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ER/LA Opioid REMS EducationThis course is designed in accordance with the FDAs Blueprint for Prescriber Education for Extended-Release and Long-Acting

(ER/LA) Opioid Analgesics.

Audience

This course is designed for all physicians (MD/DO), physician

assistants and nurse practitioners.

Course ObjectiveThe purpose of this course is to educate prescribers with regards

to Risk Evaluation and Mitigation Strategies (REMS) in

accordance with the FDA Blueprint for Prescriber Education.

Learning ObjectivesCompletion of this course will better enable the course participant to:

1. Describe the two major competing responsibilities ofclinicians related to the prescription of opioid pain

medications

2. Describe 6 pain-related components of an initial patientevaluation

3. Explain the term universal precautions as it applies to theevaluation of patients for risk of opioid dependence or abuse

4.

Describe 2 tools for patient risk assessment5. Describe 3 advantages of creating written patient/provideropioid agreements

6. Explain the value of function-based treatment goals asopposed to pain-relief goals

7. Describe the 4 key steps to take prior to initiating treatmentwith an opioid pain medication

8. Explain why special care must be taken with extended-release/long-acting (ER/LA) opioid formulations

9. Explain why methadone must be prescribed with particularcaution

10. Describe 2 ways to potentially address unpleasant orintolerable opioid side effects

11. Explain the potential value of using PDMPs

How to Receive Credit

1. Read the course materials

2. Complete the self-assessment questions at the end. A score

of 70% is required.

3. Return your customer information/answer sheet, evaluation,

and payment to Informed by mail, phone, fax or complete

online at course website under NETPASS.

Accreditation Statement

Informed is accredited by the Accreditation Council for

Continuing Medical Education (ACCME) to provide continuing

medical education for physicians.

Designation of CreditInformed designates this enduring material for a maximum of 3

AMA PRA Category 1 Credits. Physicians should claim only

the credit commensurate with the extent of their participation in

the activity.

This activity developed without Commercial Support

Faculty

Sorin J. Brull, MD, FCARCSI (Hon)

Professor of Anesthesiology, Mayo Clinic, College of Medicine

Consultant, Department of Anesthesiology, Mayo Clinic

Lynn R. Webster, MD, FACPM, FASAMMedical Director and Founder, Lifetree Clinical Research &

Pain Clinic

Director-At-Large for the American Academy of Pain Medicine

Stewart B. Leavitt, MA, PhD

Executive Director, Pain Treatment Topics

Stephen Braun

Medical Writer

Braun Medical Media

Activity Director

Sarina J. Grosswald, EdD

Director of CME, Informed

SJ Grosswald & Associates

Disclosure

Resolution of Conflicts of Interest

In accordance with the ACCME Standards for Commercial

Support of CME, the Informed implemented mechanisms, prior to

the planning and implementation of this CME activity, to identify

and resolve conflicts of interest for all individuals in a position to

control content of this CME activity.

Staff and Content Validation Reviewer Disclosure

Informed staffinvolved with this activity and any content

validation reviewers of this activity have reported no relevant

financial relationships with commercial interests.

Planning Committee/Faculty Disclosure

The following faculty and/or planning committee members have

indicated they have no relationship(s) with industry to disclose

relative to the content of this CME activity:

Sarina J. Grosswald, EdD

Stephen Braun

The following faculty and/or planning committee members have

indicated that they have relationship(s) with industry to disclose:

Lynn R. Webster, MD, FACPM, FASAMhas received

honoraria related to formal advisory activities and as a

consultant from American Academy of Pain Management,

American Board of Pain Medicine, Covidien Mallinckrodt,

Iroko Pharmaceuticals, LLC, Medtronic, Inc., Nektar

Therapeutics, Pfizer Inc., and Salix Pharmaceuticals, Inc.

Stewart B. Leavitt, MA, PhDhas received unrestricted

Medical Education Grants from Purdue Pharmaceuticals,

Endo Pharmaceuticals, and Millenium Laboratories.

Sorin J. Brull, MD, FCARCSI (Hon)has received

honoraria from Merck, Inc as a member of their Global

Advisory Board.2013. All rights reserved. These materials, except those in the public domain, may no

be reproduced without permission from InforMed. This publication is designed to

provide general information prepared by professionals in regard to the subject matter

covered. It is provided with the understanding that InforMed, Inc. is not engaged in

rendering legal, medical or other professional services. Although prepared by

professionals, this publication should not be utilized as a substitute for professional

services in specific situations. If legal advice, medical advice or other expert assistance

is required, the service of a professional should be sought.


