METHADONE GUIDELINES

Facilitated by the College of Physicians and Surgeons of Ontario November 2004

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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 Ontario 80 College Street, Toronto, Ontario, Canada M5G 2E2 Telephone: (416) 967-2661

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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

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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 1

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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/Introduction
In the early 1960’s, Dr. Robert Halliday of British Columbia, and later Drs. Vincent Dole and Marie Nyswander of New York, began using methadone in the treatment of opioid-addicted patients. Methadone, itself a potent opioid, is used to stabilize and maintain opioid-addicted patients due to its slow elimination half-life and less reinforcing character. More recently, methadone has been ‘rediscovered’ as a potent and unique analgesic for use in the management of non-cancer pain. Although methadone is a versatile drug, it has not been demonstrated to be superior to morphine as a first-line opioid in the management of any type of chronic pain, including pain of a neuropathic origin. Under Canadian legislation, methadone is a prohibited substance that may be prescribed only by physicians who have an exemption permitting them to do so. The term ‘exemption’, as it applies in the context of the prescription of methadone, comes from the fact that practitioners who apply to use this otherwise prohibited substance for the treatment of either pain or opioid addiction must be exempted from this federal regulation. For practical purposes, the methadone exemption can be thought of as a license to prescribe methadone for pain management, opioid maintenance, or both indications. The federal Office of Controlled Substances grants all exemptions to prescribe methadone, under section 56 of the Controlled Drugs and Substances Act. The provincial medical authorities (the Colleges of Physicians and Surgeons of each province) have the ability to recommend physicians for an exemption to prescribe methadone for the treatment of opioid dependence. Exemptions to prescribe methadone as an analgesic are granted by the federal authorities without the participation of provincial medical authorities. As of September 2004, a total of 182 Ontario physicians have been granted an exemption to prescribe methadone to treat pain and 266 physicians have been granted an exemption to treat opiate dependent individuals under the Methadone Maintenance Treatment (MMT) Program. Twenty-four physicians have received exemptions to prescribe methadone for both indications. Methadone was first synthesized as an analgesic in the 1940’s and during the next four decades, it was used almost exclusively as a treatment for addiction. Its unique pharmacokinetics were quickly recognized when methadone was compared to other opioids. It is effective in the treatment of addiction because it prevents withdrawal symptoms, diminishes cravings for opioids, and blocks

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the euphoria effect if other opioids are used concurrently. Methadone’s long half-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 analgesic properties and its long elimination half-life makes it very useful in certain pain management situations. Unfortunately, because of the drug’s association with the treatment of addiction, and the complex pharmacokinetic properties of the drug, there has been some confusion about its role in managing pain and uncertainties in the practicalities of prescribing the drug for this purpose.

Scope and Purpose
These guidelines are intended to address these uncertainties and facilitate the use of methadone to treat non-cancer pain in a safe and effective manner. They reflect a general consensus of practice in Ontario for prescribing methadone in the treatment of chronic pain. The target users of these guidelines include any physician with an exemption to prescribe methadone for pain. The guidelines are not intended to substitute for sound clinical judgement. In a specific instance where the individual circumstances of a patient provide clinical justification for deviation from these guidelines, a physician may do so. However, it is expected that the physician will balance the risks and benefits to the patient and document any departure from the guidelines in the patient’s medical record with an indication of the clinical reason(s) for the deviation. Physicians should seek assistance, either formally or informally, in difficult or complex cases, from a pain management specialist who is knowledgeable in the use of methadone. For a complete explanation of the guideline development process, please see Appendix A.

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The Pharmacology of Methadone
Methadone is a potent full mu and delta opioid agonist with good oral bioavailability, and has a long duration of action. The extended elimination half-life (generally greater than 24 hours) is useful to prevent opioid withdrawal symptoms in those who are physiologically dependent on opioids. The duration of action with respect to its pain relieving effect is more modest, however, typically six to eight hours, which often necessitates three or four times daily dosing to treat pain. This is in sharp contrast to the once daily dosing pattern usually 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 may be linked to pain processing and spinal neural plasticity, although its exact role and how it can be manipulated awaits further clarification. Still, it is felt by many to have a significant effect in treating pain, especially neuropathic pain. For various reasons, there is significant individual variability in patient response to methadone, making initiation of therapy and rotation to methadone from other opioids, at times unpredictable. As such, it does require some special care and knowledge in its use. The use of “equivalency tables” to calculate a dose of methadone is unreliable and to be avoided.

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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 the treatment of opioid dependance was transferred to the provinces. The College entered into a formal partnership with the Ministry of Health and Long-Term Care to provide an office-based methadone maintenance treatment program for patients with an opioid addiction. The mandate of the College’s methadone program is to improve the quality and accessibility of methadone maintenance treatment in Ontario. This is accomplished in conjunction with the Centre for Addiction and Mental Health (CAMH) and the Ontario College of Pharmacists (OCP). The profile of methadone maintenance treatment in Ontario has been enhanced through outreach activities and through the recruitment of physicians across the province to prescribe methadone for opioid dependence to address excessively long treatment waiting lists.
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Specific guidelines for MMT1 were revised in October 2001 by the CPSO Methadone Expert Advisory Committee and offer practical information to physicians who prescribe methadone for the treatment of opioid addiction. It is important to remember that the MMT program is well structured and regulated. Patients who meet the criteria for opioid addiction are eligible to obtain a prescription for methadone from a methadone-exempted medical practitioner who is in good standing with the College at the time of application; has completed a minimum of eight hours of approved training; and has observed, for two full days, a physician in an office-based setting with an exemption to prescribe methadone for the treatment of opioid addiction. These patients are registered in a central database at the College as methadone maintenance treatment patients. Initially, patients are monitored closely both for signs of relapse and to encourage any behavioural changes made as a result of treatment. Patient responsibility with the drug is extremely limited in the early phase of treatment. Patients are required to attend daily at a pharmacy where their ingestion of this dose is witnessed. As patients become more stable, in part as evidenced by appropriate urine drug screen results, they are given more responsibility with daily doses of methadone. This graduated responsibility with the drug is commonly referred to as a “carry” or “take-home” dose. Clearly, early in treatment, the ‘locus of control’ as defined by the degree of self control experienced by the patient (compared to that which the system applies to help achieve stability) with respect to his or her responsibility to safely manage his or her use of methadone is largely external to the MMT patient. This gradually moves towards a more shared responsibility as evidence of stability, through ongoing treatment, mounts. This helps to limit the potential for drug misuse, especially diversion.
1. 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 of reinforcement. Psychol Monograph 80:1-28. 3. The American Heritage® Stedman’s Medical Dictionary © 2002, 2001, 1995, Houghton Mifflin Company.

‘Locus of control’2 is in fact a theoretical construct designed to assess a person’s perceived control over his or her behaviour3. For the purpose of these guidelines, ‘locus of control’ refers to the degree to which patients are able to control their use of medications, as compared to external controls placed on them by the health care system. The pharmacist also plays an integral part in the MMT program. The pharmacy dispenses a once-daily unit dose of methadone, usually mixed into 100 ml of an orange flavoured drink. Two important points here are that methadone is not dispensed in a stock solution of fixed concentration and it is mixed with some form of flavouring to reduce the risk of parenteral administration. This is a requirement of the methadone guidelines for the treatment of opioid addiction. In contrast, a formal program does not exist for the use of methadone in the treatment of chronic pain at the physician and pharmacy levels, and methadone
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is regulated no differently at the patient level than any other opioid. As such, patients might attempt to access methadone for the treatment of addiction through the less structured pain management field. Fewer rules and regulations, and less apparent stigma may all contribute to a patient’s desire to access methadone outside the traditional methadone maintenance paradigm. This makes it all the more important for those contemplating prescribing methadone for pain management to understand its use in the field of addiction medicine. Increased availability of methadone through pain management channels may serve to undermine the methadone maintenance program if physicians remain naïve to the dual role of this drug.

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Methadone for Chronic Pain Management
Methadone may have a particularly unique role in pain management on the basis of its activity at the NMDA receptor. As well, its long half-life may help stabilize patients who experience fluctuations in their opioid drug levels and who are developing withdrawal symptoms between doses (also referred to as “withdrawal mediated pain”). It may be particularly useful for the small but important subgroup of pain patients who suffer from addictive disorders, as well as chronic pain. It is, in fact, this effectiveness in both managing pain and opioid addictive disorders which leads naturally to the division of patients into three broad groups4:

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

Group II: Pain patients with past or active substance dependence
Pain patients who have either a past or active history of drug (a substance other than opioids) or alcohol dependence, including problematic use of prescription drugs 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.

4. Gourlay, D., Heit, HA., Almarhezi, A. (March 2005). Universal Precautions in Pain Management: A rational approach to management of chronic pain. Pain Medicine (6):2. 5. Savage, SR. Long-term opioid therapy: assessment of consequences and risks. J. Pain Symptom Manage. 1996. 11:275-286.

