose should bespecified as both a volume and weight. (Refer to Appendix G for an example of aprescription.) It is important to prescribe sufficient medication to allow thepatient to titrate the dose upward, according to a previously agreed upon schedule.In some patients, particularly the elderly or infirm, very small doses of methadonemay be quite effective and generally better tolerated. It is important to rememberthat the dose can always be increased. ‘Start low, go slow’ is wise advice. Due togradual accumulation to a steady state, methadone’s effectiveness as an analgesicmay improve gradually after a dose increase, for up to four or five days.Experience gained through methadone maintenance programs has shown thatmost deaths occur during the first week of therapy as a result of accumulation,emphasizing the importance of careful monitoring during the initiation of therapy.

Methadone blood levels continue to rise for approximately five days afterstarting treatment or raising a previously stable dose. Death by accumulatedtoxicity may result from increasing a dose before the full effect of the currentdose is known.

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Practitioners must be careful when prescribing methadone solutions. It isrecommended that to avoid any confusion, a physician specify both the milligramdose along with the volume of solution to be taken at any given time. Confusionrelated to ambiguous orders can lead to tragic outcomes, especially early on intreatment. The physician should clearly specify the concentration to be used.

In general, there are three ways that methadone kills12:

1. Single Overdose: In this case, the first dose is a fatal overdose. This most oftenis seen in accidental ingestion in an intolerant individual, or in previouslytolerant users who have had interruptions in their use of methadone.

2. Accumulated Toxicity: Doses accumulate over several days and toxicitydevelops. Today’s dose isn’t lethal, tomorrow’s dose isn’t lethal, but the entirethird days dose plus half of the second and one quarter of the first doseaccumulate to a lethal level. This is most commonly seen in overly aggressiveinitiation protocols.

3. Drug-Drug Interactions: Methadone can be lethal when used with sedatives,other opioids or alcohol. In these cases, neither methadone nor the sedativedrug alone is lethal, but in combination, death results. This is mostcommonly seen in the ‘stable’ methadone patient who periodically abusessedative drugs such as benzodiazepines and/or alcohol. Drugs, which inhibitcertain enzymes within the cytochrome system, can also result in methadoneaccumulation and toxicity.

Changing to Methadone(Switching from another opioid to methadone)

For most patients, methadone is not the first choice of opioid or the first opioidused to manage pain. Frequently, a practitioner may want to rotate a patientfrom another opioid onto methadone. Although there are several publishedtables of opioid equivalency, it is important to realize that these tables refer tosingle-dose situations. There is no reliable conversion factor that can be appliedwhen converting from any other opioid onto methadone.

Once again, “start low, go slow” is the safest course to follow, especially in thecontext of the outpatient setting. More aggressive titration can be safelyconducted in the inpatient setting where peak dose effects can be monitored anddoses adjusted accordingly.

When switching to methadone, it is important to assume that any new sideeffect related to sedation or respiratory depression is due to methadone and notto the opioid that the patient was previously taking. When there are signs of

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12. Gourlay, D., Heit, HA., Letterto the Editor, March 2004.Vol. 5 Iss.1, Pain Medicine,109-110.

sedation, hold the next dose of methadone and consider reducing subsequentdoses. To overestimate tolerance exposes the patient to the risks of inadvertenttoxicity, and certainly increases the risk of the more common problem ofassociated accumulated toxicity because of the relatively long elimination half-life of methadone. Similarly, to underestimate tolerance puts the patient atincreased risk for experiencing continued and possibly worsening pain.

There are various methods to transition from one opioid to another, includingmethadone. One common method is to reduce the first opioid by one-thirdevery day, while titrating upward the second opioid. In those cases where thepractitioner believes the pain is likely to be opioid responsive and wheresignificant tolerance to other full mu agonists such as morphine orhydromorphone has developed, it may be reasonable to discontinue the firstagent and institute methadone in three-times-per-day dosing, titrating upwardswith caution. After an initial trial period, the patient normally increases thedose, on their own initiative, with guidance by the prescriber who is followingapproved medication standards and is accurately documenting this in the record.During this transitional period, practitioners are reminded of the importance offrequent assessments of patients.

In any opioid rotation, sedation should always be assumed to be due to theeffects of the new opioid NOT the additive effects of the drug being tapered. If sedation occurs during the switchover, slow down or stop the methadonetitration until the drowsiness clears. Unlike truly slowly eliminated agents likemethadone, controlled release drug delivery systems do not alter the rate of drugaccumulation.

Withdrawal Mediated PainIn those patients who are managed for prolonged periods with short-acting,immediate release agents, pain may actually cycle in response to fluctuating andinadequate opioid levels. Many patients suffer from problems related to thechronic use of immediate release short-acting opioids. This is particularly wellseen in the case of worsening morning pain, with the chronic use ofacetaminophen with codeine or oxycodone. Due in part to the development oftolerance or accelerated drug metabolism, these drugs may only be active for twoto three hours after ingestion and during periods where they are not taken withthis frequency, such as overnight, symptoms of early withdrawal may develop.By the next morning, the patient’s pain is often more generalized; sometimesdescribed as ‘feeling like a truck has hit them’. This can sometimes be relievedwith the use of a controlled-release version of the same drug or by changing to

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an agent such as methadone. In this group of patients, single or twice dailydosing of a truly long-acting opioid like methadone, until there is no evidence ofopioid withdrawal over the 24 hour period, may be helpful to determine whatcomponent of the pain is in fact withdrawal mediated.

Immediate release agents tend to be highly reinforcing due in part to the rapidonset to peak effects and the precipitous offset seen at the end of the effectiveduration of action. Even in the absence of a coexisting addictive disorder,aberrant dosing frequency (>6 times per day) may be seen, due to the diminishedeffective duration of action seen over time with the short-acting drug.

When managing withdrawal mediated pain, one approach is to discontinue theshort-acting opioid while methadone is added, in a once daily morning dosingregimen as is routine in methadone maintenance therapy. The methadone dose isincreased until there is no evidence of withdrawal in the period prior to the firstdose of the morning. After this “opioid debt” is corrected and any withdrawalcomponent of the pain is removed, in patients with opioid responsive pain, theremay be a step-wise relief of pain lasting 6-8 hours after each dose. At this point, thedose could be divided into three and increased no more than 10 – 20 mg everythree days during the initiation phase (first 1-2 weeks). After this, dose increases canbe made more quickly, limited only by side-effects or acceptable relief of pain. Afterthe patient is stabilized, in terms of opioid medication, it may be useful to trypreviously ineffective agents such as NSAIDs (in patients without contraindications)or other adjuvant medications, such as tricyclic antidepressants or anticonvulsants.

Using Methadone to Assess Opioid ResponsivenessMethadone is a compound that is unique, in that its elimination half-life ofapproximately 24 hours (which governs its use in MMT) and its duration ofaction as an analgesic (approximately 6-8 hours) are markedly different. Thisproperty can be used to assist in assessing opioid responsiveness.

In some situations, where the practitioner is concerned about the value of furtherincreases in a three-times-daily dosing regimen with methadone, the mid-day-dosecan be split temporarily between the morning and evening doses. This representsa 50% increase in the unit dose of drug in a twice-daily dosing schedule. Giventhe differences between the duration of action of methadone as an analgesic andwhen used in MMT, this unit dose increase may be expected to result in animprovement in opioid responsive pain, but only for a duration of 6-8 hours. Ifthere is endorsement of improvement, resumption of a three or four times dailydosing interval with titration upward to effect is recommended.

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Failure to see improvement around this unit dose increase, especially in the contextof the patient’s persistent concern that they “no longer feel the drug working”should lead to a reevaluation of the current treatment strategy and theappropriateness of continuing with methadone.

Assessing Opioid Responsiveness: A patient on 50 mg methadone, three timesdaily for pain complains of “no longer feeling the drug working”. Redistributingthe total 24-hour dose of 150 mg into a 75 mg twice-daily dosing scheduleyields a reduction of pain scores by 50%, but only for 6-8 hours around eachdose. This represents a unit dose related increase in analgesia of appropriateduration for methadone. In this case, returning to a three or even four-timesdaily dose with careful titration upward is recommended. Persistent claims of“not feeling the effect” despite the 50% increase in the unit doses of methadoneargue against the continued use of this drug, and points to the need forreevaluation of the need for methadone in particular and of opioids in general.

It is always important to regularly assess opioid responsiveness. In those patientswhose ongoing opioid use serves largely to maintain adequate basal opioid levelsrather than to effect analgesia, careful discontinuation of opioid therapy mayactually lead to improvement of previously unresponsive pain conditions ratherthan a worsening of the pain. Inappropriate rapid tapering of opioids may resultin a worsening of any pain condition, even those conditions that are notbenefiting from ongoing opioid therapy.