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Best Practices for Opioid Prescribing in Chronic Non-Cancer Pain

Introduction

Opioid analgesics are widely accepted forthe treatment of severe acute pain and chronic pain

related to active cancer or at the end of life.1

Thewidespread use of opioids for other types ofmoderate-to-severe chronic pain, however, has beenevolving in the past 2 decades and continues togenerate controversy. Prior to the 1990s, cliniciansoften viewed opioid pain medications withskepticism and avoided prescribing them, even whenrisks were thought to be low.2This perspective gaveway to the recognition that many patients were beingunder-treated for their pain, leading to increasedinterest in the clinical value of opioids and adramatic rise in rates of opioid prescribing for

analgesia. Prescriptions for opioids escalated fromaround 40 million in 1991 to roughly 257 million in2009.3In 2011, hydrocodone/acetaminophen was thesingle most-prescribed drug in the U.S., with a littleover 4 million prescriptions dispensed.4

Unfortunately, escalating opioid prescribingrates have been mirrored by similar escalations indrug diversion and nonmedical uses of opioids. Theopioid medications associated with these problemsinclude immediate- and extended- release products,as well as methadone. Many people directly affectedby the crisis have been previously healthy and have

had no history of substance misuse.

5

The scope ofthe problem can be seen in the following statistics:

In 2009, the latest year for which data areavailable, an estimated 7 million Americanswere abusing prescription drugsmore thanthe number abusing cocaine, heroin,hallucinogens, and inhalants, combined.6

Emergency-room visits related to non-medical use of opioids rose 111% between2004 and 2008.7

Between1998 and 2008, the rate of opioidmisuse increased 400%.8

Drug overdose is now the second-leadingcause of accidental death in America,exceeded only by car crashes.9

This rising tide of abuse, addiction,overdose, and death has led to calls for tighterregulation of opioid pain medications and for greaterprudence in prescribing on the part of clinicians. InJuly 2012, the U.S. Food and Drug Administration

(FDA) released its final Risk Evaluation andMitigation Strategies (REMS) content guidelines forprescriber education related to extended-release(ER) and long-acting (LA) opioid analgesics.10The

previous year, the White House Office of NationalDrug Control Policy, in collaboration with otherbranches of the federal government, introduced theAction Plan To Address National Prescription DrugAbuse Epidemic.11These initiatives, echoingstatements in recent clinical guidelines, seek tobalance a crack-down on non-medical use of opioidswhile simultaneously protecting the delivery ofeffective pain management to legitimate patients.1

Also in 2012, the FDA required labelingchanges for ER/LA opioids that attempt to narrowtheir use. Where these opioids were previously

indicated for "the relief of moderate to severe pain inpatients requiring continuous, around-the-clocktreatment," the new indication is for "themanagement of pain severe enough to require daily,around-the-clock, long-term opioid treatment and forwhich alternative treatment options areinadequate."12In addition, new cautionary languagewas added: "Because of the risks of addiction, abuseand misuse with opioids, even at recommendeddoses, and because of the greater risks of overdoneand death with extended-release opioid formulations,reserve [Tradename] for use in patients for whom

alternative treatment options (e.g. non-opioidanalgesics or immediate-release opioids) areineffective, not tolerated, or would be otherwiseinadequate to provide sufficient management ofpain."12

In 2014, the DEA, following earlier FDAapproval, formally moved some opioid combinationproducts containing hydrocodone (e.g., Vicodin,Lortab) from Schedule III to the more restrictiveSchedule II in an effort to tighten control.13In 2013,however, the FDA approved a new extended-releasehigh-dose hydrocodone-only product (Zohydro ER)

that has no abuse-deterrent features, a move thatsparked controversy at both state and federallevels.14

This CME monograph on best practices forprescribing opioids for chronic noncancer pain is instep with these important efforts, covering theeducational themes emphasized by the FDA and thenew federal plan to combat prescription drug misuse.


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This program offers clinicians a solid foundation forresponsible and vigilant opioid prescribing.

Definitions

The International Association for the Studyof Pain defines chronic pain as pain that persists

beyond normal tissue healing time, which isassumed to be three months.15Numerous diseasesand syndromes can result in chronic pain. For thepurposes of this monograph, all chronic paindisorders outside of cancer pain or pain at end of lifeare collectively labeled chronic noncancer pain(CNCP).

Many treatment modalities exist forCNCPopioid pain medications are only one ofmany tools in the pain management armamentarium.Not all patients are appropriate candidates for opioidmedications, either because of the nature of their

condition, the existence of relevant comorbidconditions, or their assessed risk for opioid abuse.Opioid therapy may be a useful component of a painmanagement plan, but in selecting patients for anopioid trial, clinicians must weigh the potentialbenefits of opioids against the risk of significantharms, including a wide range of adverse effects aswell as adverse outcomes associated with abusepotential.

The Challenge of Pharmacovigilance

In their daily practice, clinicians who treat

patients with chronic non-cancer pain face mustbalance pain relief with the risks associated withopioid analgesics. The term pharmacovigilancerefers to the range of procedures and processes usedto achieve this balance. As will become clearthroughout this monograph, such procedures neednot be burdensome and are not unlike the kinds ofbalancing acts required in the prescription of a greatmany other therapeutic agents. What makes opioidsof particular concern is the fact that not only are theypotentially dangerous for patients, they are alsohighly sought-after by recreational drug users and

criminal elements in society.In their efforts to find the appropriate,

effective middle ground between relieving pain andpreventing diversion and misuse of prescriptionopioids, clinicians must bear in mind the fact that theproblem of unrelieved pain remains as urgent asever. Chronic pain was estimated in a 2011 study toaffect approximately 100 million Americans and tocost roughly $635 billion annually in treatment and

lost productivity.16In fact, the incidence of chronicpain in the U.S. is greater than that of diabetes, heartdisease, and cancer combined.17,18

At the same time, opioids are subject toabuse, as previously mentioned, and also have awide range of potential adverse effects that can

predispose a patient to serious morbidity and evenmortality. Risk is increased among older adults;those with impaired renal or hepatic function;individuals with obesity, cardiopulmonary disorders,sleep apnea, or mental illness; and in patients whocombine opioids with other respiratory depressantssuch as alcohol, sedative-hypnotics,benzodiazepines, or barbiturates.