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Family history should go back a minimum of two generations to credibly assess risk since alcohol and other drug problems often skip generations. Past drug use histories other than opioids are also significant as risk factors. Although nicotine dependency is acknowledged as a risk factor, its weight must be appropriately considered. This population of patients is more complicated and needs clearer boundary setting around prescribed medications. Most clinicians would endorse the use of carefully set boundaries for the use of opioids, beyond what might be normally used with patients without identified risk (Group I). Although these patients would not meet the criteria for methadone maintenance therapy, they often have risk factors and/or behavioural issues that might move the clinician to include much of the structure developed within MMT programs in managing their chronic pain. There must be a balance between safety and risk of drug misuse on the one hand, and patient convenience and drug effectiveness on the other hand. In most cases, unit dosing, the standard dispensing of each dose individually, will not be suitable for the treatment of chronic pain.

Group III: Pain patients with concurrent opioid addiction
Patients with an opioid addiction who would otherwise qualify for methadone maintenance under the CPSO Methadone Maintenance Treatment guidelines and are suffering from concurrent pain problems. These patients can, and often do, require pain management and some will benefit from the use of chronic opioids. It is the expectation of the College that practitioners will follow the MMT guidelines as much as possible, while managing the patient’s pain. It is important to appreciate that the use of methadone for the treatment of opioid responsive pain will, by necessity, require increased responsibility for this drug by persons who might not be behaviourally stable. Although pain management often necessitates that subsequent doses of the drug be taken throughout the day, it is still important early in therapy to dispense these doses daily, with the ingestion of the first dose of the day being witnessed by a pharmacist or other responsible third party. Applying the CPSO office-based MMT guidelines to the first witnessed dose of each day can still encourage graduated responsibility with this drug. After two months on the program, with evidence of increased stability with respect to illicit drug use, the patient can be given one full day’s methadone (normally three unit doses) for each month of sustained abstinence from the misuse of illicit 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 should be registered with the CPSO in the methadone maintenance program. Patients in this group are ideally managed by, or in consultation with, an addiction medicine specialist knowledgeable in the use of methadone as maintenance therapy for opioid addiction. Due to resource limitations, however, the ideal may not always be available.

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Table 1. Patient Categories for Methadone Management for Pain

Group
Features

I
Pain patients with no identified risk factors for addiction beyond that expected in the general population.

II

III

Pain patients who have either a Patients with an opioid addiction past or active history of drug (to a who would otherwise qualify for substance other than opioids) or methadone maintenance treatalcohol dependence, including ment under the CPSO MMT problematic use of prescription guidelines and are suffering from drugs or abuse as diagnosed in concurrent pain problems. the DSM-IV.

Using Methadone to Treat Pain
It should be noted that these guidelines are not designed to assess who should be given a trial of methadone for pain management, but rather, once the decision has been made to use a trial of methadone for pain management, how to do it safely. Nevertheless, the principles of sound practice in pain management should be followed. The reader is referred to the Evidence-Based Recommendations for Medical Management of Chronic Non-Malignant Pain6 available from the College website at www.cpso.on.ca. Some general principles to consider and document in the management of chronic pain patients follow.

Assessment Phase
The assessment of patients with chronic pain should follow the principles of sound medical practice. The workup includes taking a history, conducting a systems review and a relevant physical examination, and ordering pertinent investigations. Special attention is usually expected in certain areas, such as the patient’s previous therapies and concomitant illness, especially the presence of past or present substance dependence or abuse. Some helpful points to consider include the following:

6. College of Physicians and Surgeons of Ontario. Evidence-Based Recommendations for Medical Management of Chronic NonMalignant Pain. November 2000.

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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 approximately 10% of the general population. The true prevalence of addiction within the chronic pain population is, at the present time unknown, but it is unlikely to be less than that observed in the general population. As such, the likelihood that pain and addiction can coexist in the same patient is not insignificant. The diagnosis of addiction is most commonly made prospectively, over time. Even a previous problem with drug or alcohol use does not, in itself, preclude a successful trial of opioids. While a past history of substance abuse is important, and may increase risk for problematic use of prescription medications in the future, it does not absolutely contraindicate their use. By setting reasonable boundaries for the patient to remain within, it is possible to assess aberrant behaviour in the context of an emerging diagnosis of an addictive disorder. In general, the diagnosis of an addictive disorder is made prospectively, over time. A specific diagnosis should be formulated, if possible; it may be possible only to treat the most likely mechanism of pain (i.e., nociceptive, neuropathic). Some measurement tool to assess function and pain (such as a visual analog or numerical scale) is often very helpful, and can be utilized over time to document the efficacy of treatments employed.

Treatment Phase
This section deals with general considerations in the ongoing management of pain with 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 to safely treat a patient with methadone. Given the regulatory peculiarities of this drug, as well as unique safety concerns, prescriptions to patients who live outside of a physician’s geographical catchment area may be problematic. Each case must 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 geographically remote unless adequate local medical support and supervision is available. A previously agreed upon plan for transfer of care back to the referring physician can be useful to prevent overloading the limited resources of secondary or tertiary consultative care.

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Informed Consent/Treatment Agreements
Informed consent should include a discussion of tolerance and withdrawal, as well as side effects and an outline of expectations. The likelihood of physical dependence and the possibility of developing true addiction, no matter how small, 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 be used to tighten boundaries for patients at risk for drug misuse. While it may not always be necessary to have a signed, written agreement, this can be an effective means of accurately documenting this important part of the medical record. In fact, it has been suggested that a “tripartite treatment agreement” can help to bring the pain specialist and primary care doctors together to improve communication, thus improving patient care7. Treatment agreements should include consent for communicating with all individuals involved in the patient’s care (refer to Appendix E for an example of a treatment agreement).

Monitoring
Opioid therapy in general, and methadone therapy in particular, requires careful and ongoing assessment to reduce risk and improve outcomes. Practitioners should 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-up assessment. Interval dispensing and careful adherence to boundaries are essential components of a safe treatment program. Assessment of the “5-As” should be performed 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 regularly and recorded in the chart as evidence of a successful trial of therapy. (Affect added by E. Covington9).
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 nonmalignant pain: Overcoming 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.

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Specific Cautions
Patients should be cautioned about sedation/impairment of psychomotor function during the titration phase of methadone initiation. Methadone can be lethal to someone naïve to opioid use — proper and secure storage must be discussed. Specific advice regarding the safe storage and use of this drug is expected as part of the treatment plan and should be revisited periodically, as appropriate, during the course of treatment. A locked box to securely store the drug is strongly recommended to reduce the risk of accidental ingestion of a potentially fatal dose of medication by an opioid naïve or intolerant individual. Sedatives, other non-prescribed opioids, and alcohol must be used with extreme caution, if at all. In the absence of other sedating drugs, chronic, stable opioid use has not been shown to adversely affect cognitive function or limit the performance of complex motor tasks such as operating a motor vehicle10. The most common cause of sedation in patients on stable doses of opioids is the effect of concurrent sedative use such as benzodiazepines and alcohol.

The Role of Family and Supportive Others
Family members are always affected when their loved one is ill and they are often involved in the long-term management of a family member with chronic pain. They may provide information on symptoms, response to treatment, and overall patient status, which the patient may be unable or unwilling to give. This information 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 given explicit consent, family members can supply collateral information, which may be crucial to treatment decisions. The family may also provide support and practical advice in the long-term management of chronic pain disorders. In some cases, family members and significant others may be unable to provide a safe and supportive environment to assist in the often complex pharmacotherapy seen in chronic pain management. Although tempting, it may be unwise to try to enlist a significant other in the daily control of prescription medications. Where possible, objective support from knowledgeable professionals such as nurses/pharmacists should be employed.

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

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Misuse/Diversion of Methadone
Any concerns about misuse or diversion of methadone should be followed up carefully. Consultation, and at times joint management with other health professionals knowledgeable in addiction treatment, can be very helpful, although not always readily available. Urine drug screening is becoming a more widely accepted practice in the management of chronic pain with opioids. It should be presented to the patient as an adjunct to treatment rather than as a monitoring tool. Testing must be patient-centred and not designed to “catch” patients who might have chronic pain, as well as an underlying substance use disorder. Having either condition does not rule out the other. Refer to Appendix F and/or the Monograph Urine Drug Testing in Primary Care11, available at www.familydocs.org/UDT.pdf and the reference guide www.familydocs.org/UDT_RefCard.pdf. All laboratory results should be used to open a dialogue with the patient to assist, where necessary, in healthy change. It is important when using urine drug testing to use the results carefully. An unexpected result should be checked with the testing laboratory and with the patient before any decision is made to change the patient’s care. In particular, the absence of a prescribed medication should not be seen as proof of drug diversion. Other reasons for a negative test for a prescribed medication include laboratory error, limits of technology, or the patient overusing the drug and running out in advance of the test.

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Documentation
The importance of accurate and complete documentation cannot be over emphasized. The medical record must clearly reflect the decision-making process that resulted in any given medical outcome. Even if the result was less than optimum, thorough records will protect both the doctor’s and the patient’s interests. Remember, good records demonstrate that a service was provided to the patient and establish that the service provided was medically necessary.

Methadone Dosing in the Management of Pain
The initial titration of methadone begins after the medical assessment has been completed and the decision for a trial of methadone as therapy for pain has been made.