Special ConsiderationsOptimal DoseDespite years of experience with methadone, there is tremendous variability inthe initiation and stabilization dose as evidenced by a careful review of the use ofmethadone in chronic non-cancer pain. Given the kinetic peculiarities of thisdrug, careful titration to effect is recommended.

In fact, the optimal methadone dose is that dose which relieves painsymptoms, without sedation or other significant side effects. As with allopioids there is a wide variability in individual response to methadone, anotherreason to consider initiating therapy with small doses. With experience, theoptimal dose for the majority of patients can be established within two to sixweeks of methadone initiation. Doses above 200 mg per day13 are considered tobe in the “high range”. Although in some situations doses above this level maybe necessary, the physician should reassess the patient. If the physician hasdifficulty in stabilizing the patient’s dose above this level, it is recommended thata second opinion or consultation be sought.

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13.Gil, M., Sala, M., Auguera, I.,Chapinal, O., Cervantes, M.,Guma, JR., Segura, F. QTProlongation and Torsades dePointes in patients infected withhuman immunodeficiency virusand treated with methadone. J. Cardiol. 15-Oct-2003;92(8): 995-997.

Doses above 200 mg per day are termed in the “high range” and have beenreported to be associated with increased risk of malignant dysrhythmias such asTorsades de Pointes. In methadone maintenance treatment literature, 120 mg isconsidered in the “high range.”

For higher doses of methadone, there is some evidence that there may be a dose-related prolongation of the corrected QT interval, which has been reported asleading to potentially fatal cardiac rhythm disturbances (i.e., Torsades dePointes)14. This is especially true for those patients with other factors known toincrease QTc intervals.

What actually constitutes a “high dose” of a drug is open to much interpretationand debate. While the number cited in this document is 200 mg per day, someliterature refers to a high dose in the order of 300 mg per day. Practitioners areadvised to be cautious with doses in excess of 200 mg per day. A baseline ECGmay be useful in those patients who have reached daily doses in excess of 200mg per day. Those patients found to have prolonged corrected QT intervalsshould be referred for cardiology consultation. In some cases, the dose ofmethadone may need to be reduced or discontinued altogether.

Vomited DosesMethadone is rapidly absorbed from the upper GI tract. Given the inability tocompletely empty the stomach even with forceful emesis, the risk of replacingvomited doses of methadone is that of accumulated toxicity. Since no morethan 60% of stomach contents can be cleared through even vigorous vomiting,repeated replacement of lost doses can result in significant accumulation. Theunderlying cause of the vomiting should always be sought. Risk of emesis can bereduced by encouraging the patient to drink smaller quantities over time therebyreducing the risk of complete dose replacement.

Whenever emesis persists, an underlying cause should be sought. In women ofreproductive age, pregnancy must be ruled out. Persistent use of antiemeticagents such as diphenhydramine or prochlorperazine is not recommended dueto the sedative effects of these drugs.

A common replacement strategy borrowed from the MMT literature is toreplace as follows: emesis within 15 minutes of ingestion should be replacedcompletely, between 15 and 30 minutes, 50% replacement is recommended,after 30 minutes, absorption is essentially complete and the patient can bereassured that the dose need not be replaced.

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14.Krantz, MJ., Lewkowiez, L.,Hays, H., Woodroffe, MA.,Robertson, AD., Mehler, PS.Torsades de pointes associatedwith very-high-dosemethadone. Ann. Intern Med.2002. Sep 17; 137(6):501-504.

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Missed Doses and Loss of ToleranceA clinically significant loss of tolerance to opioids may occur as quickly as threedays without methadone. For this reason, after a period of three daysabstinence, it is recommended that the physician advise the patient to reduce thetotal daily methadone dose by 50% to ensure any loss of tolerance does notresult in a “single-dose” overdose of methadone. After tolerance to that firstdose of methadone is demonstrated, the dose can be rapidly increased over aperiod of days to the previous dose for that person. After missing five or moredays of methadone, the body has essentially eliminated the drug, and so themost prudent course is to restart methadone at 30 mg or less as a total dailydose. After assessing the response to that initial dose, and continuing tomonitor over a minimum of three days to establish the accumulated response,the dose may be safely increased relatively quickly toward the previous stabledose of methadone. From a safety point of view, missing one or two doses ofmethadone is unlikely to lead to diminished opioid tolerance. It is important toremember that even relatively large doses of an opioid other than methadonemay not equate to a large dose of methadone due to incomplete cross-tolerancebetween drugs. It can be helpful to examine the reasons for irregular use ofmethadone since this may yield valuable information about the patient’s lack ofresponse to treatment.

Cross-tolerance to other opioids is often incomplete and unpredictable. The useof equivalency tables, especially with respect to methadone, can be misleadingand lead to significant morbidity and mortality, even in the apparently highlytolerant opioid user.

Methadone Drug Interactions Methadone is metabolized principally through the CYP 450 iso enzyme system. Inparticular, 3A and 2D pathways are implicated. Thus, agents that either inducethese enzymes or inhibit their activity can adversely affect the half-life of methadoneand influence the stability of a patient on methadone. As an example, consider theimplications of managing the methadone dose of a patient who is being treatedwith the potent 3A4 inducer, carbamazepine (Tegretol®). Because enzyme activityis increased due to the presence of carbamazepine, the effective half-life ofmethadone may be reduced to a few hours and frequent multiple daily dosing maybe needed to achieve stable methadone levels. If the carbamazepine is stopped, themetabolism of methadone will be reduced and the blood levels of methadone willrise, risking toxicity. Likewise, the discontinuation of a potent 3A4 inhibitor, suchas fluvoxamine (Luvox®), can lead to unexpected opioid withdrawal or loss of paincontrol, as 3A4 metabolism increases back to pre-fluvoxamine baseline, and

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methadone levels fall as it is now more rapidly eliminated. Although druginteractions are theoretically possible, they may not always be clinically relevant inany individual patient.

Due to CYP 450 3A4 enzyme inhibition, patients must be cautioned againstmixing methadone in grapefruit juice.

One particularly useful Internet resource is www.drug-interactions.com that providesboth a clinical and research-oriented table of substrates, inducers and inhibitors forcommonly prescribed drugs, including methadone. Another useful resource formethadone drug interactions is www.atforum.com.

In some cases, it is not the addition of a drug that leads to a change in clinicalstatus due to drug interactions, but rather, the discontinuation of a potentenzyme inducer or inhibitor that can result in clinically significant overdose orwithdrawal, respectively due to changes in serum drug levels.

Recently, some practitioners are trying to combine two or more different opioidsto improve side-effect profile or to augment analgesic effect. At the presenttime, this practice may be complicated, controversial and not clearly supportedin the pain literature. Small doses of methadone have been reported, anecdotally,to reduce morphine tolerance. Consultation with a practitioner knowledgeablein this practice is strongly recommended before proceeding along this course.

Managing Acute Pain in Patients on Methadone The management of acute pain poses many challenges for both the treatment team,as well as the patient. This is especially true when the acute pain occurs in thecontext of chronic pain management with opioids. A detailed examination of thistopic is beyond the scope of these guidelines but several key points will be exploredin the following section.

In general, one of the undesirable effects of chronic opioid therapy is a lowering ofpain threshold15. One proposed mechanism is down regulation of opioid receptorsdue to chronic agonist exposure. Another mechanism may be the secretion ofcertain “anti-opioid” neurotransmitters in the central nervous system pain pathways.The diminished receptor activity, coupled with suppression of endogenous opioidlevels can lead, in some patients, to an increase in the perception of pain.

In the context of pain management that is largely “opioid responsive”, this decreasein pain tolerance is accepted as a reasonable trade in the cost-benefit assessment,

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15.Doverty, M., White, JM.,Somogyi, AA., Bochner, F.,Ali, R. and Ling, W.Hyperalgesic responses inmethadone maintenancepatients. Pain 2001 Feb 1;90(1-2):91-96.

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when the overall complaint of chronic pain is improved. It does, however, makeacute pain management more challenging. When managing acute pain, chronicopioid users will generally need opioids in higher doses and will need them dosedmore frequently when compared to their opioid naïve counterparts. It should also beassumed that their previous daily opioid dose will offer no analgesic effect in themanagement of acute pain. Inadequate maintenance of previous opioid levels in anopioid dependent pain patient can lead to exacerbations, in both their acute andchronic pain.

The role of short-acting, immediate release opioids in the management of chronicpain is controversial. While immediate-release/short-acting agents are necessary formanagement of acute pain, the mainstay of chronic therapy should be eithercontrolled-release preparations of short-acting agents or truly long-acting opioids,such as methadone. While the short-term use of immediate release agents, such asoxycodone, either for breakthrough pain management or for an acute situation isacceptable, there should not be an over reliance upon these agents in managingchronic pain over the longer term.