The Centers for Disease Control andPrevention (CDC) in 2010 issued recommendationsaimed at helping clinicians find a balance betweenresponsible opioid prescribing and minimizing the

risks of abuse, addiction, and drug diversion, thoughthe recommendations were acknowledged to bebased on promising interventions and expertopinion, not rigorous evidence-based research:9

Use opioid medications for acute or chronicpain only after determining that alternativetherapies do not deliver adequate pain relief.The lowest effective dose of opioids shouldbe used.

In addition to behavioral screening and useof patient contracts, consider random,periodic, urine testing for opioids and other

drugs for any patient less than 65 years oldwith non-cancer pain who is being treatedwith opioids for more than six weeks.

Do not prescribe ER/LA opioids for acutepain.

If your state has a prescription drugmonitoring program (PDMP) periodicallyrequest a report on the history of opioidprescriptions to your patients by otherproviders.

The rest of this monograph details how to

implement these general guidelines in ways that areconsistent with the time and budgetary constraintsoften found in modern practice settings. Note thatthese guidelines are not necessarily applicable toend-of-life care, emergency room care, or acute painmanagement.


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Case Study: Initial Presentation

Matt Davidson, age 69, is a retired high school

physical education teacher. He presents to his

primary care physician for his annual physical

examination. He has a history of hypertension,

osteoarthritis, and prostate cancer, for which he wastreated 2 years ago with a combination of external

beam radiation and chemotherapy and now shows

no signs of disease, although he continues to be

troubled by mild urinary incontinence and erectile

dysfunction. On this visit, Mr. Davidson complains

of joint pain, as well as a burning, tingling pain in

his hands and feet and asks if anything can be done

for it. He says he has been taking between 800 and

1200 mg ibuprofen by mouth daily for the pain,

which he rates as 7-8 on a 10-point scale, but has

also been having heartburn as a result.

A full evaluation of the patients pain leads to a dual

diagnosis of osteoarthritis and peripheral

neuropathy secondary to chemotherapy. As part of

the evaluation, the patient is asked how his pain is

affecting his life and whether it is preventing him

from engaging in any activities. He reports

disturbed sleep, which he says makes him more

irritable during the day. He also says he no longer

plays tennis, walking has begun to hurt, and it is

becoming difficult to use the computer keyboard.

This information is used to create a treatment plan

with the functional goals of reducing nighttimeawakenings to no more than 1 per night; walking

daily at least 1 mile without pain; using the

computer without pain. A return to playing tennis is

left as a possible future goal if less strenuous goals

are achieved first. An extended-release oxycodone

product is prescribed, as well as a prophylactic

laxative. The patient is given printed information

about the safe use, storage, and disposal of opioid

medications.

Assessing Patients for Opioid Therapy

Determining if an opioid medication isappropriate for a patient with chronic non-cancerpain involves assessing both the condition itself andthe patients potential for misuse or abuse of themedications. The FDA has recommended that

providers contemplating prescribing an opioid painmedication complete a comprehensive history andphysical examination, including assessment ofpsychosocial factors and family history of substancemisuse, as well as special considerations for theelderly, women, children, and cultural/ethnic

groups.19Regulators expect to see at least a basicphysical examination as part of the evaluation thatleads to treatment with controlled substances.20Theexact components of the examination, however, areleft to the medical judgment of the clinician, who isexpected to have performed an examinationproportionate to the diagnosis that justifies atreatment.

Any basic pain assessment includes thefamiliar elements of: chief complaint; history ofpresent illness; past medical, surgical, andpsychosocial history; family history; physical

examination; and examination of imaging and otherdiagnostic studies or tests. As when assessing anypatient, clinicians should take the time to lookbeyond the specific complaint or body part/systemand evaluate holistically the broader mental, cultural,and socioeconomic contexts within which the chiefcomplaint is embedded.16

History and Physical Exam

Physical exams conducted as part of anassessment of pain should include an evaluation ofthe patients nervous system, with focus on sensory

function. Clinicians should assess for allodynia (painfrom stimulation that would not normally evokepain, such as light touch), hyperalgesia (amplifiedpain response to stimulation that would normallyevoke only mild pain), or pain insensitivity. Asensory examination could include response to lighttouch, light pressure, pinprick, cold or vibration.21The presence of important co-morbid medicalconditions should be assessed, including chronicobstructive pulmonary disease, sleep apnea, diabetesor congestive heart failure.

