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METHADONE

for pain
GUIDELINES

Facilitated by the College of Physicians and Surgeons of Ontario


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

College of Physicians and Surgeons of Ontario


80 College Street, Toronto, Ontario, Canada M5G 2E2
Telephone: (416) 967-2661
M E T H A D O N E
for pain
Table of Contents G U I D E L I N E S

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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G U I D E L I N E S Using Methadone to Assess Opioid Responsiveness . . . . . . . . . . 19

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

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

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

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

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

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

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

The Pharmacist and Methadone Dispensing for Pain Management . 25

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Preface/Introduction G U I D E L I N E S

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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G U I D E L I N E S 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 G U I D E L I N E S

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.

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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G U I D E L I N E S 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.

‘Locus of control’2 is in fact a theoretical construct designed to assess a person’s


1. College of Physicians of
Surgeons of Ontario, Centre perceived control over his or her behaviour3. For the purpose of these
for Addiction and Mental guidelines, ‘locus of control’ refers to the degree to which patients are able to
Health, Ontario College of
Pharmacists. Methadone control their use of medications, as compared to external controls placed on
Maintenance Guidelines, them by the health care system.
2nd ed 2001.
2. Rotter, J. 1996. Generalized The pharmacist also plays an integral part in the MMT program. The pharmacy
expectancies for internal versus
external control of reinforce-
dispenses a once-daily unit dose of methadone, usually mixed into 100 ml of an
ment. Psychol Monograph orange flavoured drink. Two important points here are that methadone is not
80:1-28.
dispensed in a stock solution of fixed concentration and it is mixed with some
3. The American Heritage®
Stedman’s Medical Dictionary
form of flavouring to reduce the risk of parenteral administration. This is a
© 2002, 2001, 1995, requirement of the methadone guidelines for the treatment of opioid addiction.
Houghton Mifflin Company.
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, G U I D E L I N E S
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.

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). 4. Gourlay, D., Heit, HA.,
Almarhezi, A. (March 2005).
Universal Precautions in Pain
Group II: Pain patients with past or active Management: A rational
substance dependence approach to management of
chronic pain. Pain Medicine
Pain patients who have either a past or active history of drug (a substance other (6):2.

than opioids) or alcohol dependence, including problematic use of prescription 5. Savage, SR. Long-term opioid
therapy: assessment of conse-
drugs or abuse as diagnosed in the DSM-IV (see Appendix D). Other factors, quences and risks. J. Pain
such as a family history of drug or alcohol problems also increase risk. Symptom Manage. 1996.
11:275-286.

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G U I D E L I N E S 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, G U I D E L I N E S
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.

Table 1. Patient Categories for Methadone Management for Pain


Group I II III
Features Pain patients with no identified Pain patients who have either a Patients with an opioid addiction
risk factors for addiction past or active history of drug (to a who would otherwise qualify for
beyond that expected in the substance other than opioids) or methadone maintenance treat-
general population. alcohol 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
6. College of Physicians and
patient’s previous therapies and concomitant illness, especially the presence of Surgeons of Ontario.
past or present substance dependence or abuse. Some helpful points to consider Evidence-Based
include the following: Recommendations for Medical
Management of Chronic Non-
Malignant Pain. November
2000.

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G U I D E L I N E S 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 G U I D E L I N E S
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.

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 7. Fishman, SM., Mahajan, G.,
Jung, SW., et al. 2002. The
and ongoing assessment to reduce risk and improve outcomes. Practitioners trilateral opioid contract:
should follow up with patients frequently, documenting treatment outcomes, Bridging the pain clinic and
the primary care physician
the effectiveness of opioid therapy, along with discussions of side effects. As well,
through the opioid contract.
ongoing monitoring for problem drug use should be part of each follow-up J. Pain Symptom Management
assessment. Interval dispensing and careful adherence to boundaries are essential 24:335-344.
8. Passik, SD., Weinreb, HJ.,
components of a safe treatment program. Assessment of the “5-As” should be
2000. Managing chronic non-
performed and documented in the chart at frequent intervals. malignant pain: Overcoming
obstacles to the use of opioids.
The 5-As refers to the assessment of analgesia (effectiveness), adverse effects, Advances in Therapy
17(2):70-83.
aberrant behaviour, activity8, and affect. The 5-As should be assessed regularly
9. Covington, E. Oct. 2001.
and recorded in the chart as evidence of a successful trial of therapy. (Affect Lawful Opioid Prescribing and
added by E. Covington9). Prevention of Diversion;
Dannemiller Education
Foundation, CD ROM.

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G U I D E L I N E S 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
10. Zacny, J. A review of the
effects of opioids on psychomo- nurses/pharmacists should be employed.
tor and cognitive functioning in
humans. Experimental and
Clinical Psychopharmacology.
1995. 3(4):432-466.