It is important in the context of acute pain management in the opioid dependentpatient to maintain the previous daily opioid levels. Inadequate replacement of thepatient’s previous daily opioid requirements may result in an “opioid debt” whichcould frustrate any attempts at management of acute pain. Chronic opioid usersusually require increasingly more frequent dosing with short-acting opioids tomanage acute pain. Again, the use of equivalency tables can be very misleading.Dosing is to effect.

Obtaining a Methadone ExemptionIn Ontario, physicians who wish to use methadone for the treatment of chronicpain must apply for an exemption from the Office of Controlled Substances,Health Canada under section 56 of the Controlled Drugs and Substances Act. Awritten application is required, which indicates the practitioner’s desire to usemethadone in the treatment of pain. In the absence of any restrictions imposedby the College, this authorization will be granted. At the present time, noadditional training is required by Health Canada or the CPSO to obtain thisexemption. The exemption to prescribe methadone for the treatment of chronicpain must be obtained separate from any other exemption, including theexemption to prescribe methadone for the treatment of opioid addiction. Toobtain an exemption for the use of methadone in the treatment of opioidaddiction, details are available from the College of Physicians and Surgeons ineach province.

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Contact Health Canadafor more informationon obtaining amethadone exemptionby calling the Office ofControlled Substances,Methadone Program at(613) 946-5139, or byfax at (613) 952-2196.

The Pharmacist and MethadoneDispensing for Pain ManagementThe Standards of Practice for Pharmacists16, developed by the Ontario College ofPharmacists (OCP) sets forth the standards that all pharmacists are held to.These standards cover the full spectrum of practice issues, including theprovision of patient-focused care; compliance with legal requirements andethical principles; provision of drug and practice-based information to achievesafe and effective care; ongoing dialogue with patients and care providers; andpharmacy operations and management with the goal of optimizing patient careand inter-professional relations.

Pharmacists are always an integral part of the treatment team but they assume amore evident role in monitoring patient response to therapy when they dispensemethadone. In many ways, methadone maintenance therapy for the treatmentof opioid addiction is a model of patient care in which the pharmacist andphysician work as a team on an ongoing basis.

Although methadone use is strictly controlled when used to treat opioidaddiction, its use in managing pain will be much more the responsibility of andcontrolled by the patient. Pharmacists whose experience is based on treating theopioid-addicted patient may find marked differences in the way methadone ishandled in the pain patient. As a result, collaboration with the prescribingphysician should take place before dispensing begins and, on an ongoing basisduring therapy. This collaboration is essential, not only for dispensing andlabelling instructions, but to involve the pharmacist in the care of the patient,consistent with the OCP Standards of Practice. Physicians should be aware thatthere are differences in Ontario Drug Benefit (ODB) coverage when methadoneis prescribed for pain. Whereas methadone compounded by the pharmacist forMMT is covered as a compounded product under the ODB, neither thecommercially available tablets nor solutions prescribed for pain are covered.Coverage must be requested through the Independent Clinical Review orSection 8 process, whereby the physician outlines the reasons for the request.Decisions regarding coverage may take several weeks. In this regard, physiciansand pharmacists must work closely to ensure that there is neither any unduedelay in commencing treatment, nor gap in treatment related to billing issues.The pharmacist may provide crucial information about the patient based on hisor her experience with that individual, and physicians should welcome suchobservations.

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16.Ontario College ofPharmacists, The Standards ofPractice for Pharmacists.January 1, 2003.

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In general, pharmacists will:

• Advise the OCP that they are dispensing methadone and inform the OCP oftheir status with respect to accepting new patients.

• Ensure the labelling requirements of the federal and provincial governments,and the OCP are met.

• Have a process to positively identify the patient.• Confirm with the CPSO at (416) 967-2661, Office of Controlled Substances,

Health Canada at 1 (866) 358-0453 or the Ontario College of Pharmacists at(416) 962-4861 that the prescriber holds a current and specific exemption forthe use of methadone in the treatment of pain.

• Ensure that there is an agreement in place with the patient consenting to thesharing of information between physicians and pharmacists with respect tomatters related to pain management.

Some specific ways that methadone use for pain management will differ fromthe pharmacist’s experience with methadone in the addicted population willinclude the following:

• Methadone may be dispensed in an aqueous form or as tablets rather thandiluted in a flavoured drink.

• Larger quantities of methadone may often be dispensed.• Dosing intervals may be more frequent.• Measuring of doses may become the responsibility of the patient.• Observed ingestion usually will not be necessary (i.e., all doses may be dis-

pensed as carries or take-home doses) depending on the category of risks (i.e., Group I, II, or III on page 9).

• Pain patients on methadone typically do not have start and stop dates on theirprescriptions. Pain patients may have a small amount of their prescription leftover.

All of these differences may or may not be a part of any patient’s treatment. Inkeeping with the OCP Standards of Practice, pharmacists should feelcomfortable contacting the prescribing physician to prevent any confusion aboutthe way methadone is prescribed and/or taken.

Standards of Practice for pharmacists require a pharmacist to:

• Confirm the accuracy of dosage conversion when a patient is being switchedfrom another opioid analgesic to methadone. Due to the highly variablenature of methadone equivalency, it may be necessary for the pharmacist todiscuss conversion doses with the prescriber, if there is any doubt in thepharmacists mind as to the safety of the ordered dose.

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• Confirm the current dosing schedule and amount to be dispensed. Given theexpectation that patients will appropriately titrate their dose, the actualprescribed dose and the dosing schedule adopted by the patient may bedifferent. Significant departure from the written order should be clarified withthe prescriber.

• Monitor the efficacy of methadone (i.e., assisting in pain assessment, reportingobservations to physician) and safety (i.e., identifying emerging adverse drugeffects, aberrant behaviour or misuse/diversion).

• Monitor for drug interactions and consult with physicians where dosageadjustments of methadone or other concurrent medications may be necessary.

• Communicate, with the consent of the patient, with other pharmacies,hospitals or institutions, whenever the care of the patient is transferred fromone setting to another (i.e., confirm current dose, dosing and dispensinginterval, concurrent medications, etc.).

In the management of chronic pain, patients will frequently vary their daily doseof drug taken. In this context, it is important to compare the pharmacist’srecorded dosing schedule with the patients “actual” pattern of use, includingtime and quantity of last dose and when concerned, inform the prescriber.

Pharmacists play a fundamental role in patient education and nowhere is thisfunction more crucial than in the use of methadone for the management of painor addiction. Examples include:

• Providing specific instructions about security and safety.

• Educating the patient, paying special attention to dosing. The pharmacistmust confirm that the patient understands how to self-administer the correctdose and, where indicated, how to titrate the dose according to the physician’sdirections. Where multiple doses are ordered, the pharmacist must provide thepatient with an appropriate measuring device (i.e., measuring syringe), of theappropriate capacity and accuracy to deliver the dose prescribed, and provideinstructions on the use of such a device.

• Talking with the patient to ascertain the actual current dosing schedule;inquiring about any concurrent medications; identifying any side effects; andreinforcing instructions with respect to dosing, storage and security.

When there is any interruption in dosing, the pharmacist must notify theprescriber, as well as be able to advise the patient, where appropriate, of the needfor cautious reintroduction of this drug.

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When there are changes in the dose or dose frequency, the physician, wherepossible, should communicate this to the pharmacist, either verbally or by anotation on the prescription.

Missing one or two doses of methadone is unlikely to result in clinicallysignificant changes in blood levels or tolerance. In all cases, the reason formissed doses should be sought and where appropriate, the patient should becounselled regarding the effective use of this medication.

Practical considerations in the handling of methadone at the pharmacy are morecompletely covered in the Ontario College of Pharmacists’ MMT guidelines.Again, these are considerations within the context of methadone maintenancetherapy programs, and while there may be overlap, there are considerabledifferences in the implementation of methadone dosing in pain management.Some common principles to consider include the following:

• Maintaining a bulk-compounding log where the details of compoundingstock solutions of methadone is documented.

• Keeping a perpetual inventory system where the disposition of stock solutionis documented.

• The requirements for appropriate weighing devices and dosage measuringdevices.

• Labelling requirements for stock solutions.• Labelling requirements for dispensing including the use of auxiliary warning

labels.

Cooperation and communication amongst pharmacist, physician, and patient,as partners in the management of pain, is of crucial importance whenmethadone is prescribed and should be encouraged. Pharmacist feedback onpatient behaviour, the pattern of medication use, and general health status mayassume a greater importance with this patient population. Groups I, II, and IIIdescribed in an earlier section (see section Methadone for Chronic PainManagement) involve different levels of structure and support. It is importantto realize that in many ways the groupings are artificial and arbitrary; a patientmay move from Group II to Group III and back again, over time. Thepharmacist may be the first member of the health care team to recognize such achange in status and should communicate such information to the attendingphysician. Physicians must be aware of the importance of this information, andcommunication and collaboration between pharmacist and physician should becollegial and ongoing.