It is important for clinicians to avoid the

mistake of assuming that if an organic pathologycannot be found, the patients pain is all in theirhead. As Goodwin and Bajwa (2004) note, Pain iswhat the patient says it is.21 Psychological factorsmay be important in a patients experience of pain,

Figure 1: Numeric Pain Scale

0 1 2 3 4 5 6 7 8 9 10

No Pain Moderate pain Worst pain possibleSource: Goodwin J, Bajwa ZH. Evaluating the patient with chronic pain. In: Principles and Practice of Pain Medicine 2ndEd. Warfield CA, and Bajwa

ZH., Eds. 2004. New York, NY, McGraw-Hill Companies, Inc. Page 65, column 1, paragraph 3.


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and the importance of such factors should be takenseriously and incorporated into the overall treatmentplan.21

A comprehensive evaluation of a patient inpain usually requires moving beyond the typical listof questions asked during a general history. It may

be possible to gather this information before an in-person visit by using paper or online questionnaires.In most cases where pain is the chief complaint, it isappropriate to begin a conversation by asking aboutthe pain, but then it is usually best to review thebroader context and impact of that pain.16Here aresome points that may be useful to cover in an initialevaluation:16

Location of pain Character of pain (i.e., shooting or stinging,

continuous or intermittent, worse at night orin the morning)

Lowest and highest pain on 0 to 10 scale in atypical day

Usual pain on 0 to 10 scale on a typical day(augmented by verbal descriptors)

How and when pain started

Exacerbating and relieving factors (i.e.,stress, alcohol, other medical concerns)

Effect of pain on sleep Effect of pain on mood

Effect of pain on functioning at work

Effect of pain on quality of personal life,such as relationships, sex, or recreation

Is the patient involved in a legal orprotracted insurance process connected tohis or her chronic pain, such as a motorvehicle accident or a disability case?

What activities could the patient do beforepain impacted his or her life that he or shecant do now?

What does the patient expect frommedications or other treatments in terms ofanalgesia or recovered function?

Review of past experience/exposure toopioids

Review of past medical/surgical history Review of family medical history Assessment of patient history of drug,

alcohol, and tobacco use

Psychosocial evaluation (including historyof mental illness)

Women of child-bearing age who havereproductive capacity should be asked about

the possibility of pregnancy at each visit.For women who wish to avoid unintendedpregnancy, use of long-acting reversiblecontraceptives should be discussed. Thewoman should be referred to an appropriatehigh-risk obstetrician.

During an initial evaluation, cliniciansshould be alert for signs that a patient is minimizinghis or her pain. This may result from a variety ofpsychological or emotional factors. For example,some patients may worry that they will be labeled asa complainer if they mention pain, or that theirhealth care provider will suspect they are addicted ifthey ask about opioid pain medications. Otherpatients may under-report pain because they fear thatpain medications will dull their cognitive abilities,lead to addiction, or produce undesirable sideeffects. Clinicians should be empathic, supportiveand honest, neither promising too much norremoving all hope, when evaluating a patient inchronic pain.20

Psychosocial Evaluation

Pain affects every aspect of a patients life.It is vital, therefore, to evaluate the ways pain maybe impacting, or may be affected by, psychosocialelements of a patients life.1Clinicians must be alertfor signs of depression or anxiety, which are verycommon. Be particularly alert for suicidal thoughtssince the risk of suicide is roughly double forpatients with chronic pain.23Some freely-accessibleinstruments for gathering a psychiatric history areavailable [see, for example, the Depression Anxiety& Positive Outlook Scale (www.dapos.org) or thePatient Health Questionnaire (PHQ Screeners(www.phqscreeners.com)]. Referral to a mental-health professional is warranted if the cliniciansjudgment suggests the patient has activepsychological issues beyond his or her expertise.

Clinicians should also probe for ways inwhich pain may be affecting the patients familysystem, work, or social activities. Pain can seriously

erode these spheres of life and evaluating thesechallenges and addressing them during treatment(for instance by referral to a vocational counselor orsocial worker) is just as important as treating themore immediate medical issues that may becontributing to chronic pain.


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Evaluating Patients for Risk of Opioid Dependenceor Abuse

Whenever a clinician considers treating painwith a controlled substance, such as an opioid, riskof misuse or diversion is always a possibility, nomatter how remote, and must be assessed.Prescribers should obtain a Urine Drug Test (UDT)

or a comparable test on oral fluids, before initiatingopioid therapy. Exactly whom to suspect and whento be proactive in investigating risk factors is an areaof great debate. To date, no convincing data exist tosupport the strategy of focusing on any one specificpopulation or settingwhich means that prescribersmust be vigilant with allpatients.20The concept ofuniversal precautions has been applied to this

approach, which means that any patient in paincould have a drug misuse problemjust as anypatient requiring a blood draw for a simple lab testcould have HIV.24Treating everyone with the samescreens, diagnostic tests, and administrativeprocedures can help remove bias and level the

playing field so everyone is treated equally andscreened thoroughly.