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

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Prescribing and Dispensing General Considerations
As mentioned earlier, under Canadian legislation, methadone is a prohibited substance that may be prescribed only by physicians who have an exemption permitting them to do so. The term ‘exemption’, as it applies in the context of the prescription of methadone, comes from the fact that practitioners who apply to use this otherwise prohibited substance for the treatment of either pain or opioid addiction must be exempted from this federal regulation. For practical purposes, the methadone exemption can be thought of as a license to prescribe methadone for pain management, opioid maintenance, or both indications. Methadone is available in tablets or as a powder, which is dissolved into a solution by the pharmacist prior to dispensing, or as a commercially prepared solution. Methadone maintenance therapy patients are dispensed each dose of methadone individually, diluted in orange juice or another suitable vehicle, a practice sometimes called unit dosing. In contrast, patients being treated for pain with methadone usually have their drug dispensed as a concentrated solution, 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 left largely to the patients themselves. The need for multiple daily dosing, and titration-to-effect within any given day, necessitates the patient taking the dominant role in dosing. In the MMT population, the locus of control, especially early on in therapy, is largely external to the patient and the dominant role in dosing stays with the prescribing physician. Unlike MMT, there are no specific rules governing the use of methadone in the treatment of pain. The notion of carry medication or take-home medication is an artificial construct that has been found to be useful in the safe and effective treatment of persons suffering from opioid addiction. The controlling factor in pain management, unlike in MMT, must reside largely with the patient.

Methadone Availability
As of the writing of this document, a tablet form of methadone has recently been 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 the present time, due to peculiarities in the approved product monograph for the commercially available forms of methadone (Metadol® liquid/methadone tablets), prescribers are advised to carefully read Health Canada’s approved product inserts.
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In the management of pain, oral methadone is generally used in a multiple daily dosing fashion, usually three-times-daily. Although methadone has recently been made available in a tablet form, a uniform concentration of 5 or 10 mg/ml as a solution is currently the preferred form. Common concentrations for methadone solution are 5 mg/ml (compounded by the pharmacist) or more recently, as a commercially prepared 1mg/ml or 10 mg/ml stock solution. For patient safety, a graduated oral syringe must be used to measure out individual doses, which should be specified on the prescription. “Use as directed” is strongly discouraged without some limits being stated on the order. Once daily dosing of methadone is not normally adequate for the treatment of pain. The duration of action of methadone when prescribed as an analgesic is shorter than the duration of action when prescribed as maintenance therapy of opioid addiction. When prescribing methadone in tablet/capsule form, care should be exercised to select patients with low risk of drug diversion/misuse.

G U I D E L I N E S

Table 2. Methadone Dosing Options Available
Form
Unit Dose Liquid

Clinical Indication
Group III,

Available Doses

Pro
Safest for physician to titrate. Large volume has reduced abuse liability. Easiest to control in unstable patient.

Con
Difficult to give 3 doses per day beyond 1 week at a time. Difficult for patient to titrate dose. Bitter taste, and limited shelflife due to flavoured additive. Storage/handling of drug can be difficult. Pure aqueous form easiest to abuse via injection.

Variable concentraUnstable Group tion in 100 ml volume II

Liquid Concentrate (*1mg/ml, 5mg/ml, *10mg/ml in aqueous) Tablets

Group I, Highly Stable Group II

Specific stock concentration

Easiest form for patient to titrate up and down, easily stored, a familiar form to both patients and pharmacists. If compounded with flavoured crystals, may reduce parenteral abuse liability.

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, diverted/trafficked. Easily converted to parenteral route for abuse. Higher cost.

*commercially available

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G U I D E L I N E S
Unfortunately, not all pharmacists choose to dispense methadone, even though at the present time, there are no specific regulations that limit their ability to stock and dispense this drug. In some locations, pharmacy staff may only be familiar with the use of methadone in the treatment of opioid addiction. It is important to clarify treatment goals with the pharmacist and to discuss any concerns they may have related to dispensing methadone for the treatment of chronic pain.

Opioid Naïve Patients
(May also apply to patients on relatively small doses of opioids or who have been using opioids erratically for whatever reason) The initial prescription generally does not exceed 15-30 mg/day for the first three days, but may be as low as 1-2 mg every 12 hours in older or debilitated patients. Prescription Example: Methadone solution X mg/ml Take X mg (Y ml) PO every 4 hours, to a maximum of 30 mg daily (6 ml) for three days, then as directed to a maximum of 45 mg/day divided in three times daily doses. M: yyy ml It is important that the quantity of drug to be dispensed is unambiguously stated in the order. Since the concentration of stock solution has been specified, it is sufficient to state the volume of stock solution alone to be dispensed. For added security, it may be useful to also specify the volume to be dispensed written in words. On the directions to the patient, the dose or range of dose should be specified as both a volume and weight. (Refer to Appendix G for an example of a prescription.) It is important to prescribe sufficient medication to allow the patient to titrate the dose upward, according to a previously agreed upon schedule. In some patients, particularly the elderly or infirm, very small doses of methadone may be quite effective and generally better tolerated. It is important to remember that the dose can always be increased. ‘Start low, go slow’ is wise advice. Due to gradual accumulation to a steady state, methadone’s effectiveness as an analgesic may improve gradually after a dose increase, for up to four or five days. Experience gained through methadone maintenance programs has shown that most 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 after starting treatment or raising a previously stable dose. Death by accumulated toxicity may result from increasing a dose before the full effect of the current dose is known.
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Practitioners must be careful when prescribing methadone solutions. It is recommended that to avoid any confusion, a physician specify both the milligram dose along with the volume of solution to be taken at any given time. Confusion related to ambiguous orders can lead to tragic outcomes, especially early on in treatment. 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 often is seen in accidental ingestion in an intolerant individual, or in previously tolerant users who have had interruptions in their use of methadone. 2. Accumulated Toxicity: Doses accumulate over several days and toxicity develops. Today’s dose isn’t lethal, tomorrow’s dose isn’t lethal, but the entire third days dose plus half of the second and one quarter of the first dose accumulate to a lethal level. This is most commonly seen in overly aggressive initiation protocols. 3. Drug-Drug Interactions: Methadone can be lethal when used with sedatives, other opioids or alcohol. In these cases, neither methadone nor the sedative drug alone is lethal, but in combination, death results. This is most commonly seen in the ‘stable’ methadone patient who periodically abuses sedative drugs such as benzodiazepines and/or alcohol. Drugs, which inhibit certain enzymes within the cytochrome system, can also result in methadone accumulation and toxicity.

G U I D E L I N E S

Changing to Methadone
(Switching from another opioid to methadone) For most patients, methadone is not the first choice of opioid or the first opioid used to manage pain. Frequently, a practitioner may want to rotate a patient from another opioid onto methadone. Although there are several published tables of opioid equivalency, it is important to realize that these tables refer to single-dose situations. There is no reliable conversion factor that can be applied when converting from any other opioid onto methadone. Once again, “start low, go slow” is the safest course to follow, especially in the context of the outpatient setting. More aggressive titration can be safely conducted in the inpatient setting where peak dose effects can be monitored and doses adjusted accordingly. When switching to methadone, it is important to assume that any new side effect related to sedation or respiratory depression is due to methadone and not to the opioid that the patient was previously taking. When there are signs of
12. Gourlay, D., Heit, HA., Letter to the Editor, March 2004. Vol. 5 Iss.1, Pain Medicine, 109-110.

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sedation, hold the next dose of methadone and consider reducing subsequent doses. To overestimate tolerance exposes the patient to the risks of inadvertent toxicity, and certainly increases the risk of the more common problem of associated accumulated toxicity because of the relatively long elimination halflife of methadone. Similarly, to underestimate tolerance puts the patient at increased risk for experiencing continued and possibly worsening pain. There are various methods to transition from one opioid to another, including methadone. One common method is to reduce the first opioid by one-third every day, while titrating upward the second opioid. In those cases where the practitioner believes the pain is likely to be opioid responsive and where significant tolerance to other full mu agonists such as morphine or hydromorphone has developed, it may be reasonable to discontinue the first agent and institute methadone in three-times-per-day dosing, titrating upwards with caution. After an initial trial period, the patient normally increases the dose, on their own initiative, with guidance by the prescriber who is following approved medication standards and is accurately documenting this in the record. During this transitional period, practitioners are reminded of the importance of frequent assessments of patients. In any opioid rotation, sedation should always be assumed to be due to the effects of the new opioid NOT the additive effects of the drug being tapered. If sedation occurs during the switchover, slow down or stop the methadone titration until the drowsiness clears. Unlike truly slowly eliminated agents like methadone, controlled release drug delivery systems do not alter the rate of drug accumulation.