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Urine Drug TestingAt the present time, the use of drug testing in pain management is controversial.Part of the reason for this has resulted from people’s perceptions of testing in theworkplace or in drug testing of athletes. In the clinical context, however, urinedrug testing is playing an increasingly valuable role in the clinical managementof patients who are being treated for chronic painful conditions.

Urine drug testing (UDT) should be a consensual and patient-centred process.It can be used to benefit the patient in several ways. Advocacy, initiation ofbehavioural change, maintenance of healthy changes already made, as well as theearly diagnosis of substance use disorders, are all positive roles for urine drugtesting. UDT should not be used to “catch” patients nor should it be the finalword on the detection of drug diversion.

It is important to approach clinical drug testing from a patient-centredperspective. In particular, drug-test results can play a valuable role in helpingpatients maintain healthy behavioural change. It can be used as a tool foradvocating on behalf of the patient, as well as assisting with the earlyidentification of potentially treatable concurrent disorders, such as addiction. Itis not particularly useful as a means of assessing medication compliance becausea variety of reasons can explain an apparent negative drug-test result for aprescribed drug such as methadone. Results should always be used in asupportive fashion that leads to improved patient care. Urine drug tests that arepositive for illicit substances or substances not prescribed can help identifyundiagnosed substance use problems, but in no way should they be seen todiminish the patient’s claims of pain. Pain management is often complex andcertainly patients may suffer from more than one treatable condition at a time.

The publication Urine Drug Testing in Primary Care: Dispelling the Myths andDesigning Strategies provides a more complete discussion of the role of urinedrug testing and its practical application, and can be viewed on-line atwww.familydocs.org/UDT.pdf.

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Methadone WithdrawalWhen a patient is being taken off methadone, the very long elimination half-lifeof this drug must be considered. Rapid reduction or abrupt discontinuation ofmethadone may lead to a classic opioid withdrawal syndrome consisting of someor all of the following symptoms:

• Anxiety, often intense;• Insomnia;• Lacrimation and/or rhinitis;• Dilated pupils;• Abdominal pain/cramping;• Diarrhea;• Vomiting;• Piloerection;• Arthralgia/myalgia.

One often-overlooked effect of early withdrawal is an increase in pain in thosepatients suffering from chronic pain syndromes. In part due to methadone’slong elimination half-life, some patients can continue to suffer withdrawalsymptoms weeks to months after discontinuing this drug. Patients are taperedfrom methadone as a result of a number of factors and methods tend to becategorized as either “therapeutic” or “administrative” tapers.

Therapeutic TaperIn a therapeutic taper, the physician and patient have made the decision to loweror discontinue the use of methadone. Resolution of the underlying painfulcondition, intolerable side effects, inadequate analgesic effect, failure to improvequality of life despite an aggressive trial of opioid therapy, or deterioratingfunction are common reasons to consider a therapeutic taper. Arbitrary opioidlevels do not measure success.

Therapeutic tapers can be slow or fast but should be conducted in a humanefashion as to minimize severe withdrawal symptoms, if possible. One commontaper schedule is to reduce the dose by approximately 10% of the initial doseevery 2-4 weeks until the final 20-30% at which point the dose is decreased by5% every 4-8 weeks until finished. This schedule recognizes the fact that thefrequent, large dose reductions that are tolerated at the beginning of a taper maynot be well tolerated at the end.

To effect a more rapid taper, the average elimination half-life kinetics ofmethadone can be used. Assuming an elimination half-life of 24 hours, a

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10-20% drop every 3-5 days can result in the patient being off methadone inless than one month.

Assuming a 24-hour half-life, three days represents 87.5% steady state; five daysrepresents steady state.

A rapid taper risks precipitating severe withdrawal symptoms. Increased painmay be the dominant complaint with too rapid a taper. Holding the taper at thecurrent dose or increasing the dose to the previously tolerated level will usuallyresolve this situation. It is unfortunate that the often dramatic improvement inpain relief that is experienced when the dose is adjusted back upwards issometimes attributed to the analgesic properties of the drug when, in fact, itmay be due to the relief of withdrawal mediated pain which has appeared as thedose was reduced during the taper. This common mistake can trap both thepatient and the physician in an opioid-based treatment paradigm. On the otherhand, a temporary increase in pain is common in the first 1-2 weeks of opioidwithdrawal but may decrease afterwards.

It is important to avoid substituting other drugs, including other opioids, if thegoal of the taper is to reduce or discontinue the drug. In particular, resumingpreviously misused agents, such as immediate release oxycodone preparations, isto be avoided. Overly aggressive tapering may lead to an opioid debt which willlikely exacerbate any painful condition.

It is sometimes useful, in the absence of any contraindication, to prescribemedications at the end of the taper to blunt the symptoms of opioid withdrawal.A common approach is to prescribe oral clonidine (0.1 – 0.2 mg up to fourtimes a day), an anti-inflammatory agent, and an antidiarrheal such asloperamide for the 1-2 weeks commonly associated with the worst symptoms ofopioid withdrawal.

When prescribing clonidine, the first dose is best administered at bedtime toavoid the risk of orthostatic hypotension. When used in excess of .4 mg/day orfor longer than 1 week, the drug should not be abruptly discontinued due to therisk of rebound hypertension.

Administrative TaperIn rare circumstances, the decision to terminate the use of methadone isunilaterally made, most often by the prescriber. The reasons for anadministrative taper are limited and commonly due to severe behaviouralproblems by the patient. Staff or patient safety concerns might necessitateinvoluntary termination of methadone treatment. It must be remembered thatinvoluntary discontinuation of methadone can, for some people, lead to

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significant harm due to aberrant and sometimes illegal activity to cope withopioid withdrawal symptoms. Referral, where possible, to an opioid addictiontreatment program is strongly recommended as an alternative to abruptdiscontinuation of this drug. The reasons for methadone discontinuation, aswell as any other recommendations made to the patient, should be carefullydocumented in the patient’s chart.

In some cases, the physician’s decision to stop prescribing methadone will leadthe patient to terminate the doctor-patient relationship. If the termination isthe patient’s wish, the physician will have no further responsibilities toward thatpatient (beyond transferring the medical record if that should be requested). Insome cases, however, the physician’s decision to stop prescribing methadone willcause irreparable damage to the doctor-patient relationship, leading thephysician to discontinue the relationship. In this situation, the physician shouldensure that he or she adheres to the CPSO policy Ending the Physician-PatientRelationship, which includes the expectation that the physician will provide thepatient with reasonable notice to find a new doctor and, in the interim, ensurethat the patient is not acutely in need of immediate care.

In many cases, a formal treatment agreement can be added to explicitly outlinethe treatment team’s expectations of the patient, as well as what the patient canexpect of the treatment team. Common to virtually all treatment agreements isthe requirement that the patient does not obtain opioids from other than thedesignated prescriber; the patient select and use only one pharmacy forprescription medications; and that lost or stolen medications will not normallybe replaced. More recently, treatment agreements have begun to includespecifics about urine drug testing, and consent to speak with any and all healthcare professionals who have been involved in the patient’s care as a condition ofinitiation or continuation on strong opioids. A sample treatment agreement isincluded in Appendix E.

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Managing Patients with Pain and Addictive DisordersAlthough treating the majority of chronic pain patients will be straightforward,without the complications of an active or past history of a substance usedisorder, some will not. Unfortunately, it is impossible to determine in advance,with any certainty, those patients who will ultimately exhibit behaviouralproblems. The diagnosis of addiction is usually made prospectively, over time.Even with a careful personal and family history around drug and alcohol use, itis only with time that the behavioural components of an addictive disorder willbecome evident. In fact, some patients who appear initially to be Group I, withno obvious increased risk of addiction, may better fit Group II, as they becomemore comfortable disclosing their past or current drug use. Sometimes it is onlyby careful assessment of behavioural markers such as early prescription refills,double-doctoring or inappropriate urine toxicology results that it becomesevident that there is at least problematic, if not addictive use of medications orillicit drugs. With this information in hand, the patient may be referred to ahealth professional with more resources and experience in the assessment andtreatment of concurrent substance use disorders. The diagnosis of addiction andsubstance abuse in the pain population is difficult, even for those with a specialinterest in this problem. One of the major stumbling blocks to accuratediagnosis is the over reliance on the DSM-IV criteria for Substance Dependence.

The presence of a concurrent addictive disorder does not, in itself, diminish thevalidity of the patient’s complaints of pain. It does increase the risk aroundappropriate management with pharmaceutical agents, including opioids.