Nonetheless, it is also true that some patientcharacteristics are predictive of a potential for drugabuse, misuse, or other aberrant behaviors. Thefactor that appears to be most strongly predictive inthis regard is a personal or family history of alcoholor drug abuse.1Some studies have also shown thatyounger age and the presence of psychiatricconditions are also associated with aberrant drug-related behaviors.1

In evaluating patients with chronic pain for

risk of addiction or signs that they may be abusing acontrolled substance, it may be helpful to considerthe sets of characteristics listed in Table 1.

Many tools have been developed for theformal assessment of a patients risk of having asubstance misuse problem, some of which areappropriate for routine clinical use because they arerelatively brief and easily implemented. Table 2 liststhe tools that appear to have good content, and faceand construct validity for assessing patient risksrelated to chronic opioid therapy, although to date,no single tool has been widely endorsed or

thoroughly validated.1

Written Agreements/Documentation

Written documentation of all aspects of apatients care, including assessments, informedconsent, treatment plans, and provider/patientagreements, are a vital part of opioid prescription

Table 2: Tools for Patient Risk Assessment

Tool UseWho

Administers?Length Access

Current Opioid MisuseMeasure (COMM)

Monitor for misuseby patients

currently on long-term opioid therapy

Patient self-report 17 items www.inflexxion.com/COMM/

Diagnosis, Intractability,Risk, Efficacy (DIRE)

Screen for risk ofopioidaddiction

Clinician 7 items Belgrade MJ, et al.J Pain.2006;7:671681.

Opioid Risk Tool (ORT) Screen for risk ofopioid addiction

Clinician orpatient self-report

5 yes/noquestions

www.opioidrisk.com/node/887

Screener and OpioidAssessment for Patients withPain, Version 1 and Revised(SOAPP, and SOAPP-R)

Screen for risk ofopioidaddiction

Patient self-report 24 items www.inflexxion.com/SOAPP/

Table 1: Characteristics of Chronic-Pain

Patients v. Addicted Patients

Chronic-Pain Patient Addicted Patient

Medication use is not outof control

Medication use is out ofcontrol

Medication use improves

quality of life

Medication use impairs

quality of lifeWants to decreasemedication if adverseeffects develop

Medication use continuesor increases despite adverseeffects

Is concerned about thephysical problem beingtreated with the drug

Unaware of or in denialabout any problems thatdevelop as a result of drugtreatment

Follows the practitioner-patient agreement for useof the opioid

Does not follow opioidagreement

May have left overmedication

Does not have leftovermedication

Loses prescriptionsAlways has a story aboutwhy more drug is needed

Adapted from: Webster LR, Dove B. Avoiding Opioid Abuse While Managing Pain. SunriseRiver Press, North Branch, MN. 2007.


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best practices. Such documentation provides atransparent and enduring record of a cliniciansrationale for a particular treatment and provides abasis for ongoing monitoring and, if needed,modifications of a treatment plan.16

Many computerized systems are now

available for the acquisition, storage, integration,and presentation of medical information. Most offeradvantages that will benefit both patients andprescribers, such as maintaining up-to-date records,and providing instant availability of informationrelevant to prescribing or treatment. Althoughautomation can help, clear documentation is notdependent on electronic record-keeping; it merelyrequires a commitment to creating clear andenduring communication in a systematic fashion.Good documentation can be achieved with the mostelaborate electronic medical record systems, with

paper and pen, or with dictated notes. Cliniciansmust decide for themselves how thoroughly, andhow frequently, their documentation of a patientstreatment should be.

Informed Consent

Informed consent is a fundamental part ofplanning for any treatment, and must be obtainedprior to initiating treatment with an opioid or othercontrolled substance, given the potential risks ofsuch therapy. At its best, consent also fortifies theclinician/patient relationship.

Prescribers must be able to answer withconfidence four key questions when obtaininginformed consent in the context of treatment withopioids:25

1. Does the patient understand the variousoptions for treatment?

2. Has the patient been reasonably informed ofthe potential benefits and risks associatedwith each of those options?

3. Is the patient free to choose among thoseoptions, free from coercion by the healthcareprofessional, the patients family, or others?

4. Does the patient have the capacity tocommunicate his or her preferencesverbally or in other ways (e.g., if the patientis deaf or mute)?

Documentation related to these key areascan be accomplished by creating a separate paper orelectronic informed consent form or byincorporating informed consent language into a

larger treatment plan or patient/provider agreement.