Withdrawal Mediated Pain
In those patients who are managed for prolonged periods with short-acting, immediate release agents, pain may actually cycle in response to fluctuating and inadequate opioid levels. Many patients suffer from problems related to the chronic use of immediate release short-acting opioids. This is particularly well seen in the case of worsening morning pain, with the chronic use of acetaminophen with codeine or oxycodone. Due in part to the development of tolerance or accelerated drug metabolism, these drugs may only be active for two to three hours after ingestion and during periods where they are not taken with this frequency, such as overnight, symptoms of early withdrawal may develop. By the next morning, the patient’s pain is often more generalized; sometimes described as ‘feeling like a truck has hit them’. This can sometimes be relieved with 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 daily dosing of a truly long-acting opioid like methadone, until there is no evidence of opioid withdrawal over the 24 hour period, may be helpful to determine what component of the pain is in fact withdrawal mediated. Immediate release agents tend to be highly reinforcing due in part to the rapid onset to peak effects and the precipitous offset seen at the end of the effective duration of action. Even in the absence of a coexisting addictive disorder, aberrant dosing frequency (>6 times per day) may be seen, due to the diminished effective duration of action seen over time with the short-acting drug. When managing withdrawal mediated pain, one approach is to discontinue the short-acting opioid while methadone is added, in a once daily morning dosing regimen as is routine in methadone maintenance therapy. The methadone dose is increased until there is no evidence of withdrawal in the period prior to the first dose of the morning. After this “opioid debt” is corrected and any withdrawal component of the pain is removed, in patients with opioid responsive pain, there may be a step-wise relief of pain lasting 6-8 hours after each dose. At this point, the dose could be divided into three and increased no more than 10 – 20 mg every three days during the initiation phase (first 1-2 weeks). After this, dose increases can be made more quickly, limited only by side-effects or acceptable relief of pain. After the patient is stabilized, in terms of opioid medication, it may be useful to try previously ineffective agents such as NSAIDs (in patients without contraindications) or other adjuvant medications, such as tricyclic antidepressants or anticonvulsants.

G U I D E L I N E S

Using Methadone to Assess Opioid Responsiveness
Methadone is a compound that is unique, in that its elimination half-life of approximately 24 hours (which governs its use in MMT) and its duration of action as an analgesic (approximately 6-8 hours) are markedly different. This property can be used to assist in assessing opioid responsiveness. In some situations, where the practitioner is concerned about the value of further increases in a three-times-daily dosing regimen with methadone, the mid-day-dose can be split temporarily between the morning and evening doses. This represents a 50% increase in the unit dose of drug in a twice-daily dosing schedule. Given the differences between the duration of action of methadone as an analgesic and when used in MMT, this unit dose increase may be expected to result in an improvement in opioid responsive pain, but only for a duration of 6-8 hours. If there is endorsement of improvement, resumption of a three or four times daily dosing interval with titration upward to effect is recommended.
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G U I D E L I N E S
Failure to see improvement around this unit dose increase, especially in the context of the patient’s persistent concern that they “no longer feel the drug working” should lead to a reevaluation of the current treatment strategy and the appropriateness of continuing with methadone. Assessing Opioid Responsiveness: A patient on 50 mg methadone, three times daily for pain complains of “no longer feeling the drug working”. Redistributing the total 24-hour dose of 150 mg into a 75 mg twice-daily dosing schedule yields a reduction of pain scores by 50%, but only for 6-8 hours around each dose. This represents a unit dose related increase in analgesia of appropriate duration for methadone. In this case, returning to a three or even four-times daily dose with careful titration upward is recommended. Persistent claims of “not feeling the effect” despite the 50% increase in the unit doses of methadone argue against the continued use of this drug, and points to the need for reevaluation of the need for methadone in particular and of opioids in general. It is always important to regularly assess opioid responsiveness. In those patients whose ongoing opioid use serves largely to maintain adequate basal opioid levels rather than to effect analgesia, careful discontinuation of opioid therapy may actually lead to improvement of previously unresponsive pain conditions rather than a worsening of the pain. Inappropriate rapid tapering of opioids may result in a worsening of any pain condition, even those conditions that are not benefiting from ongoing opioid therapy.

Special Considerations
Optimal Dose
Despite years of experience with methadone, there is tremendous variability in the initiation and stabilization dose as evidenced by a careful review of the use of methadone in chronic non-cancer pain. Given the kinetic peculiarities of this drug, careful titration to effect is recommended. In fact, the optimal methadone dose is that dose which relieves pain symptoms, without sedation or other significant side effects. As with all opioids there is a wide variability in individual response to methadone, another reason to consider initiating therapy with small doses. With experience, the optimal dose for the majority of patients can be established within two to six weeks of methadone initiation. Doses above 200 mg per day13 are considered to be in the “high range”. Although in some situations doses above this level may be necessary, the physician should reassess the patient. If the physician has difficulty in stabilizing the patient’s dose above this level, it is recommended that a second opinion or consultation be sought.

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 immunodeficiency virus and treated with methadone. J. Cardiol. 15-Oct-2003; 92(8): 995-997.

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Doses above 200 mg per day are termed in the “high range” and have been reported to be associated with increased risk of malignant dysrhythmias such as Torsades de Pointes. In methadone maintenance treatment literature, 120 mg is considered in the “high range.” For higher doses of methadone, there is some evidence that there may be a doserelated prolongation of the corrected QT interval, which has been reported as leading to potentially fatal cardiac rhythm disturbances (i.e., Torsades de Pointes)14. This is especially true for those patients with other factors known to increase QTc intervals. What actually constitutes a “high dose” of a drug is open to much interpretation and debate. While the number cited in this document is 200 mg per day, some literature refers to a high dose in the order of 300 mg per day. Practitioners are advised to be cautious with doses in excess of 200 mg per day. A baseline ECG may be useful in those patients who have reached daily doses in excess of 200 mg per day. Those patients found to have prolonged corrected QT intervals should be referred for cardiology consultation. In some cases, the dose of methadone may need to be reduced or discontinued altogether.

G U I D E L I N E S

Vomited Doses
Methadone is rapidly absorbed from the upper GI tract. Given the inability to completely empty the stomach even with forceful emesis, the risk of replacing vomited doses of methadone is that of accumulated toxicity. Since no more than 60% of stomach contents can be cleared through even vigorous vomiting, repeated replacement of lost doses can result in significant accumulation. The underlying cause of the vomiting should always be sought. Risk of emesis can be reduced by encouraging the patient to drink smaller quantities over time thereby reducing the risk of complete dose replacement. Whenever emesis persists, an underlying cause should be sought. In women of reproductive age, pregnancy must be ruled out. Persistent use of antiemetic agents such as diphenhydramine or prochlorperazine is not recommended due to the sedative effects of these drugs. A common replacement strategy borrowed from the MMT literature is to replace as follows: emesis within 15 minutes of ingestion should be replaced completely, between 15 and 30 minutes, 50% replacement is recommended, after 30 minutes, absorption is essentially complete and the patient can be reassured that the dose need not be replaced.
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):501504.

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G U I D E L I N E S

Missed Doses and Loss of Tolerance
A clinically significant loss of tolerance to opioids may occur as quickly as three days without methadone. For this reason, after a period of three days abstinence, it is recommended that the physician advise the patient to reduce the total daily methadone dose by 50% to ensure any loss of tolerance does not result in a “single-dose” overdose of methadone. After tolerance to that first dose of methadone is demonstrated, the dose can be rapidly increased over a period of days to the previous dose for that person. After missing five or more days of methadone, the body has essentially eliminated the drug, and so the most prudent course is to restart methadone at 30 mg or less as a total daily dose. After assessing the response to that initial dose, and continuing to monitor over a minimum of three days to establish the accumulated response, the dose may be safely increased relatively quickly toward the previous stable dose of methadone. From a safety point of view, missing one or two doses of methadone is unlikely to lead to diminished opioid tolerance. It is important to remember that even relatively large doses of an opioid other than methadone may not equate to a large dose of methadone due to incomplete cross-tolerance between drugs. It can be helpful to examine the reasons for irregular use of methadone since this may yield valuable information about the patient’s lack of response to treatment. Cross-tolerance to other opioids is often incomplete and unpredictable. The use of equivalency tables, especially with respect to methadone, can be misleading and lead to significant morbidity and mortality, even in the apparently highly tolerant opioid user.

Methadone Drug Interactions
Methadone is metabolized principally through the CYP 450 iso enzyme system. In particular, 3A and 2D pathways are implicated. Thus, agents that either induce these enzymes or inhibit their activity can adversely affect the half-life of methadone and influence the stability of a patient on methadone. As an example, consider the implications of managing the methadone dose of a patient who is being treated with the potent 3A4 inducer, carbamazepine (Tegretol®). Because enzyme activity is increased due to the presence of carbamazepine, the effective half-life of methadone may be reduced to a few hours and frequent multiple daily dosing may be needed to achieve stable methadone levels. If the carbamazepine is stopped, the metabolism of methadone will be reduced and the blood levels of methadone will rise, risking toxicity. Likewise, the discontinuation of a potent 3A4 inhibitor, such as fluvoxamine (Luvox®), can lead to unexpected opioid withdrawal or loss of pain control, 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 drug interactions are theoretically possible, they may not always be clinically relevant in any individual patient. Due to CYP 450 3A4 enzyme inhibition, patients must be cautioned against mixing methadone in grapefruit juice. One particularly useful Internet resource is www.drug-interactions.com that provides both a clinical and research-oriented table of substrates, inducers and inhibitors for commonly prescribed drugs, including methadone. Another useful resource for methadone drug interactions is www.atforum.com. In some cases, it is not the addition of a drug that leads to a change in clinical status due to drug interactions, but rather, the discontinuation of a potent enzyme inducer or inhibitor that can result in clinically significant overdose or withdrawal, respectively due to changes in serum drug levels. Recently, some practitioners are trying to combine two or more different opioids to improve side-effect profile or to augment analgesic effect. At the present time, this practice may be complicated, controversial and not clearly supported in the pain literature. Small doses of methadone have been reported, anecdotally, to reduce morphine tolerance. Consultation with a practitioner knowledgeable in this practice is strongly recommended before proceeding along this course.