The DSM-IV, as a tool for diagnosing opioid addiction within the painpopulation, is inadequate. The terms addiction and dependence are usedinterchangeably, which is inappropriate. Also, by over reliance on the physicalmanifestations of chronic opioid use (withdrawal and tolerance) in the diagnosisof addiction, the DSM-IV is unreliable in the chronic pain population. Despitethe fact that the preamble to the DSM-IV diagnosis of substance dependencespecifies a “maladaptive” pattern of use, it remains up to the clinician to decidewhat use is maladaptive. The emergence of unified definitions for addiction,dependence and tolerance (see Appendix H) will help ensure that terms, such asaddiction and dependence, are not used interchangeably.

At the present time, it is often difficult to obtain consultation with a substanceabuse professional. The following suggestions can be useful in setting tighterlimits on patients to help them reduce harm and normalize their behaviour.

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The first important point is to have a clear treatment agreement in place, for allpatients, from the outset. For those who have both pain and opioid addictivedisorders, it is strongly recommended to get this agreement in writing. Failureto comply with a reasonable treatment agreement should be seen as a problemrequiring further investigation, not as evidence of fraud or deception. As well, itis essential to be able to contact patients’ present or previous treating physicians,whenever necessary. A patient who refuses to allow contact with past or presenttreatment providers is severely hampering the physician’s ability to deliver safeand effective care. Such refusal should be considered a relative contraindicationto initiation or continuation of chronic opioid therapy.

Some individuals continually run out of medications early. While it may be thatthis represents under medication, it may also represent aberrant behavioursuggestive of addiction or drug misuse. In this situation, the use of interval orcontingency dispensing may be used to clarify this point.

By reducing the dispensing interval to weekly, or even more frequently, a patientwho is struggling with medication control will be prevented from “borrowingmedication from tomorrow to pay for today”. Even if the patient is only seen on amonthly basis, it is often useful to have patients experiencing this problem pickup their medications on a weekly or twice monthly basis (interval dispensing).

Sometimes, placing conditions on the ongoing receipt of medication can be auseful tool to help patients stay within agreed upon limits. In the case oftransdermal analgesic products, which can be misused by leaving old patches onwhen new ones are applied, making the receipt of new patches “contingent” onthe return of spent patches to the pharmacy can greatly assist in re-establishingpatient control with respect to usage (contingency dispensing).

Interval/contingency dispensing of medications can be a very useful technique tohelp patients stay within prescribed boundaries. Changing the dispensinginterval from monthly to weekly can assist in uncovering problematicbehaviours, such as bingeing or inappropriate dose escalation.

In Ontario, the Addiction Clinical Consultation Service operated by the Centrefor Addiction and Mental Health can be consulted at 1 (888) 720-2227 on thegeneral issues around management of patients who may have substance-relatedproblems.

Patients who continuously run out early, rely heavily on immediate-release,short-acting opioids, or who frequently have their medications lost or stolenshould be seen as probable Group II or Group III patients and should bereferred for assessment by a health professional knowledgeable in addictionmedicine. In some cases, this is not practical, and the advice of such a specialist

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should be sought informally and documented in the patient’s chart. In all cases,the clinician is encouraged to collaborate with the dispensing pharmacist toimprove patient care and reduce the risk of drug misuse or diversion.

Common drugs that can be problematic for some patients are the sedative classof drugs. The main drugs are alcohol and benzodiazepines, but over-the-countermedications such as antiemetics or antihistamines can also cause problems.Impairment due to concurrent use of sedatives is more commonly theexplanation for episodic intoxication in the patient who is on an apparentlystable dose of opioid.

It is not uncommon for some patients to decompensate when their access tomedications is altered. For example, a patient who is normally given a one-month supply of medication may consume significantly more of the medicationat the beginning of the month, relying on substitutes such as acetaminophenanalgesics containing codeine to minimize the discomfort of withdrawal seenlater in the month. By providing only a one-week supply of medication at atime, a patient who binges will run out much earlier than usual, thus helpingthe treatment team to identify a pattern of medication overuse. This will oftennecessitate a call to the doctor’s office for early release of medication. Fullyexplore this with the patient at the next visit. Again, this method does not serveto dismiss any complaint of pain, but rather can be a motivational tool to movethe patient along the readiness to change model into a place where they can beproperly assessed for a drug-related problem. Some patients will welcome theopportunity for further investigation and treatment of a possible concurrentaddictive disorder. Others will not, electing to move on to another prescriber. If the information gained by boundary tightening is reflected back to thepatient, carefully charted, and used in a non-judgemental fashion, the patientmay well decide to accept the physician’s advice for further assessment andtreatment of a possible concurrent substance use disorder.

In conclusion, it is hoped that these guidelines are a useful tool in the clinicalmanagement of patients with pain using methadone. While it is recognized thatthe use of any opiate carries some degree of risk for the patient, methadone, withits unique pharmacokinetic properties behaves differently than other opiates. Inparticular, its long elimination half-life and duration of action present significantsafety concerns especially during the early stages of initiation onto the drug andduring titration to effect. Once the practitioner makes the decision to usemethadone to treat pain, this guideline is intended to provide a framework inwhich to use methadone balancing issues of patient safety while offering a viabletreatment for pain.

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References1. College of Physicians of Surgeons of Ontario, Centre for Addiction and Mental

Health, Ontario College of Pharmacists. Methadone Maintenance Guidelines, 2nd ed 2001.

2. Rotter, J. 1996. Generalized expectancies for internal versus external control ofreinforcement. Psychol Monograph 80:1-28.

3. The American Heritage® Stedman’s Medical Dictionary © 2002, 2001, 1995,Houghton Mifflin Company.

4. Gourlay, D., Heit, HA., Almarhezi, A. (March 2005). Universal Precautions inPain Management: A rational approach to management of chronic pain. PainMedicine (6):2.

5. Savage, SR. Long-term opioid therapy: assessment of consequences and risks. J. Pain Symptom Manage. 1996. 11:275-286.

6. College of Physicians and Surgeons of Ontario. Evidence-BasedRecommendations for Medical Management of Chronic Non-Malignant Pain.November 2000.

7. Fishman, SM., Mahajan, G., Jung, SW., et al. 2002. The trilateral opioid contract:Bridging the pain clinic and the primary care physician through the opioid contract.J. Pain Symptom Management 24:335-344.

8. Passik, SD., Weinreb, HJ., 2000. Managing chronic non-malignant pain:Overcomng obstacles to the use of opioids. Advances in Therapy. 17(2):70-83.

9. Covington, E. Oct. 2001. Lawful Opioid Prescribing and Prevention of Diversion;Dannemiller Education Foundation, CD ROM.

10. Zacny, J. A review of the effects of opioids on psychomotor and cognitive functioningin humans. Experimental and Clinical Psychopharmacology. 1995. 3(4):432-466.

11. Heit, HA., Gourlay, D. March 2004. Urine Drug Testing in Pain Medicine.Journal of Pain and Symptom Management, 27 (3).

12. Gourlay, D., Heit, HA., Letter to the Editor, March 2004. Vol. 5 Iss. 1, PainMedicine, 109-110.

13. Gil, M., Sala, M., Auguera, I., Chapinal, O., Cervantes, M., Guma, JR., Segura, F.QT Prolongation and Torsades de Pointes in patients infected with human immun-odeficiency virus and treated with methadone. J. Cardiol. 15-Oct-2003; 92(8):995-997.

14. Krantz, MJ., Lewkowiez, L., Hays, H., Woodroffe, MA., Robertson, AD., Mehler, PS.Torsades de pointes associated with very-high-dose methadone. Ann. Intern Med.2002. Sep 17; 137(6):501-504.

15. Doverty, M., White, JM., Somogyi, AA., Bochner, F., Ali, R. and Ling, W.Hyperalgesic responses in methadone maintenance patients. Pain 2001 Feb 1;90(1-2):91-96.

16. Ontario College of Pharmacists, The Standards of Practice for Pharmacists.January 1, 2003.

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17. Sandoval, A., Furlan, A., Mailis-Gagnon, A. (2004) Results of a systematicreview of oral methadone for chronic non-malignant pain. (Submitted for publication).

18. McQuay, H., Moore, A. An Evidence-Based Resource for Pain Relief. Oxford U.Press, 1998.

19. Canadian Pain Society. 1998. Use of opioid analgesics for the treatment ofchronic noncancer pain – A consensus statement and guidelines from theCanadian Pain Society. Pain Management and Research 3(4).

Suggested ReadingsAmerican Psychiatric Association Task Force on DSM-IV: Diagnostic and StatisticalManual of Mental Disorders. Fourth Edition. American Psychiatric Association Press,Washington, 1994.