Patient-Provider Agreements

A written agreement between a clinician anda patient about the specifics of their pain treatmentwith opioids can help clarify the plan with the

patient, the patients family, and other clinicianswho may become involved in the patients care.1Such agreements can also reinforce expectationsabout the appropriate and safe use of opioids.1Caution must be exercised, however, to ensure thatpatient/provider agreements are not used in acoercive way to unethically place patients in theposition of having to agree to its terms or else losean important component of their treatment (or evenlose alltreatment).21

Although evidence is lacking about the mosteffective methods to convey the information

included in most patient-provider agreements, suchagreements have been widely used and arerecommended by regulators and many experts ontreatment guidelines for long-term opioid therapy.1Recently, the Veterans Administration and U.S.Department of Defense chartered an expert panel toundertake a systematic review of existing medicalliterature on this subject. In the clinical practiceguidelines resulting from that work, the panelconcluded that opioid treatment agreements are astandard of care when prescribing long-term opioidtherapy.26[Samples of several commonly-used

agreements, including a low-literacy version, areavailable at: http://opioids911.org/media/doc/Op911-OpioidRxAgreements.doc]

Provider/patient agreements have manypotential advantages, including:20

Allowing treatment to start on a note ofmutual respect and partnership

Enhancing transparency Engaging patients in a collaborative

education and decision-making process

Helping to set functional goals andclarifying the clinicians and patients roles

and responsibilities in attaining these goals Documenting acceptance of treatment risks

and benefits

Documenting informed consent Helping avoid misunderstandings that may

occur over long treatment time periods Providing a foundation for subsequent

decisions about changes in medications ortermination of treatment


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Basing treatment plans on functional goals isespecially valuable in the context of prescribingopioid pain medications, because such goals mayhelp differentiate a patient who is truly opioidaddicted from one who merely seems to beaddicted.This differentiation is possible because addiction

often leads to decreased functioning, while effectivepain relief typically improves functioning.

Functional decline itself may result from arange of problems, including inadequate pain relief,non-adherence to a regimen, function-limiting sideeffects, or untreated affective disorders. Sometimesimpaired functioning is the result of addiction ormisuse, and these objective results may shedvaluable light on an otherwise confusingpresentation of a patients pain symptoms.

Functional treatment goals should berealistic. Progress in restoring function is usually

slow and gains are typically incremental. Chronicnon-cancer pain is often marked by long-standingphysical and psychological deconditioning, andrecovery may require reconditioning that may takeweeks, months, or years. It is much better to setgoals that are slightly too low than slightly too high.Raising goals after a patient has succeeded inachieving them is far more motivational andencouraging than lowering goals after a patient hasfailed.

Table 3 illustrates some simple functionalgoals and ways they might be verified.

The responsibility for obtaining evidence ofsuccess in meeting a functional goal lies with thepatient and should be made explicit in theprescribing agreement. If a patient is unable todocument or achieve the progress outlined in atreatment plan, this may suggest a need for goalreadjustment.

Components of an Effective Treatment Plan

The creation of an effective function-basedtreatment plan must be a collaboration betweenpatient and clinician. A patients pain score will bejust one of many variables to be considered inframing goals. These goals should be realistic,meaningful to the patient, and verifiable. The detailsof a function-based treatment plan are necessarilyspecific to the patient, but one way to initiate theprocess is to begin with the question: What do youhope to do as a result of treatment that you cant donow?

The treatment plan can include a discussionof, and the setting of expectations about, periodic re-assessment of goals. Patients may stabilize at acertain level of function, and the clinician andpatient together must decide if this is acceptable or

whether changes are needed.Treatment plans should include an

expectation that female patients will tell the providerif they want to avoid unintended pregnancy, and willtell the provider promptly if they become pregnant.

As is the case in drafting other types ofpatient/provider documents, patients should bereminded of the benefits and risks of a chosentherapy. With opioids, these include the realities oftolerance and physical dependence and the potentialneed to taper the medication slowly to avoidwithdrawal. Patients must also be educated about the

possibility that opioids may be either ineffective orhave intolerable adverse effects, and that there isalso the possibility of psychological dependence,which could lead to misuse, addiction, or death.

Another critical component of any treatmentplan is a description of how treatment with an opioidmedication might be terminated. Stopping opioidtherapy in cases of chronic non-cancer pain is oftenmore difficult than starting it. Being clear about the

Table 3: Evidence for Functional GoalsFunctional Goal Evidence

Begin physical therapy Letter from physicaltherapist

Sleeping in bed as opposedto lounge chair

Report by family memberor friend (either in-person

or in writing)*Participation in pain supportgroup

Letter from group leader

Increased activities of dailyliving

Report by family memberor friend

Walk around the block Pedometer recordings orwritten log of activity

Increased social activities Report by family memberor friend

Resumed sexual relations Report by partner

Returned to work Pay stubs from employeror letter confirming thepatient is off of disability

leaveDaily exercise Gym attendance records or

report from familymember or friend

* Involving other persons requires explicit permission from the patient,and this permission should be documented, preferably in writing.

Source: Fishman SM.Responsible Opioid Prescribing: A CliniciansGuide, 2ndEd.Waterford Life Sciences. 2012 (in press).