G U I D E L I N E S

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 the context of chronic pain management with opioids. A detailed examination of this topic is beyond the scope of these guidelines but several key points will be explored in the following section. In general, one of the undesirable effects of chronic opioid therapy is a lowering of pain threshold15. One proposed mechanism is down regulation of opioid receptors due to chronic agonist exposure. Another mechanism may be the secretion of certain “anti-opioid” neurotransmitters in the central nervous system pain pathways. The diminished receptor activity, coupled with suppression of endogenous opioid levels 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 decrease in pain tolerance is accepted as a reasonable trade in the cost-benefit assessment,

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.

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G U I D E L I N E S
when the overall complaint of chronic pain is improved. It does, however, make acute pain management more challenging. When managing acute pain, chronic opioid users will generally need opioids in higher doses and will need them dosed more frequently when compared to their opioid naïve counterparts. It should also be assumed that their previous daily opioid dose will offer no analgesic effect in the management of acute pain. Inadequate maintenance of previous opioid levels in an opioid dependent pain patient can lead to exacerbations, in both their acute and chronic pain. The role of short-acting, immediate release opioids in the management of chronic pain is controversial. While immediate-release/short-acting agents are necessary for management of acute pain, the mainstay of chronic therapy should be either controlled-release preparations of short-acting agents or truly long-acting opioids, such as methadone. While the short-term use of immediate release agents, such as oxycodone, either for breakthrough pain management or for an acute situation is acceptable, there should not be an over reliance upon these agents in managing chronic pain over the longer term. It is important in the context of acute pain management in the opioid dependent patient to maintain the previous daily opioid levels. Inadequate replacement of the patient’s previous daily opioid requirements may result in an “opioid debt” which could frustrate any attempts at management of acute pain. Chronic opioid users usually require increasingly more frequent dosing with short-acting opioids to manage acute pain. Again, the use of equivalency tables can be very misleading. Dosing is to effect.

Obtaining a Methadone Exemption
In Ontario, physicians who wish to use methadone for the treatment of chronic pain must apply for an exemption from the Office of Controlled Substances, Health Canada under section 56 of the Controlled Drugs and Substances Act. A written application is required, which indicates the practitioner’s desire to use methadone in the treatment of pain. In the absence of any restrictions imposed by the College, this authorization will be granted. At the present time, no additional training is required by Health Canada or the CPSO to obtain this exemption. The exemption to prescribe methadone for the treatment of chronic pain must be obtained separate from any other exemption, including the exemption to prescribe methadone for the treatment of opioid addiction. To obtain an exemption for the use of methadone in the treatment of opioid addiction, details are available from the College of Physicians and Surgeons in each province.

Contact Health Canada for more information on obtaining a methadone exemption by calling the Office of Controlled Substances, Methadone Program at (613) 946-5139, or by fax at (613) 952-2196.

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The Pharmacist and Methadone Dispensing for Pain Management
The Standards of Practice for Pharmacists16, developed by the Ontario College of Pharmacists (OCP) sets forth the standards that all pharmacists are held to. These standards cover the full spectrum of practice issues, including the provision of patient-focused care; compliance with legal requirements and ethical principles; provision of drug and practice-based information to achieve safe and effective care; ongoing dialogue with patients and care providers; and pharmacy operations and management with the goal of optimizing patient care and inter-professional relations. Pharmacists are always an integral part of the treatment team but they assume a more evident role in monitoring patient response to therapy when they dispense methadone. In many ways, methadone maintenance therapy for the treatment of opioid addiction is a model of patient care in which the pharmacist and physician work as a team on an ongoing basis. Although methadone use is strictly controlled when used to treat opioid addiction, its use in managing pain will be much more the responsibility of and controlled by the patient. Pharmacists whose experience is based on treating the opioid-addicted patient may find marked differences in the way methadone is handled in the pain patient. As a result, collaboration with the prescribing physician should take place before dispensing begins and, on an ongoing basis during therapy. This collaboration is essential, not only for dispensing and labelling instructions, but to involve the pharmacist in the care of the patient, consistent with the OCP Standards of Practice. Physicians should be aware that there are differences in Ontario Drug Benefit (ODB) coverage when methadone is prescribed for pain. Whereas methadone compounded by the pharmacist for MMT is covered as a compounded product under the ODB, neither the commercially available tablets nor solutions prescribed for pain are covered. Coverage must be requested through the Independent Clinical Review or Section 8 process, whereby the physician outlines the reasons for the request. Decisions regarding coverage may take several weeks. In this regard, physicians and pharmacists must work closely to ensure that there is neither any undue delay in commencing treatment, nor gap in treatment related to billing issues. The pharmacist may provide crucial information about the patient based on his or her experience with that individual, and physicians should welcome such observations.

G U I D E L I N E S

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

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G U I D E L I N E S
In general, pharmacists will: • Advise the OCP that they are dispensing methadone and inform the OCP of their 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 for the use of methadone in the treatment of pain. • Ensure that there is an agreement in place with the patient consenting to the sharing of information between physicians and pharmacists with respect to matters related to pain management. Some specific ways that methadone use for pain management will differ from the pharmacist’s experience with methadone in the addicted population will include the following: • Methadone may be dispensed in an aqueous form or as tablets rather than diluted 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 dispensed 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 their prescriptions. Pain patients may have a small amount of their prescription left over. All of these differences may or may not be a part of any patient’s treatment. In keeping with the OCP Standards of Practice, pharmacists should feel comfortable contacting the prescribing physician to prevent any confusion about the 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 switched from another opioid analgesic to methadone. Due to the highly variable nature of methadone equivalency, it may be necessary for the pharmacist to discuss conversion doses with the prescriber, if there is any doubt in the pharmacists mind as to the safety of the ordered dose.
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• Confirm the current dosing schedule and amount to be dispensed. Given the expectation that patients will appropriately titrate their dose, the actual prescribed dose and the dosing schedule adopted by the patient may be different. Significant departure from the written order should be clarified with the prescriber. • Monitor the efficacy of methadone (i.e., assisting in pain assessment, reporting observations to physician) and safety (i.e., identifying emerging adverse drug effects, aberrant behaviour or misuse/diversion). • Monitor for drug interactions and consult with physicians where dosage adjustments 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 from one setting to another (i.e., confirm current dose, dosing and dispensing interval, concurrent medications, etc.). In the management of chronic pain, patients will frequently vary their daily dose of drug taken. In this context, it is important to compare the pharmacist’s recorded dosing schedule with the patients “actual” pattern of use, including time and quantity of last dose and when concerned, inform the prescriber. Pharmacists play a fundamental role in patient education and nowhere is this function more crucial than in the use of methadone for the management of pain or addiction. Examples include: • Providing specific instructions about security and safety. • Educating the patient, paying special attention to dosing. The pharmacist must confirm that the patient understands how to self-administer the correct dose and, where indicated, how to titrate the dose according to the physician’s directions. Where multiple doses are ordered, the pharmacist must provide the patient with an appropriate measuring device (i.e., measuring syringe), of the appropriate capacity and accuracy to deliver the dose prescribed, and provide instructions 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; and reinforcing instructions with respect to dosing, storage and security. When there is any interruption in dosing, the pharmacist must notify the prescriber, as well as be able to advise the patient, where appropriate, of the need for cautious reintroduction of this drug.
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G U I D E L I N E S
When there are changes in the dose or dose frequency, the physician, where possible, should communicate this to the pharmacist, either verbally or by a notation on the prescription. Missing one or two doses of methadone is unlikely to result in clinically significant changes in blood levels or tolerance. In all cases, the reason for missed doses should be sought and where appropriate, the patient should be counselled regarding the effective use of this medication. Practical considerations in the handling of methadone at the pharmacy are more completely covered in the Ontario College of Pharmacists’ MMT guidelines. Again, these are considerations within the context of methadone maintenance therapy programs, and while there may be overlap, there are considerable differences 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 compounding stock solutions of methadone is documented. • Keeping a perpetual inventory system where the disposition of stock solution is documented. • The requirements for appropriate weighing devices and dosage measuring devices. • 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 when methadone is prescribed and should be encouraged. Pharmacist feedback on patient behaviour, the pattern of medication use, and general health status may assume a greater importance with this patient population. Groups I, II, and III described in an earlier section (see section Methadone for Chronic Pain Management) involve different levels of structure and support. It is important to realize that in many ways the groupings are artificial and arbitrary; a patient may move from Group II to Group III and back again, over time. The pharmacist may be the first member of the health care team to recognize such a change in status and should communicate such information to the attending physician. Physicians must be aware of the importance of this information, and communication and collaboration between pharmacist and physician should be collegial and ongoing.