American Academy of Pain Medicine, American Pain Society and American Societyof Addiction Medicine. Definitions Related to the Use of Opioids for the Treatment ofPain, 2001.

Fishman, SM., Wilsey, B., Mahajan, G., Molina, P. Methadone Reincarnated: NovelClinical Applications with Related Concerns, Pain Medicine 3(4) 2002.

Friedman R., Li V., Mehrotra D. Treating Pain Patients at Risk: Evaluation of aScreening Tool in Opioid-Treated Pain Patients With and Without Addiction; PainMedicine 4(2) 2003.

Kahan, M., Selby, P., Wilson, L. Management of Alcohol, Tobacco and Other DrugProblems: A Physician’s Manual. CAMH, 2002.

Gourlay, D., Caplan, Y., Heit, HA. Urine Drug Testing in Primary Care: Dispelling theMyths and Designing Strategies. California Academy of Family Physicians. August2002. www.familydocs.org/UDT.pdf; www.familydocs.org/UDT_RefCard.pdf

Gourlay, D., Heit, HA., Almarhezi, A. (March 2005) Universal Precautions in PainMedicine: A rational approach to management of chronic pain. Pain Medicine (6):2.

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Appendix A

Guideline Development Process

ObjectivesOn January 25, 2002, the College convened a committee, including experts onaddiction and pain management, for the purpose of developing guidelines onthe use of methadone for pain. This working group was mandated to:

• address the lack of clear guidelines for the use of methadone for chronic painmanagement;

• complete a relevant literature review on the use of methadone in pain management;

• offer a basic set of consensus guidelines in the use of methadone in themanagement of chronic pain that would help to reduce risk and improvepatient care.

The following was undertaken to complete this project:

• A needs assessment that surveyed the perceptions and needs of physicians whowere prescribing methadone.

• A liaison with the Ontario Guidelines Collaborative.• A liaison with the CPSO task force that was developing evidence-based rec-

ommendations for management of chronic non-cancer pain.• A review of these guidelines in draft by relevant stakeholders.

Beginning March 14, 2002, the working group met approximately every twomonths. Dr. Graeme Cunningham chaired the committee, and representativesincluded:

• Two members of the CPSO task force on Evidence-Based Recommendations forMedical Management of Chronic Non-Malignant Pain.

• A delegate from the Ontario College of Pharmacists.• Physicians with expertise in the area of management of opioids.• A public member of the CPSO Council.• Staff support from the CPSO, under the supervision of the Methadone

Committee.

In September 2002, a needs assessment was conducted. A questionnaire wascirculated to methadone prescribers in Ontario, to assess methadone utilizationand perceived needs or problems. This information was collated and used, inpart, to direct the content of this document. The results of the survey are foundin Appendix B.

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MethodologyAs a first step, the CPSO’s Evidence-Based Recommendations for MedicalManagement of Chronic Non-Malignant Pain was reviewed. Other documents werealso reviewed, including a selected bibliography on the use of opioids for thetreatment of pain; the results of a systematic review on the use of methadone inpain management17 (see Appendix C); and published guidelines by otherjurisdictions concerning the use of opioids for the treatment of pain (see Referencessection). The results from the systematic review on the use of methadone for painmanagement revealed an absence of Level I evidence, i.e., strong evidence from atleast one systematic review of multiple, well designed randomized controlled trials.The source for this rating system was An Evidence-Based Resource for Pain Relief 18.

In the absence of Level I evidence, the working group agreed to use the bestavailable information, including expert opinion, to develop a set of consensus-basedguidelines. This approach had been used with favourable results in thedevelopment of the College’s MMT guidelines. The Methadone for PainGuidelines provide Level V evidence, except where otherwise stated, i.e., opinionsof respected authorities, based on clinical evidence; descriptive studies; or reports ofexpert committees. Through the literature review, the results of the needsassessment survey (Appendix B), material from presentations, and discussionamongst experts, the content of the draft guidelines was formulated and brought tothe committee for discussion, input and modification. Consensus was reached bydiscussion and debate. The final document represents the consensus of all membersof the working group.

External Review ProcessThe draft guidelines were distributed for peer review to professional andconsumer groups. The feedback received was incorporated, where appropriate,into the final document. In total, the guidelines were sent to 507 reviewers,including the following:

• 383 Ontario physicians who have an exemption to prescribe methadone forpain and/or opioid addiction;

• 124 reviewers from the following areas:• CPSO Methadone Program’s Patient Advisory Group• Physicians practicing pain management• CPSO Council• CPSO Executive Committee• CPSO Methadone Committee• Methadone for pain working group• CPSO senior management

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17.Sandoval, A., Furlan, A.,Mailis-Gagnon, A. (2004)Results of a systematic reviewof oral methadone for chronicnon-malignant pain. (Submittedfor publication).

18.McQuay, H., Moore, A. AnEvidence-Based Resource forPain Relief. Oxford U. Press,1998.

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• Chairs of CPSO Committee’s • OMA Sections on: Drugs and Pharmacology; Anaesthesia; Addiction

Medicine; Chronic Pain; General and Family Practice; Rural Practice;Neurology; Sports Medicine; Emergency Medicine; Oncology; CriticalCare Medicine; and Palliative Care

• AIDS Committee of Toronto• Coalition of Family Physicians• Ontario Patient Representative Association• Ontario College of Family Physicians• Ontario Hospital Association• Ontario Pharmacists Association• Ontario College of Pharmacists• Professional Association of Internes and Residents of Ontario• Homewood Health Centre• Centre for Addiction and Mental Health• Emergency Physician Services• Centre for Evaluation Medicines• Canadian national societies and associations, such as the Canadian Pain

Society; Society of Rural Physicians of Canada; Canadian Centre onSubstance Abuse; Canadian Anaesthesiologists Society; Canadian Societyof Medical Evaluators; Canadian Neurological Society; Canadian PainCoalition; Royal College of Physicians and Surgeons of Canada; TheFederation of Medical Regulatory Authorities of Canada; College ofFamily Physicians of Canada; and the Canadian Cancer Society.

In total, the committee received a 26% response rate (133 responses) from theexternal review, after follow-up was conducted to obtain feedback from thosewho had not initially responded. The final draft document was submitted to theCPSO Council for review and approval for publication.

Dissemination and ImplementationThe College will inform the profession that these guidelines are available for usein clinical practice through Members’ Dialogue and the College’s website.Additional implementation strategies are being explored, such as workshops andcourses. The College will measure outcomes on patient services and monitor theimpact of the guidelines through quality assessments by peer assessors.

Updating this DocumentIt is the intention of the College to reconvene the working group in three years,to conduct a survey to determine the applicability and utility of the guidelines,and to recommend changes or updating, if necessary. The external reviewprocess will be repeated to validate the revised guidelines.

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Appendix B

Survey of Methadone Prescribers

Results

• 285 surveys distributed• 54% response rate (154/285)

Demographics of Respondents

• 30% females - 70% males • 36% between 30-45-years-old• 49% between 46-59-years-old• 15% between 60-75-years-old

What is your area of practice?

• 28.1% general/family medicine • 18.0% chronic pain management • 5.5% general/family medicine and chronic pain management • 3.9% general/family medicine and addiction• 3.1% general/family medicine, addiction, chronic pain management and

other• 1.6% chronic pain management and addiction• 1.6% general/family medicine, addiction, and chronic pain management• 38.3% other

Which statement best reflects your pain practice?

• 69% speciality practice providing consulting and ongoing care of somepain patients

• 60% general/family practice with the usual mix of patients, includingthose with chronic pain

• 24% speciality practice providing consulting, stabilization and eventualreturn to primary care physician for follow-up

• 8% speciality practice providing consulting only• 3% treating addictions primarily, getting other specialists involved in

managing chronic pain

Approximately what percentage of your patients is chronic painthe primary focus?

• 71% responded that for 0-24% of patients, chronic pain is the primary focus

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• 14% responded that for >75% of patients, chronic pain is the primary focus



What types of chronic pain do you manage in your practice? (Please select all that apply)*

• 127 neuropathic pain• 117 low back pain• 96 chronic soft tissue pain• 95 chronic pain in the elderly• 92 neck pain• 90 post-traumatic pain• 84 headaches• 79 work injury pain• 64 rheumatic disease patients• 60 post-operative pain• 60 spinal cord post-stroke pain• 53 pain in addicts• 50 other• 25 HIV• 6 chronic pain in children

What clinical treatments do you generally utilize for patients withchronic pain? (Please select all that apply)*

• 143 opioids• 142 NSAIDs or antipyretics• 131 non-opioid pharmacotherapy• 74 methadone for chronic non-malignant pain• 73 nerve blocks• 67 multi-modal rehabilitation• 51 alternative therapies• 25 surgical methods• 18 other clinical treatments not listed

(*numbers do not total 154 in questions where respondents were asked to select “all that apply” as noted)

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What is your level of clinical education and training in the management of chronic pain?