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Misuse/Diversion of Methadone G U I D E L I N E S
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.

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 11. Heit, HA., Gourlay, D. March
2004. Urine Drug Testing in
Pain Medicine. Journal of Pain
The initial titration of methadone begins after the medical assessment has been and Symptom Management,
completed and the decision for a trial of methadone as therapy for pain has been 27(3)
made.

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M E T H A D O N E
for pain
G U I D E L I N E S 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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M E T H A D O N E
for pain
In the management of pain, oral methadone is generally used in a multiple daily G U I D E L I N E S
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.

Table 2. Methadone Dosing Options Available


Clinical Available
Form Pro Con
Indication Doses
Unit Dose Group III, Variable concentra- Safest for physician to titrate. Difficult to give 3 doses per
Liquid day beyond 1 week at a time.
Unstable Group tion in 100 ml vol- Large volume has reduced
II ume abuse liability. Difficult for patient to titrate
Easiest to control in unstable dose.
patient. Bitter taste, and limited shelf-
life due to flavoured additive.

Liquid Group I, Highly Specific stock con- Easiest form for patient to Storage/handling of drug can
Concentrate Stable Group II centration titrate up and down, easily be difficult.
stored, a familiar form to both Pure aqueous form easiest to
(*1mg/ml,
patients and pharmacists. abuse via injection.
5mg/ml,
*10mg/ml in If compounded with flavoured
aqueous) crystals, may reduce parenter-
al abuse liability.

Tablets Group I 1, 5, 10, 25 mg Easy form for patient to use. Can be easily abused, divert-
Easily stored and transported. ed/trafficked.

A familiar form for patients. Easily converted to parenteral


route for abuse.
Higher cost.

*commercially available

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M E T H A D O N E
for pain
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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M E T H A D O N E
for pain
Practitioners must be careful when prescribing methadone solutions. It is G U I D E L I N E S
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.

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.
12. Gourlay, D., Heit, HA., Letter
When switching to methadone, it is important to assume that any new side to the Editor, March 2004.
effect related to sedation or respiratory depression is due to methadone and not Vol. 5 Iss.1, Pain Medicine,
109-110.
to the opioid that the patient was previously taking. When there are signs of

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M E T H A D O N E
for pain
G U I D E L I N E S 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 half-
life 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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M E T H A D O N E
for pain
an agent such as methadone. In this group of patients, single or twice daily G U I D E L I N E S
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.

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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M E T H A D O N E
for pain
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
13. Gil, M., Sala, M., Auguera, I., opioids there is a wide variability in individual response to methadone, another
Chapinal, O., Cervantes, M.,
Guma, JR., Segura, F. QT reason to consider initiating therapy with small doses. With experience, the
Prolongation and Torsades de optimal dose for the majority of patients can be established within two to six
Pointes in patients infected with
human immunodeficiency virus weeks of methadone initiation. Doses above 200 mg per day13 are considered to
and treated with methadone. be in the “high range”. Although in some situations doses above this level may
J. Cardiol. 15-Oct-2003;
92(8): 995-997.
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.
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M E T H A D O N E
for pain
Doses above 200 mg per day are termed in the “high range” and have been G U I D E L I N E S
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 dose-
related 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.

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


14. Krantz, MJ., Lewkowiez, L.,
replace as follows: emesis within 15 minutes of ingestion should be replaced Hays, H., Woodroffe, MA.,
completely, between 15 and 30 minutes, 50% replacement is recommended, Robertson, AD., Mehler, PS.
after 30 minutes, absorption is essentially complete and the patient can be Torsades de pointes associated
with very-high-dose
reassured that the dose need not be replaced. methadone. Ann. Intern Med.
2002. Sep 17; 137(6):501-
504.

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M E T H A D O N E
for pain
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
22
M E T H A D O N E
for pain
methadone levels fall as it is now more rapidly eliminated. Although drug G U I D E L I N E S
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.

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 15. Doverty, M., White, JM.,
certain “anti-opioid” neurotransmitters in the central nervous system pain pathways. Somogyi, AA., Bochner, F.,
The diminished receptor activity, coupled with suppression of endogenous opioid Ali, R. and Ling, W.
Hyperalgesic responses in
levels can lead, in some patients, to an increase in the perception of pain. methadone maintenance
patients. Pain 2001 Feb 1;
In the context of pain management that is largely “opioid responsive”, this decrease 90(1-2):91-96.
in pain tolerance is accepted as a reasonable trade in the cost-benefit assessment,

23
M E T H A D O N E
for pain
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
Contact Health Canada written application is required, which indicates the practitioner’s desire to use
for more information methadone in the treatment of pain. In the absence of any restrictions imposed
on obtaining a by the College, this authorization will be granted. At the present time, no
methadone exemption additional training is required by Health Canada or the CPSO to obtain this
by calling the Office of exemption. The exemption to prescribe methadone for the treatment of chronic
Controlled Substances, pain must be obtained separate from any other exemption, including the
Methadone Program at exemption to prescribe methadone for the treatment of opioid addiction. To
(613) 946-5139, or by obtain an exemption for the use of methadone in the treatment of opioid
fax at (613) 952-2196. addiction, details are available from the College of Physicians and Surgeons in
each province.