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Urine Drug Testing
At 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 the workplace or in drug testing of athletes. In the clinical context, however, urine drug testing is playing an increasingly valuable role in the clinical management of 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 of behavioural change, maintenance of healthy changes already made, as well as the early diagnosis of substance use disorders, are all positive roles for urine drug testing. UDT should not be used to “catch” patients nor should it be the final word on the detection of drug diversion. It is important to approach clinical drug testing from a patient-centred perspective. In particular, drug-test results can play a valuable role in helping patients maintain healthy behavioural change. It can be used as a tool for advocating on behalf of the patient, as well as assisting with the early identification of potentially treatable concurrent disorders, such as addiction. It is not particularly useful as a means of assessing medication compliance because a variety of reasons can explain an apparent negative drug-test result for a prescribed drug such as methadone. Results should always be used in a supportive fashion that leads to improved patient care. Urine drug tests that are positive for illicit substances or substances not prescribed can help identify undiagnosed substance use problems, but in no way should they be seen to diminish the patient’s claims of pain. Pain management is often complex and certainly patients may suffer from more than one treatable condition at a time. The publication Urine Drug Testing in Primary Care: Dispelling the Myths and Designing Strategies provides a more complete discussion of the role of urine drug testing and its practical application, and can be viewed on-line at www.familydocs.org/UDT.pdf.

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Methadone Withdrawal
When a patient is being taken off methadone, the very long elimination half-life of this drug must be considered. Rapid reduction or abrupt discontinuation of methadone may lead to a classic opioid withdrawal syndrome consisting of some or 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 those patients suffering from chronic pain syndromes. In part due to methadone’s long elimination half-life, some patients can continue to suffer withdrawal symptoms weeks to months after discontinuing this drug. Patients are tapered from methadone as a result of a number of factors and methods tend to be categorized as either “therapeutic” or “administrative” tapers.

Therapeutic Taper
In a therapeutic taper, the physician and patient have made the decision to lower or discontinue the use of methadone. Resolution of the underlying painful condition, intolerable side effects, inadequate analgesic effect, failure to improve quality of life despite an aggressive trial of opioid therapy, or deteriorating function are common reasons to consider a therapeutic taper. Arbitrary opioid levels do not measure success. Therapeutic tapers can be slow or fast but should be conducted in a humane fashion as to minimize severe withdrawal symptoms, if possible. One common taper schedule is to reduce the dose by approximately 10% of the initial dose every 2-4 weeks until the final 20-30% at which point the dose is decreased by 5% every 4-8 weeks until finished. This schedule recognizes the fact that the frequent, large dose reductions that are tolerated at the beginning of a taper may not be well tolerated at the end. To effect a more rapid taper, the average elimination half-life kinetics of methadone 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 in less than one month. Assuming a 24-hour half-life, three days represents 87.5% steady state; five days represents steady state. A rapid taper risks precipitating severe withdrawal symptoms. Increased pain may be the dominant complaint with too rapid a taper. Holding the taper at the current dose or increasing the dose to the previously tolerated level will usually resolve this situation. It is unfortunate that the often dramatic improvement in pain relief that is experienced when the dose is adjusted back upwards is sometimes attributed to the analgesic properties of the drug when, in fact, it may be due to the relief of withdrawal mediated pain which has appeared as the dose was reduced during the taper. This common mistake can trap both the patient and the physician in an opioid-based treatment paradigm. On the other hand, a temporary increase in pain is common in the first 1-2 weeks of opioid withdrawal but may decrease afterwards. It is important to avoid substituting other drugs, including other opioids, if the goal of the taper is to reduce or discontinue the drug. In particular, resuming previously misused agents, such as immediate release oxycodone preparations, is to be avoided. Overly aggressive tapering may lead to an opioid debt which will likely exacerbate any painful condition. It is sometimes useful, in the absence of any contraindication, to prescribe medications 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 four times a day), an anti-inflammatory agent, and an antidiarrheal such as loperamide for the 1-2 weeks commonly associated with the worst symptoms of opioid withdrawal. When prescribing clonidine, the first dose is best administered at bedtime to avoid the risk of orthostatic hypotension. When used in excess of .4 mg/day or for longer than 1 week, the drug should not be abruptly discontinued due to the risk of rebound hypertension.

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Administrative Taper
In rare circumstances, the decision to terminate the use of methadone is unilaterally made, most often by the prescriber. The reasons for an administrative taper are limited and commonly due to severe behavioural problems by the patient. Staff or patient safety concerns might necessitate involuntary termination of methadone treatment. It must be remembered that involuntary discontinuation of methadone can, for some people, lead to
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significant harm due to aberrant and sometimes illegal activity to cope with opioid withdrawal symptoms. Referral, where possible, to an opioid addiction treatment program is strongly recommended as an alternative to abrupt discontinuation of this drug. The reasons for methadone discontinuation, as well as any other recommendations made to the patient, should be carefully documented in the patient’s chart. In some cases, the physician’s decision to stop prescribing methadone will lead the patient to terminate the doctor-patient relationship. If the termination is the patient’s wish, the physician will have no further responsibilities toward that patient (beyond transferring the medical record if that should be requested). In some cases, however, the physician’s decision to stop prescribing methadone will cause irreparable damage to the doctor-patient relationship, leading the physician to discontinue the relationship. In this situation, the physician should ensure that he or she adheres to the CPSO policy Ending the Physician-Patient Relationship, which includes the expectation that the physician will provide the patient with reasonable notice to find a new doctor and, in the interim, ensure that the patient is not acutely in need of immediate care. In many cases, a formal treatment agreement can be added to explicitly outline the treatment team’s expectations of the patient, as well as what the patient can expect of the treatment team. Common to virtually all treatment agreements is the requirement that the patient does not obtain opioids from other than the designated prescriber; the patient select and use only one pharmacy for prescription medications; and that lost or stolen medications will not normally be replaced. More recently, treatment agreements have begun to include specifics about urine drug testing, and consent to speak with any and all health care professionals who have been involved in the patient’s care as a condition of initiation or continuation on strong opioids. A sample treatment agreement is included in Appendix E.

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Managing Patients with Pain and Addictive Disorders
Although treating the majority of chronic pain patients will be straightforward, without the complications of an active or past history of a substance use disorder, some will not. Unfortunately, it is impossible to determine in advance, with any certainty, those patients who will ultimately exhibit behavioural problems. The diagnosis of addiction is usually made prospectively, over time. Even with a careful personal and family history around drug and alcohol use, it is only with time that the behavioural components of an addictive disorder will become evident. In fact, some patients who appear initially to be Group I, with no obvious increased risk of addiction, may better fit Group II, as they become more comfortable disclosing their past or current drug use. Sometimes it is only by careful assessment of behavioural markers such as early prescription refills, double-doctoring or inappropriate urine toxicology results that it becomes evident that there is at least problematic, if not addictive use of medications or illicit drugs. With this information in hand, the patient may be referred to a health professional with more resources and experience in the assessment and treatment of concurrent substance use disorders. The diagnosis of addiction and substance abuse in the pain population is difficult, even for those with a special interest in this problem. One of the major stumbling blocks to accurate diagnosis is the over reliance on the DSM-IV criteria for Substance Dependence. The presence of a concurrent addictive disorder does not, in itself, diminish the validity of the patient’s complaints of pain. It does increase the risk around appropriate management with pharmaceutical agents, including opioids. The DSM-IV, as a tool for diagnosing opioid addiction within the pain population, is inadequate. The terms addiction and dependence are used interchangeably, which is inappropriate. Also, by over reliance on the physical manifestations of chronic opioid use (withdrawal and tolerance) in the diagnosis of addiction, the DSM-IV is unreliable in the chronic pain population. Despite the fact that the preamble to the DSM-IV diagnosis of substance dependence specifies a “maladaptive” pattern of use, it remains up to the clinician to decide what use is maladaptive. The emergence of unified definitions for addiction, dependence and tolerance (see Appendix H) will help ensure that terms, such as addiction and dependence, are not used interchangeably. At the present time, it is often difficult to obtain consultation with a substance abuse professional. The following suggestions can be useful in setting tighter limits 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 all patients, from the outset. For those who have both pain and opioid addictive disorders, it is strongly recommended to get this agreement in writing. Failure to comply with a reasonable treatment agreement should be seen as a problem requiring further investigation, not as evidence of fraud or deception. As well, it is essential to be able to contact patients’ present or previous treating physicians, whenever necessary. A patient who refuses to allow contact with past or present treatment providers is severely hampering the physician’s ability to deliver safe and effective care. Such refusal should be considered a relative contraindication to initiation or continuation of chronic opioid therapy. Some individuals continually run out of medications early. While it may be that this represents under medication, it may also represent aberrant behaviour suggestive of addiction or drug misuse. In this situation, the use of interval or contingency dispensing may be used to clarify this point. By reducing the dispensing interval to weekly, or even more frequently, a patient who is struggling with medication control will be prevented from “borrowing medication from tomorrow to pay for today”. Even if the patient is only seen on a monthly basis, it is often useful to have patients experiencing this problem pick up their medications on a weekly or twice monthly basis (interval dispensing). Sometimes, placing conditions on the ongoing receipt of medication can be a useful tool to help patients stay within agreed upon limits. In the case of transdermal analgesic products, which can be misused by leaving old patches on when new ones are applied, making the receipt of new patches “contingent” on the return of spent patches to the pharmacy can greatly assist in re-establishing patient control with respect to usage (contingency dispensing). Interval/contingency dispensing of medications can be a very useful technique to help patients stay within prescribed boundaries. Changing the dispensing interval from monthly to weekly can assist in uncovering problematic behaviours, such as bingeing or inappropriate dose escalation. In Ontario, the Addiction Clinical Consultation Service operated by the Centre for Addiction and Mental Health can be consulted at 1 (888) 720-2227 on the general issues around management of patients who may have substance-related problems. Patients who continuously run out early, rely heavily on immediate-release, short-acting opioids, or who frequently have their medications lost or stolen should be seen as probable Group II or Group III patients and should be referred for assessment by a health professional knowledgeable in addiction medicine. 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 to improve patient care and reduce the risk of drug misuse or diversion. Common drugs that can be problematic for some patients are the sedative class of drugs. The main drugs are alcohol and benzodiazepines, but over-the-counter medications such as antiemetics or antihistamines can also cause problems. Impairment due to concurrent use of sedatives is more commonly the explanation for episodic intoxication in the patient who is on an apparently stable dose of opioid. It is not uncommon for some patients to decompensate when their access to medications is altered. For example, a patient who is normally given a onemonth supply of medication may consume significantly more of the medication at the beginning of the month, relying on substitutes such as acetaminophen analgesics containing codeine to minimize the discomfort of withdrawal seen later in the month. By providing only a one-week supply of medication at a time, a patient who binges will run out much earlier than usual, thus helping the treatment team to identify a pattern of medication overuse. This will often necessitate a call to the doctor’s office for early release of medication. Fully explore this with the patient at the next visit. Again, this method does not serve to dismiss any complaint of pain, but rather can be a motivational tool to move the patient along the readiness to change model into a place where they can be properly assessed for a drug-related problem. Some patients will welcome the opportunity for further investigation and treatment of a possible concurrent addictive disorder. Others will not, electing to move on to another prescriber. If the information gained by boundary tightening is reflected back to the patient, carefully charted, and used in a non-judgemental fashion, the patient may well decide to accept the physician’s advice for further assessment and treatment of a possible concurrent substance use disorder. In conclusion, it is hoped that these guidelines are a useful tool in the clinical management of patients with pain using methadone. While it is recognized that the use of any opiate carries some degree of risk for the patient, methadone, with its unique pharmacokinetic properties behaves differently than other opiates. In particular, its long elimination half-life and duration of action present significant safety concerns especially during the early stages of initiation onto the drug and during titration to effect. Once the practitioner makes the decision to use methadone to treat pain, this guideline is intended to provide a framework in which to use methadone balancing issues of patient safety while offering a viable treatment for pain.