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conditions under which opioid therapy will end isimportant because opioids are not curative, have nostandard duration of treatment, and may beassociated with substantial risks.20

Termination may be required for manyreasons, including:

Healing or resolution of a specific pathologyunderlying the pain

The experience of intolerable side effects

Lack of adequate response to a medication interms of either pain relief or functionalimprovement

Evidence of non-medical or inappropriate useof the medication(s)

If inappropriate use of a prescriptionmedication is discovered, treatment must usually besuspended, although provisions should be in place

for continuation of some kind of pain treatmentand/or referral to other professionals or members ofa pain management team. Some clinicians may bewilling and able to continue a regimen of opioidtherapy even after the discovery of aberrant behaviorif done with intensified monitoring, patientcounseling, and careful documentation of alldirectives. This level of vigilance and riskmanagement, however, may exceed the abilities andresources of the average prescriber. In such cases,referral to a provider with specialized skill orexperience in dealing with high-risk patients may be

prudent.Case Study: Treatment Hits a Roadblock

Mr. Davidson returns for a follow-up after 2 weeks.

He reports that his arthritis pain has gotten only

slightly better, but that he is still experiencing the

burning/tingling pain in his hands and feet. He has

not achieved any of his functional goals. Upon

questioning, he reveals that he has not been taking

the opioid medication as frequently as prescribed

because he doesnt want to become an addict.

This common patient fear is allayed with careful,compassionate education that explains the

differences between addiction and tolerance and

that communicates the key principle that proper use

of an opioid may improve functioning and quality of

life. The prescription for the ER-LA opioid is

continued, and a prescription for 10 mg extended-

release gabapentin is added.

Initiating Treatment With Opioids

Prior to an initial prescription of an opioidpain medication, clinicians should be certain that (1)all other potentially effective treatments that offer amore optimal benefit-to-risk profile have been

considered or tried; (2) a complete evaluation hasbeen performed and fully documented; (3) thepatients level of opioid tolerance has beendetermined; and (4) informed consent and agreementto treat have been obtained.16A patient having beenprescribed opioids by a previous provider is not, inand of itself, a reason to continue opioids, and noprovider is obligated to continue opioid therapy thatwas started by another provider.52 In addition, theuse of an opioid, if necessary, should be just onecomponent of a treatment plan that includes othermodalities of pain management, such as physicaltherapy, exercise, the use of heat or cold, or any of arange of other techniques that can facilitateimproved function and a decreased reliance onopioids.

At the outset, both the clinician and thepatient should view a new opioid prescription as ashort-term trial of therapy.1The goal of the trial is toprovide data to guide decisions on the continuedappropriateness of opioid medications and on thespecific dose and formulation of medication used.Such a trial might be as brief as a few days or aslong as several months.

Opioid selection, initial dosing, and titrationmust be individualized to the patients health status,previous exposure to opioids, and treatment plan.1

Caution should be exercised when usingopioids in patients with conditions that may becomplicated by adverse effects from opioids,including chronic obstructive pulmonary disease(COPD), congestive heart failure, sleep apnea,current or past alcohol or substance misuse, mentalillness, advanced age, or patients with a history ofrenal or hepatic dysfunction.31

All newly pregnant women should have a urinedrug test administered by the appropriate womenshealth provider. In addition, providers shoulddiscuss a birth control plan to prevent unintendedpregnancy with every woman of child-bearing agewho has reproductive capacity when opioids areinitiated. Finally, chronic pain should never betreated with controlled substances throughtelemedicine.


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All chronic opioid therapy should be handled bya single provider or practice and all prescriptionsshould be filled in a single pharmacy, unless theprovider is informed and agrees that the patient cango to another pharmacy for a specific reason.

A decision to continue opioid therapy after

an appropriate trial should be based on carefulreview of the trial outcomes. Outcomes to considerinclude:20

Progress toward meeting therapeutic goals Changes in functional status Presence and nature of opioid-related

adverse effects

Changes in the underlying pain condition Changes in medical or psychiatric

comorbidities Degree of opioid tolerance in the patient Identification of altered or aberrant

behaviors, misuse, or diversion

Dose Titration

Patients who are opioid-nave or havemodest previous opioid exposure should be started atthe lowest dose possible of a short-acting opioid andtitrated slowly upward to decrease the risk of opioid-related adverse effects.1If it is unclear whether apatient has recently been using opioids (eitherprescribed or non-prescribed), the clinician shouldassume that the patient is opioid-nave (i.e., nottolerant) and proceed as just described.

Opioid tolerance should be establishedbefore prescribing an ER/LA opioid.32The selectionof a starting dose and manner of titration are clinicaldecisions that must be made on a case-by-case basisbecause of the many variables involved. Somepatients, such as frail older persons or those withcomorbidities, may require an even more cautioustherapy initiation.1Short-acting opioids are usuallysafer for initial therapy since they have a shorterhalf-life and may be associated with a lower risk ofoverdose from drug accumulation.1

Further studies are needed to confirm more

consistent control of pain and improved adherence toprescribed therapy with use of ER/LA opioids.1Although low-dose, short-acting opioids may offerthe greatest safety for initiating opioid therapy,clinicians must recognize that short-acting opioidsare not intrinsically safer than other formulations,and stress to their patients the importance of strictadherence to prescribed doses/administration.1

Patients on opioid doses of 100 MEDD orgreater should be referred to a pain specialist forconsultation and/or management.52 If a providercannot make the required consultation, he/she shouldclearly document why not. (Note: a pain specialist isa health care provider who has undergone fellowship

training from the American Board of Pain Medicine(ABPM) or other training sufficient to obtain ABPMdiplomat status.)