• 30% CME events• 30% self-taught (e.g., journals)• 17% residency program or medical school• 12% clinical preceptorship• 11% other

What is your level of clinical education and training in the use ofmethadone for chronic pain?

• 35% self-taught (e.g., journals)• 26% CME events • 17% other• 10% none• 9% clinical preceptorship• 3% residency program or medical school

I am concerned about the issues of safety of methadone?

• 44% agree• 22% disagree• 18% strongly agree• 12% unsure• 4% strongly disagree

Could you indicate where you feel there is a gap in resources inthe area of methadone for chronic pain? (Please select all that apply)*

• 120 education• 76 expert clinics• 71 experts• 48 pharmacies• 31 pharmacy rules• 31 other• 30 college oversight

Which topics would you be interested in learning more about forusing methadone for chronic pain? (Please select all that apply)*

• 104 methadone dosing issues• 94 understanding pharmacology• 94 indications for methadone use in treating chronic pain• 57 assessment tools

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• 52 screening for addiction, monitoring and managing addiction• 30 criteria for admission for methadone treatment for management of

opioid addiction

In addition to clinical practice guidelines, what other resources doyou feel would be helpful to you in using methadone to treatchronic pain?

• 28% access to experts/peers (opinions or individual cases)• 27% educational events on using methadone • 22% electronic resources• 21% printed resources• 2% other

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Appendix C

Results of a systematic review of oral methadonefor chronic non-malignant pain.Title: Oral methadone for chronic non-malignant pain. A systematic literaturereview of reasons for administration, prescription patterns, effectiveness and sideeffects.

Authors: Juan Alberto Sandoval1 MD, Andrea D. Furlan1,3,4,5 MD, AngelaMailis-Gagnon1,2,3 MD, MSc, FRCPC

Affiliations:

1.Comprehensive Pain Program, Toronto Western Hospital.2. Krembil Neuroscience Center, Toronto Western Hospital. 3. University of Toronto Centre for the Study of Pain. 4. Institute for Work & Health, Toronto, ON, Canada. 5. Health Policy Management and Evaluation, University of Toronto, Canada.

Address for correspondence:

Angela Mailis-Gagnon MD, MSc, FRCPC(PhysMed) Medical Director, Comprehensive Pain Program Toronto Western Hospital,Senior Investigator, Krembil Neuroscience Center andToronto Western Research Institute,4F811, 399 Bathurst St. Toronto ON Canada M5T 2S8Tel: 416-603-5380 Fax: 416-603-5725E-mail: [email protected]

Acknowledgments: Andrea Furlan is funded by grants from the CanadianInstitute of Health Research and by the University of Toronto Centre for Studyof Pain.

ABSTRACT

Objective: To assess the indications, prescription patterns, effectiveness and side-effects of oral methadone for the treatment of chronic non-malignant pain.

Methods: We conducted searches of several electronic databases, textbooks andreference lists for controlled or uncontrolled studies in humans. Effectiveness

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was assessed using a dichotomous classification of “meaningful” versus “non-meaningful” outcomes.

Results: Twenty-one papers (one small randomized trial, 13 case reports andseven case series) involving 545 patients with multiple non-cancer painconditions were included. In half of the patients, no specific diagnosis wasreported. Methadone was administered primarily when previous opioidtreatment was ineffective or produced intolerable side effects. Starting dosesranged from 0.2 to 80 mg/day and maximum doses ranged from 20 to 930mg/day. Pain outcomes were meaningful in 59% of the patients in theuncontrolled studies. The randomized trial demonstrated a statisticallysignificant improvement in pain for methadone (20 mg/day) compared withplacebo. Side effects were considered minor.

Discussion: Oral methadone is used for various non-malignant pain syndromes,at different settings and with no prescription pattern that could be identifiable.Starting, maintenance and maximum doses showed great variability. The figureof 59% effectiveness of methadone should be interpreted very cautiously, as itseems overrated due to the poor quality of the uncontrolled studies and theirtendency to report positive results. The utilization of oral methadone for non-malignant pain is based on primarily uncontrolled literature. Well-designedcontrolled trials may provide more accurate information on the drug’s efficiencyin pain syndromes and in particular neuropathic pain.

Key words: Methadone, effectiveness, systematic review, and non-malignantpain

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Appendix DReprinted with permission from the Diagnostic and Statistical Manual of MentalDisorders, Text Revision, Copyright 2000, American Psychiatric Association.

Diagnostic Criteria for Substance Dependence

Criteria for Substance Dependence

A maladaptive pattern of substance use, leading to clinically significantimpairment or distress, as manifested by three (or more) of the following,occurring at any time in the same 12-month period:

1. Tolerance, as defined by either of the following:a) the need for markedly increased amounts of the substance to achieve

intoxication or the desired effect;b) markedly diminished effect with continued use of the same amount of

the substance.

2. Withdrawal, as manifested by either of the following:a) the characteristic withdrawal syndrome for the substance (refer to

Criteria A and B of the criteria sets for withdrawal from specific substances);

b) the same (or closely related) substance is taken to relieve (or avoid)withdrawal symptoms.

3. The substance is often taken in larger amounts or over a longer period thanwas intended.

4. There is a persistent desire or unsuccessful efforts to cut down or controlsubstance use.

5. A great deal of time is spent in activities necessary to obtain the substance(e.g., visiting multiple doctors or driving long distances), use the substance(e.g., chain smoking), or to recover from its effects.

6. Important social, occupational or recreational activities are given up orreduced because of substance use.

7. The substance use is continued despite knowledge of having a persistent orrecurrent physical or psychological problem that is likely to have been causedor exacerbated by the substance (e.g., current cocaine use despite recognitionof cocaine-induced depression, or continued drinking despite recognition thatan ulcer was worsened by alcohol consumption).

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Specify if:

With psychological dependence: evidence of tolerance or withdrawal (i.e., either Item 1 or 2 is present)

Without psychological dependence: no evidence of tolerance or withdrawal(i.e., neither Item 1 nor 2 is present)

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Appendix E

Sample Treatment AgreementSample of a basic patient agreement (for patients at higher risk of non-compliance with opioid therapy)19

1. I, ____________________________ agree that Dr. __________________will be the only physician prescribing OPIOID (also known as NARCOTIC)pain medication.

2. I will take the medication at the dose and frequency prescribed by myphysician. I agree not to increase the dose of opioid on my own andunderstand that doing so may lead to the treatment with opioids beingstopped.

3. I will attend all appointments, treatments and consultations as requested bymy physician.

4. I will not receive opioid pain medications from any other physician except inan emergency or in the unlikely event that I run out of medication. Shouldsuch occasions occur, I will inform my prescribing physician as soon aspossible.

5. I understand that the common side effects of opioid therapy include nausea,constipation, sweating and itchiness of the skin. Drowsiness may occur whenstarting opioid therapy or when increasing the dosage. I agree to refrain fromdriving a motor vehicle or operating dangerous machinery until suchdrowsiness disappears.

6. I understand that there is small risk that I may become addicted to theopioids I am being prescribed. As such, my physician may require that I haveadditional tests and/or see a specialist in addiction medicine should a concernabout addiction arise during my treatment.

7. I understand that the use of any mood-modifying substance, such astranquilizers, sleeping pills, alcohol or illicit drugs (such as cannabis, cocaine,heroin or hallucinogens), can cause adverse effects or interfere with opioidtherapy. Therefore, I agree to refrain from the use of all of these substanceswithout first discussing it with my physician.

8. I agree to be responsible for the secure storage of my medication at all times. I agree not to provide my prescribed pain medication to any other person.

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19.Canadian Pain Society. 1998.Use of opioid analgesics forthe treatment of chronic non-cancer pain – A consensusstatement and guidelines fromthe Canadian Pain Society.Pain Management andResearch 3(4).

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9. If I break this agreement, my physician reserves the right to stop prescribingopioid medications for me.

10. I hereby agree that my physician has the authority to disclose the prescribinginformation in my patient file to other health care professionals when it isdeemed medically necessary in the physician’s judgement.

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Appendix F

Urine Drug TestingTesting for the presence of drugs in a patient’s urine is rapidly becoming animportant adjunct to managing patients with chronic pain. It can beparticularly useful in Group II and Group III patients, those with risk factorsabove baseline for substance abuse. A comprehensive reference for this process isavailable at www.familydocs.org/UDT.pdf. Although prepared as a CME toolfor US physicians, the general principles apply to all practitioners. What followsare some practical considerations for practitioners in Ontario.