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References
1. 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 of reinforcement. 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 in Pain Management: A rational approach to management of chronic pain. Pain Medicine (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-Based Recommendations 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 functioning in humans. Experimental and Clinical Psychopharmacology. 1995. 3(4):432466. 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, Pain Medicine, 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 immunodeficiency 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 systematic review 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 of chronic noncancer pain – A consensus statement and guidelines from the Canadian Pain Society. Pain Management and Research 3(4).

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Suggested Readings
American Psychiatric Association Task Force on DSM-IV: Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. American Psychiatric Association Press, Washington, 1994. American Academy of Pain Medicine, American Pain Society and American Society of Addiction Medicine. Definitions Related to the Use of Opioids for the Treatment of Pain, 2001. Fishman, SM., Wilsey, B., Mahajan, G., Molina, P. Methadone Reincarnated: Novel Clinical Applications with Related Concerns, Pain Medicine 3(4) 2002. Friedman R., Li V., Mehrotra D. Treating Pain Patients at Risk: Evaluation of a Screening Tool in Opioid-Treated Pain Patients With and Without Addiction; Pain Medicine 4(2) 2003. Kahan, M., Selby, P., Wilson, L. Management of Alcohol, Tobacco and Other Drug Problems: A Physician’s Manual. CAMH, 2002. Gourlay, D., Caplan, Y., Heit, HA. Urine Drug Testing in Primary Care: Dispelling the Myths and Designing Strategies. California Academy of Family Physicians. August 2002. www.familydocs.org/UDT.pdf; www.familydocs.org/UDT_RefCard.pdf Gourlay, D., Heit, HA., Almarhezi, A. (March 2005) Universal Precautions in Pain Medicine: A rational approach to management of chronic pain. Pain Medicine (6):2.

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Appendix A
Guideline Development Process Objectives
On January 25, 2002, the College convened a committee, including experts on addiction and pain management, for the purpose of developing guidelines on the use of methadone for pain. This working group was mandated to: • address the lack of clear guidelines for the use of methadone for chronic pain management; • 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 the management of chronic pain that would help to reduce risk and improve patient care. The following was undertaken to complete this project: • A needs assessment that surveyed the perceptions and needs of physicians who were prescribing methadone. • A liaison with the Ontario Guidelines Collaborative. • A liaison with the CPSO task force that was developing evidence-based recommendations 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 two months. Dr. Graeme Cunningham chaired the committee, and representatives included: • Two members of the CPSO task force on Evidence-Based Recommendations for Medical 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 was circulated to methadone prescribers in Ontario, to assess methadone utilization and perceived needs or problems. This information was collated and used, in part, to direct the content of this document. The results of the survey are found in Appendix B.

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Methodology
As a first step, the CPSO’s Evidence-Based Recommendations for Medical Management of Chronic Non-Malignant Pain was reviewed. Other documents were also reviewed, including a selected bibliography on the use of opioids for the treatment of pain; the results of a systematic review on the use of methadone in pain management17 (see Appendix C); and published guidelines by other jurisdictions concerning the use of opioids for the treatment of pain (see References section). The results from the systematic review on the use of methadone for pain management revealed an absence of Level I evidence, i.e., strong evidence from at least 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 best available information, including expert opinion, to develop a set of consensus-based guidelines. This approach had been used with favourable results in the development of the College’s MMT guidelines. The Methadone for Pain Guidelines provide Level V evidence, except where otherwise stated, i.e., opinions of respected authorities, based on clinical evidence; descriptive studies; or reports of expert committees. Through the literature review, the results of the needs assessment survey (Appendix B), material from presentations, and discussion amongst experts, the content of the draft guidelines was formulated and brought to the committee for discussion, input and modification. Consensus was reached by discussion and debate. The final document represents the consensus of all members of the working group.

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External Review Process
The draft guidelines were distributed for peer review to professional and consumer 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 for pain 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

17. Sandoval, A., Furlan, A., Mailis-Gagnon, A. (2004) Results of a systematic review 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.

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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; Critical Care 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 on Substance Abuse; Canadian Anaesthesiologists Society; Canadian Society of Medical Evaluators; Canadian Neurological Society; Canadian Pain Coalition; Royal College of Physicians and Surgeons of Canada; The Federation of Medical Regulatory Authorities of Canada; College of Family Physicians of Canada; and the Canadian Cancer Society. In total, the committee received a 26% response rate (133 responses) from the external review, after follow-up was conducted to obtain feedback from those who had not initially responded. The final draft document was submitted to the CPSO Council for review and approval for publication.

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

Updating this Document
It 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 review process will be repeated to validate the revised guidelines.
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Appendix B
Survey of Methadone Prescribers
Results

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• 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% • 18.0% • 5.5% • 3.9% • 3.1%

general/family medicine chronic pain management general/family medicine and chronic pain management general/family medicine and addiction 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 some pain patients • 60% general/family practice with the usual mix of patients, including those with chronic pain • 24% speciality practice providing consulting, stabilization and eventual return 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 pain the 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 • 8% responded that for 25-50% of patients, chronic pain is the primary focus • 7% responded that for 51-75% 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 • 117 • 96 • 95 • 92 • 90 • 84 • 79 • 64 • 60 • 60 • 53 • 50 • 25 •6 neuropathic pain low back pain chronic soft tissue pain chronic pain in the elderly neck pain post-traumatic pain headaches work injury pain rheumatic disease patients post-operative pain spinal cord post-stroke pain pain in addicts other HIV chronic pain in children

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

• 143 • 142 • 131 • 74 • 73 • 67 • 51 • 25 • 18

opioids NSAIDs or antipyretics non-opioid pharmacotherapy methadone for chronic non-malignant pain nerve blocks multi-modal rehabilitation alternative therapies surgical methods 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?