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M E T H A D O N E
for pain
The Pharmacist and Methadone G U I D E L I N E S

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
16. Ontario College of
or her experience with that individual, and physicians should welcome such
Pharmacists, The Standards of
observations. 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 dis-
pensed as carries or take-home doses) depending on the category of risks
(i.e., Group I, II, or III on page 9).
• Pain patients on methadone typically do not have start and stop dates on 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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M E T H A D O N E
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• Confirm the current dosing schedule and amount to be dispensed. Given the G U I D E L I N E S
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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M E T H A D O N E
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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 G U I D E L I N E S

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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G U I D E L I N E S 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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M E T H A D O N E
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10-20% drop every 3-5 days can result in the patient being off methadone in G U I D E L I N E S
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.

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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M E T H A D O N E
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G U I D E L I N E S 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 G U I D E L I N E S

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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G U I D E L I N E S 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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M E T H A D O N E
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should be sought informally and documented in the patient’s chart. In all cases, G U I D E L I N E S
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 one-
month 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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G U I D E L I N E S 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):432-
466.
11. Heit, HA., Gourlay, D. March 2004. Urine Drug Testing in Pain Medicine.
Journal of Pain and Symptom Management, 27 (3).
12. Gourlay, D., Heit, HA., Letter to the Editor, March 2004. Vol. 5 Iss. 1, 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 immun-
odeficiency virus and treated with methadone. J. Cardiol. 15-Oct-2003; 92(8):
995-997.
14. Krantz, MJ., Lewkowiez, L., Hays, H., Woodroffe, MA., Robertson, AD., Mehler, PS.
Torsades de pointes associated with very-high-dose methadone. Ann. Intern Med.
2002. Sep 17; 137(6):501-504.
15. Doverty, M., White, JM., Somogyi, AA., Bochner, F., Ali, R. and Ling, W.
Hyperalgesic responses in methadone maintenance patients. Pain 2001 Feb 1;
90(1-2):91-96.
16. Ontario College of Pharmacists, The Standards of Practice for Pharmacists.
January 1, 2003.

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17. Sandoval, A., Furlan, A., Mailis-Gagnon, A. (2004) Results of a systematic G U I D E L I N E S
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).

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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G U I D E L I N E S 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 rec-
ommendations for management of chronic non-cancer pain.
• A review of these guidelines in draft by relevant stakeholders.

Beginning March 14, 2002, the working group met approximately every 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 G U I D E L I N E S
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.

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: 17. Sandoval, A., Furlan, A.,
Mailis-Gagnon, A. (2004)
• CPSO Methadone Program’s Patient Advisory Group
Results of a systematic review
• Physicians practicing pain management of oral methadone for chronic
• CPSO Council non-malignant pain. (Submitted
for publication).
• CPSO Executive Committee
18. McQuay, H., Moore, A. An
• CPSO Methadone Committee Evidence-Based Resource for
• Methadone for pain working group Pain Relief. Oxford U. Press,
1998.
• CPSO senior management

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M E T H A D O N E
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G U I D E L I N E S • 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 G U I D E L I N E S

Survey of Methadone Prescribers


Results

• 285 surveys distributed


• 54% response rate (154/285)

Demographics of Respondents

• 30% females - 70% males


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

What is your area of practice?

• 28.1% general/family medicine


• 18.0% chronic pain management
• 5.5% general/family medicine and chronic pain management
• 3.9% general/family medicine and addiction
• 3.1% general/family medicine, addiction, chronic pain management and
other
• 1.6% chronic pain management and addiction
• 1.6% general/family medicine, addiction, and chronic pain management
• 38.3% other

Which statement best reflects your pain practice?

• 69% speciality practice providing consulting and ongoing care of 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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G U I D E L I N E S • 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 neuropathic pain
• 117 low back pain
• 96 chronic soft tissue pain
• 95 chronic pain in the elderly
• 92 neck pain
• 90 post-traumatic pain
• 84 headaches
• 79 work injury pain
• 64 rheumatic disease patients
• 60 post-operative pain
• 60 spinal cord post-stroke pain
• 53 pain in addicts
• 50 other
• 25 HIV
•6 chronic pain in children

What clinical treatments do you generally utilize for patients with


chronic pain? (Please select all that apply)*

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

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

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What is your level of clinical education and training in the G U I D E L I N E S
management of chronic pain?