Urine Collection

Sample collection begins the process of testing for drugs in a patient’s urine andcare must be taken to ensure that the sample will yield the most accurateinformation possible. While directly observing a chronic pain patient providinga urine sample is usually unnecessary, it is nevertheless important that thesample be fresh. Samples brought in from home are unacceptable, and theclinician is wise to use techniques to minimize potential tampering with thesample. A fresh sample of urine should be warm but not hot and certainly notcold. Test strips to measure temperature are available.

Screening Tests: Urine Drug Screening

The first step is often to order a drug screen. This is a test done by immunoassaysuch as EMIT (Enzyme Multiplied Immunoassay Technique) and involvesadding urine to a medium (often a dipstick or testing strip) covered withantigens to a drug. A positive test result is usually indicated by the absence of acoloured mark. These tests, now available from several companies as an officeprocedure, are very sensitive, but for many drugs not very specific. Mostfrequently these tests look for amphetamines, benzodiazepines, cocaine, opiates*,methadone and canabinoids.

With opioids, these tests are reliably able to detect the naturally occurring drugs(morphine/codeine i.e., the opiates), less reliably detect the semi-synthetic agents(derivatives of morphine/codeine i.e., oxycodone, hydromorphone) and reliablydon’t detect the pure synthetic agents (i.e., methadone, fentanyl) unless specificassays are used. It is worth emphasizing that oxycodone may not reliably bepicked up if one simply asks for a ‘urine drug screen’. In general, the labrequisition should specify any particular drugs that are being looked for.

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*The word opiate byconvention refers toextracts of the opiumpoppy, i.e., mor-phine/codeine, andhas been replaced bythe all encompassingterm “opioid”.

Specific Identification Tests: Urine Toxicology

Further testing can often identify specific rather than simple classes of drugs ifspecifically ordered. Asking for ‘urine drug toxicology’ will give results for amuch wider range of drugs. The one notable exception is fentanyl (i.e.,Duragesic®) which is not readily identified in routine testing and must be askedfor specifically, if indicated.

This more comprehensive look at drugs present in the urine is done bychromatography; such as gas chromatograph (GC) or HPLC REMEDi (highperformance liquid chromatography with spectrophotometry). GC/MS (gaschromatography/mass spectrometry) can also be used to identify drugs and isextremely specific and able to detect very minute quantities of a substance butcan be expensive and normally only used in cases where results are unclear or inforensic investigations

It is important to understand some of the limitations of this technology wheninterpreting results. Enzyme assays or chromatography will report a drug classas ‘positive’ (i.e., present in the urine sample) only if it is measured at aconcentration which reaches an arbitrarily assigned ‘threshold’. Thus, although adrug may be present in the urine, the sample may be reported as negative for thedrug if the concentration detected does not reach this cut-off point. Equallyimportant to note is that there is no reliable relationship between drugconcentration found in the urine and quantity of drug ingested due to, amongother factors, the concentrating effects of the kidneys. This is especially truewith the semi-synthetic agents, which may be positive some of the time but notall of the time. For this reason, it is useful to determine the concentration of thesample by ordering a random urine creatinine. Diluted urine samples are lesslikely to have drug concentrations high enough to reach the threshold and somay be less reliable.

Interpreting results

As with any investigation used in diagnosis or to guide therapy, results of urinedrug tests must be interpreted with care and used to guide therapy rather thanmake arbitrary decisions. It should be emphasized that urine drug testing ismuch more helpful in finding a drug which is unexpected (i.e., cocaine) than inlooking for an expected (prescribed) drug. Interpreting a sample, which isnegative for morphine in a patient being prescribed morphine, must be donewith extreme caution due to the technical and physiological limitationsmentioned in the above sections. The main value in such results may be ingenerating discussion with the patient involved to help interpret results and

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guide future therapy, perhaps resulting in changes to boundary setting withinthe context of current therapy. Although not common, certain substancesrelated to (as in the case of amphetamine screens and decongestants) and insome cases unrelated to (opiate screens and ciprofloxacin) substances beingtested for can be falsely reported as positive. Any unexpected result should bediscussed with the testing lab to ensure accuracy, and then explored with thepatient. In no circumstances should a lab result be used in a punitive fashion.

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Appendix G

Examples of prescription formatsExample 1: Using 5 mg/ml concentrate prepared in pharmacy

Rx: methadone solution 5 mg/ml

M: 200 ml

Sig: Take 5 mg (in 1 ml) every 4 hours PO to a maximum of 30 mg (6 ml)daily for three days, then 15 mg (in 3 ml) every 8 hours to a maximum of45 mg (9 ml) daily

Example 2: Using 1 mg/ml commercially available solution

Rx: methadone solution 1 mg/ml (Metadol Oral Solution)

M: 500 ml

Sig: Take 5 mg (in 5 ml) every 4 hours PO to a maximum of 30 mg (30 ml)daily for three days, then 15 mg (in 15 ml) every 8 hours to a maximum of45 mg (45 ml) daily

Example 3: Using 10 mg/ml commercially available solution

Rx: methadone solution 10 mg/ml (Metadol Oral Concentrate)

M: 100 ml (one hundred ml)

Sig: Take 5 mg (in 0.5 ml) every 4 hours PO to a maximum of 30 mg (3 ml)daily for three days, then 15 mg (in 1.5 ml) every 8 hours to a maximum of45 mg (4.5 ml) daily.

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Appendix H

Definitions related to the use of opioids for thetreatment of pain.

Addiction

Addiction is a primary, chronic, neurobiological disease, with genetic,psychological, and environmental factors influencing its development andmanifestations. It is characterized by behaviours that include one or more ofthe following: impaired control over drug use, compulsive use, continueduse despite harm, and craving.

Physical Dependence

Physical dependence is a state of adaptation that is manifested by a drugclass specific withdrawal syndrome that can be produced by abruptcessation, rapid dose reduction, decreasing blood level of the drug, and/oradministration of an antagonist.

Tolerance

Tolerance is a state of adaptation in which exposure to a drug induceschanges that result in a diminution of one or more of the drug’s effects overtime.

Reprinted with permission from the American Pain Society, the American Academyof Pain Medicine and the American Society of Addiction Medicine, DefinitionsRelated to the Use of Opioids for the Treatment of Pain, Copyright 2001.

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Committee Members

Chair: Graeme Cunningham, MD, FRCP(C), FASAM

Director, Homewood Addiction DivisionAssociate Clinical ProfessorDepartment of Psychiatry & BehaviouralNeurosciences, McMaster University

Steven Bodley, MD, FRCP(C)Pain Management ClinicNorth Bay General Hospital

Mr. Albert Chaiet, BScPhm, MscPhm, MBADirector, Pharmaceutical ServicesCentre for Addiction and Mental HealthCouncil Member, Ontario College of Pharmacists

Jackie Gardner-Nix, MB, BS, PhD, MRCP (UK)Assistant Professor, Dept. Anaesthesia, University of Toronto,Chronic Pain Consultant,Departments of Anaesthesia,St Michael’s Hospital Pain Clinic; and Sunnybrook andWomen’s College Health Sciences Centre Pain Management Programme

Allan S. Gordon, MD, FRCP(C)Associate Professor, University of TorontoNeurologist and DirectorWasser Pain Management CentreMount Sinai Hospital

Douglas Gourlay, MD, FRCP(C), FASAMCentre for Addiction and Mental Health,Wasser Pain Management CentreMount Sinai Hospital

Angela Mailis-Gagnon, MD, MSc, FRCP(C) Director, Comprehensive Pain Program, andSenior Investigator, Krembil Nueroscience CentreToronto Western Hospital Associate Professor, Department of Medicine,Division of Physical Medicine and RehabilitationUniversity of Toronto

Mr. John MacDonaldDBR Canada Inc.Former Public Member of CPSO Council

Eldon Tunks, MD, FRCP(C)Professor Emeritus of Psychiatry, McMaster UniversityPain Management, Chedoke Rehabilitation CentreHamilton Health Sciences, Chedoke siteLiaison from CPSO Task Force on Evidence-BasedRecommendations for Management of Chronic Non-Malignant Pain

CPSO Staff:

Daniel J. Klass MD, FRCP(C)Associate RegistrarDirector, Quality Management, Registration, and Education, CPSOAdjunct Professor, Division of Pulmonary and Critical CareMedicine, Department of Medicine, University of PennsylvaniaSchool of Medicine

Ms. Helen CulbertGovernment Programs Assistant, CPSO

Ms. Margaret LiewProgram AssistantMethadone Program, CPSO

Ms. Raquel Shaw MoxamResearch CoordinatorResearch and Evaluation Department, CPSO

Mr. Wade HillierManager Government Programs, CPSO

Methadone Pain Management: Physician's guidelines Ontario Canada

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