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• 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 of methadone 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 in the area of methadone for chronic pain? (Please select all that apply)*

• 120 • 76 • 71 • 48 • 31 • 31 • 30

education expert clinics experts pharmacies pharmacy rules other college oversight

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

• 104 • 94 • 94 • 57

methadone dosing issues understanding pharmacology indications for methadone use in treating chronic pain assessment tools
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• 52 • 30 screening for addiction, monitoring and managing addiction criteria for admission for methadone treatment for management of opioid addiction

In addition to clinical practice guidelines, what other resources do you feel would be helpful to you in using methadone to treat chronic 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 methadone for chronic non-malignant pain.
Title: Oral methadone for chronic non-malignant pain. A systematic literature review of reasons for administration, prescription patterns, effectiveness and side effects. Authors: Juan Alberto Sandoval1 MD, Andrea D. Furlan1,3,4,5 MD, Angela Mailis-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 and Toronto Western Research Institute, 4F811, 399 Bathurst St. Toronto ON Canada M5T 2S8 Tel: 416-603-5380 Fax: 416-603-5725 E-mail: angela.mailis@uhn.on.ca Acknowledgments: Andrea Furlan is funded by grants from the Canadian Institute of Health Research and by the University of Toronto Centre for Study of Pain.
ABSTRACT

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Objective: To assess the indications, prescription patterns, effectiveness and sideeffects of oral methadone for the treatment of chronic non-malignant pain. Methods: We conducted searches of several electronic databases, textbooks and reference lists for controlled or uncontrolled studies in humans. Effectiveness
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was assessed using a dichotomous classification of “meaningful” versus “nonmeaningful” outcomes. Results: Twenty-one papers (one small randomized trial, 13 case reports and seven case series) involving 545 patients with multiple non-cancer pain conditions were included. In half of the patients, no specific diagnosis was reported. Methadone was administered primarily when previous opioid treatment was ineffective or produced intolerable side effects. Starting doses ranged from 0.2 to 80 mg/day and maximum doses ranged from 20 to 930 mg/day. Pain outcomes were meaningful in 59% of the patients in the uncontrolled studies. The randomized trial demonstrated a statistically significant improvement in pain for methadone (20 mg/day) compared with placebo. 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 figure of 59% effectiveness of methadone should be interpreted very cautiously, as it seems overrated due to the poor quality of the uncontrolled studies and their tendency to report positive results. The utilization of oral methadone for nonmalignant pain is based on primarily uncontrolled literature. Well-designed controlled trials may provide more accurate information on the drug’s efficiency in pain syndromes and in particular neuropathic pain. Key words: Methadone, effectiveness, systematic review, and non-malignant pain

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Appendix D
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Copyright 2000, American Psychiatric Association.

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Diagnostic Criteria for Substance Dependence
Criteria for Substance Dependence

A maladaptive pattern of substance use, leading to clinically significant impairment 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 than was intended. 4. There is a persistent desire or unsuccessful efforts to cut down or control substance 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 or reduced because of substance use. 7. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an 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 Agreement
Sample of a basic patient agreement (for patients at higher risk of noncompliance 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 my physician. I agree not to increase the dose of opioid on my own and understand that doing so may lead to the treatment with opioids being stopped. 3. I will attend all appointments, treatments and consultations as requested by my physician. 4. I will not receive opioid pain medications from any other physician except in an emergency or in the unlikely event that I run out of medication. Should such occasions occur, I will inform my prescribing physician as soon as possible. 5. I understand that the common side effects of opioid therapy include nausea, constipation, sweating and itchiness of the skin. Drowsiness may occur when starting opioid therapy or when increasing the dosage. I agree to refrain from driving a motor vehicle or operating dangerous machinery until such drowsiness disappears. 6. I understand that there is small risk that I may become addicted to the opioids I am being prescribed. As such, my physician may require that I have additional tests and/or see a specialist in addiction medicine should a concern about addiction arise during my treatment. 7. I understand that the use of any mood-modifying substance, such as tranquilizers, sleeping pills, alcohol or illicit drugs (such as cannabis, cocaine, heroin or hallucinogens), can cause adverse effects or interfere with opioid therapy. Therefore, I agree to refrain from the use of all of these substances without 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.

G U I D E L I N E S

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

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9. If I break this agreement, my physician reserves the right to stop prescribing opioid medications for me. 10. I hereby agree that my physician has the authority to disclose the prescribing information in my patient file to other health care professionals when it is deemed medically necessary in the physician’s judgement.

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Appendix F
Urine Drug Testing
Testing for the presence of drugs in a patient’s urine is rapidly becoming an important adjunct to managing patients with chronic pain. It can be particularly useful in Group II and Group III patients, those with risk factors above baseline for substance abuse. A comprehensive reference for this process is available at www.familydocs.org/UDT.pdf. Although prepared as a CME tool for US physicians, the general principles apply to all practitioners. What follows are some practical considerations for practitioners in Ontario.
Urine Collection

G U I D E L I N E S

Sample collection begins the process of testing for drugs in a patient’s urine and care must be taken to ensure that the sample will yield the most accurate information possible. While directly observing a chronic pain patient providing a urine sample is usually unnecessary, it is nevertheless important that the sample be fresh. Samples brought in from home are unacceptable, and the clinician is wise to use techniques to minimize potential tampering with the sample. A fresh sample of urine should be warm but not hot and certainly not cold. 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 immunoassay such as EMIT (Enzyme Multiplied Immunoassay Technique) and involves adding urine to a medium (often a dipstick or testing strip) covered with antigens to a drug. A positive test result is usually indicated by the absence of a coloured mark. These tests, now available from several companies as an office procedure, are very sensitive, but for many drugs not very specific. Most frequently 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 reliably don’t detect the pure synthetic agents (i.e., methadone, fentanyl) unless specific assays are used. It is worth emphasizing that oxycodone may not reliably be picked up if one simply asks for a ‘urine drug screen’. In general, the lab requisition should specify any particular drugs that are being looked for.
*The word opiate by convention refers to extracts of the opium poppy, i.e., morphine/codeine, and has been replaced by the all encompassing term “opioid”.

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Specific Identification Tests: Urine Toxicology

Further testing can often identify specific rather than simple classes of drugs if specifically ordered. Asking for ‘urine drug toxicology’ will give results for a much wider range of drugs. The one notable exception is fentanyl (i.e., Duragesic®) which is not readily identified in routine testing and must be asked for specifically, if indicated. This more comprehensive look at drugs present in the urine is done by chromatography; such as gas chromatograph (GC) or HPLC REMEDi (high performance liquid chromatography with spectrophotometry). GC/MS (gas chromatography/mass spectrometry) can also be used to identify drugs and is extremely specific and able to detect very minute quantities of a substance but can be expensive and normally only used in cases where results are unclear or in forensic investigations It is important to understand some of the limitations of this technology when interpreting results. Enzyme assays or chromatography will report a drug class as ‘positive’ (i.e., present in the urine sample) only if it is measured at a concentration which reaches an arbitrarily assigned ‘threshold’. Thus, although a drug may be present in the urine, the sample may be reported as negative for the drug if the concentration detected does not reach this cut-off point. Equally important to note is that there is no reliable relationship between drug concentration found in the urine and quantity of drug ingested due to, among other factors, the concentrating effects of the kidneys. This is especially true with the semi-synthetic agents, which may be positive some of the time but not all of the time. For this reason, it is useful to determine the concentration of the sample by ordering a random urine creatinine. Diluted urine samples are less likely to have drug concentrations high enough to reach the threshold and so may be less reliable.
Interpreting results

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

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

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Appendix G
Examples of prescription formats
Example 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 of 45 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 of 45 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 of 45 mg (4.5 ml) daily.

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Appendix H
Definitions related to the use of opioids for the treatment of pain.
Addiction

G U I D E L I N E S

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

Physical dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Tolerance

Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Reprinted with permission from the American Pain Society, the American Academy of Pain Medicine and the American Society of Addiction Medicine, Definitions Related 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 Division Associate Clinical Professor Department of Psychiatry & Behavioural Neurosciences, McMaster University Steven Bodley, MD, FRCP(C) Pain Management Clinic North Bay General Hospital Mr. Albert Chaiet, BScPhm, MscPhm, MBA Director, Pharmaceutical Services Centre for Addiction and Mental Health Council 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 and Women’s College Health Sciences Centre Pain Management Programme Allan S. Gordon, MD, FRCP(C) Associate Professor, University of Toronto Neurologist and Director Wasser Pain Management Centre Mount Sinai Hospital Douglas Gourlay, MD, FRCP(C), FASAM Centre for Addiction and Mental Health, Wasser Pain Management Centre Mount Sinai Hospital Angela Mailis-Gagnon, MD, MSc, FRCP(C) Director, Comprehensive Pain Program, and Senior Investigator, Krembil Nueroscience Centre Toronto Western Hospital Associate Professor, Department of Medicine, Division of Physical Medicine and Rehabilitation University of Toronto

Mr. John MacDonald DBR Canada Inc. Former Public Member of CPSO Council Eldon Tunks, MD, FRCP(C) Professor Emeritus of Psychiatry, McMaster University Pain Management, Chedoke Rehabilitation Centre Hamilton Health Sciences, Chedoke site Liaison from CPSO Task Force on Evidence-Based Recommendations for Management of Chronic Non-Malignant Pain

CPSO Staff:
Daniel J. Klass MD, FRCP(C) Associate Registrar Director, Quality Management, Registration, and Education, CPSO Adjunct Professor, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania School of Medicine Ms. Helen Culbert Government Programs Assistant, CPSO Ms. Margaret Liew Program Assistant Methadone Program, CPSO Ms. Raquel Shaw Moxam Research Coordinator Research and Evaluation Department, CPSO Mr. Wade Hillier Manager Government Programs, CPSO