• 30% CME events


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

What is your level of clinical education and training in the use 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 education
• 76 expert clinics
• 71 experts
• 48 pharmacies
• 31 pharmacy rules
• 31 other
• 30 college oversight

Which topics would you be interested in learning more about for


using methadone for chronic pain? (Please select all that apply)*

• 104 methadone dosing issues


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

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G U I D E L I N E S • 52 screening for addiction, monitoring and managing addiction
• 30 criteria for admission for methadone treatment for management of
opioid addiction

In addition to clinical practice guidelines, what other resources 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 G U I D E L I N E S

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

Objective: To assess the indications, prescription patterns, effectiveness and side-


effects of oral methadone for the treatment of chronic non-malignant pain.

Methods: We conducted searches of several electronic databases, textbooks and


reference lists for controlled or uncontrolled studies in humans. Effectiveness

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G U I D E L I N E S was assessed using a dichotomous classification of “meaningful” versus “non-
meaningful” 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 non-
malignant 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 G U I D E L I N E S

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

Diagnostic Criteria for Substance Dependence

Criteria for Substance Dependence

A maladaptive pattern of substance use, leading to clinically 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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G U I D E L I N E S 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 G U I D E L I N E S

Sample Treatment Agreement


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

1. I, ____________________________ agree that Dr. __________________


will be the only physician prescribing OPIOID (also known as NARCOTIC)
pain medication.

2. I will take the medication at the dose and frequency prescribed by 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 19. Canadian Pain Society. 1998.
Use of opioid analgesics for
therapy. Therefore, I agree to refrain from the use of all of these substances the treatment of chronic non-
without first discussing it with my physician. cancer pain – A consensus
statement and guidelines from
the Canadian Pain Society.
8. I agree to be responsible for the secure storage of my medication at all times.
Pain Management and
I agree not to provide my prescribed pain medication to any other person. Research 3(4).

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G U I D E L I N E S 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 G U I D E L I N E S

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

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 *The word opiate by
(morphine/codeine i.e., the opiates), less reliably detect the semi-synthetic agents convention refers to
(derivatives of morphine/codeine i.e., oxycodone, hydromorphone) and reliably extracts of the opium
poppy, i.e., mor-
don’t detect the pure synthetic agents (i.e., methadone, fentanyl) unless specific phine/codeine, and
assays are used. It is worth emphasizing that oxycodone may not reliably be has been replaced by
picked up if one simply asks for a ‘urine drug screen’. In general, the lab the all encompassing
requisition should specify any particular drugs that are being looked for. term “opioid”.

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G U I D E L I N E S 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 G U I D E L I N E S
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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G U I D E L I N E S 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 G U I D E L I N E S

Definitions related to the use of opioids for the


treatment of pain.
Addiction

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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G U I D E L I N E S

Committee Members Mr. John MacDonald


DBR Canada Inc.
Chair: Former Public Member of CPSO Council
Graeme Cunningham, MD, FRCP(C), FASAM
Eldon Tunks, MD, FRCP(C)
Director, Homewood Addiction Division
Professor Emeritus of Psychiatry, McMaster University
Associate Clinical Professor
Pain Management, Chedoke Rehabilitation Centre
Department of Psychiatry & Behavioural
Hamilton Health Sciences, Chedoke site
Neurosciences, McMaster University
Liaison from CPSO Task Force on Evidence-Based
Steven Bodley, MD, FRCP(C) Recommendations for Management of Chronic
Pain Management Clinic Non-Malignant Pain
North Bay General Hospital

Mr. Albert Chaiet, BScPhm, MscPhm, MBA CPSO Staff:


Director, Pharmaceutical Services
Daniel J. Klass MD, FRCP(C)
Centre for Addiction and Mental Health Associate Registrar
Council Member, Ontario College of Pharmacists Director, Quality Management, Registration, and Education, CPSO
Jackie Gardner-Nix, MB, BS, PhD, MRCP (UK) Adjunct Professor, Division of Pulmonary and Critical Care
Assistant Professor, Dept. Anaesthesia, University of Toronto, Medicine, Department of Medicine, University of Pennsylvania
Chronic Pain Consultant, School of Medicine
Departments of Anaesthesia, Ms. Helen Culbert
St Michael’s Hospital Pain Clinic; and Sunnybrook and Government Programs Assistant, CPSO
Women’s College Health Sciences Centre
Pain Management Programme Ms. Margaret Liew
Program Assistant
Allan S. Gordon, MD, FRCP(C) Methadone Program, CPSO
Associate Professor, University of Toronto
Neurologist and Director Ms. Raquel Shaw Moxam
Wasser Pain Management Centre Research Coordinator
Mount Sinai Hospital Research and Evaluation Department, CPSO

Douglas Gourlay, MD, FRCP(C), FASAM Mr. Wade Hillier


Centre for Addiction and Mental Health, Manager Government Programs, CPSO
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