Considerations in Opioid Selection

Opioids, as a class, comprise many specificagents available in a wide range of formulations. Agiven patient might be appropriate for ER/LAtherapy only, short-acting only, or a combination ofan ER/LA opioid with a short-acting opioid forbreakthrough pain. Providers should not prescribemore than one short-acting opioid concurrently, or,

if such dual use is deemed medically necessary, theprovider should clearly document the justification.

Short-acting, orally-administered opioidstypically have rapid onset of action (10-60 min.) andrelatively short duration of action (2-4 hours).33They are used for acute or intermittent pain, orbreakthrough pain that occurs against a backgroundof a persistent level of pain.33[Transmucosalimmediate-release fentanyl is a special class ofshort-acting opioid that is only approved forbreakthrough pain in cancer, and there is a separateFDA REMS devoted to this topic.]34

Combination products join an opioid with anon-opioid analgesic, usually for use in patients withmoderate pain. Using a combination product whendose escalation is required risks increasing adverseeffects from the non-opioid co-analgesic, even if anincrease of the opioid dose is appropriate.20In suchcases, using a pure opioid may be preferable.

Single-agent formulations are available forcodeine, morphine, oxycodone, oxymorphone,hydrocodone and hydromorphone. In 2011, theFDA announced new rules that will limit to 325 mgthe amount of acetaminophen allowed in opioid

combination products in an attempt to limit liverdamage and other ill effects from the use of theseproducts with over-the-counter analgesics.35

ER/LA opioids usually have a relativelyslow onset of action (typically between 30 and 90min.) and a relatively long duration of action (4 to72 hrs).33Such agents are typically used for patientswith constant background pain.33These agentsachieve their extended activity in various ways.


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Methadone and levorphanol have intrinsicpharmacokinetic properties that make their effectsmore enduring than many short-acting opioids.36ER/LA agents such as controlled-release morphine,oxycodone, or transdermal fentanyl achieve theirprolonged time course via a delivery system that is

modified to slow absorption or to slow the release ofthe active ingredient.32Clinicians should warnpatients that unless specifically instructed otherwise,oral ER/LA opioids should not be broken, chewed,or crushed, and patches should not be cut or tornprior to use, since this may lead to rapid release ofthe opioid and could cause overdose or death.

Prescribers should educate themselves aboutthe general characteristics, toxicities, and druginteractions for ER/LA opioid products. [Fordetailed information on current ER/LA opioidanalgesics, see the FDA Blueprint for Prescriber

Education, available at: http://www.er-la-opioidrems.com]. Respiratory depression is the mostserious adverse effect of opioids as it can beimmediately life-threatening. Constipation is themost common long-term side-effect but can often bemanaged. Drug-drug interaction profiles vary amongthe products. Knowledge of particular opioid-druginteractions, and the underlying pharmacokinetic andpharmacodynamic mechanisms, allows for the saferadministration of opioid analgesics.

Central nervous system depressants(sedatives, hypnotics, tranquilizers, tricyclic

antidepressants and alcohol) can have a potentiatingeffect on the sedation and respiratory depression dueto opioids.33Alcohol consumption should beavoided entirely with some oral products (e.g.morphine, hydromorphone, oxymorphone) becauseethanol increases the plasma concentration of theopioid.33

Opioids may enhance the neuromuscularblocking action of skeletal relaxants and produce anincreased degree of respiratory depression. Usingopioids with monoamine oxidase inhibitors(MAOIs) may result in possible increase in

confusion, anxiety, and respiratory depression.33

Opioids can reduce the efficacy of some

diuretics by inducing the release of antidiuretichormone (ADH).33In addition, some opioids interactwith various cytochrome P450 enzyme inhibitorsand inducers and thus may result in higher or lowerthan expected blood levels of the drug.

Methadone can be an effective opioid, but itmust be prescribed carefully and with full

knowledge of its highly variable pharmacokineticsand pharmacodynamics. (See page 18 for a moredetailed discussion of methadone.)

Abuse-Deterrent Formulations

As concern has risen about opioid misuse

and abuse, efforts have been made to create abuse-deterrent and tamper-resistant opioid formulations.One class of deterrent formulation incorporates anopioid antagonist into a separate compartment deepwithin a single capsule; crushing the capsule releasesthe antagonist and neutralizes the opioid effect.37The central opioid antagonist compartment iseliminated from the body unchanged if the capsule isconsumed normally without tampering. Anotherstrategy is to modify the physical structure of tabletsor incorporate compounds that make it difficult orimpossible to liquefy, concentrate, or otherwise

transform the tablets.37In July, 2014, the FDAapproved a new extended-release oxycodoneanalgesic (Targiniq ER) with abuse-deterrentproperties.37

Transdermal opioid formulations have beenperceived in the past as less vulnerable to misuse,but such formulations can be abused. For example, atransdermal, 7-day duration formulation ofbuprenorphine has been reported to be anincreasingly abused opioid, particularly in prisonpopulations.38 As a partial opioid agonist,buprenorphine was thought to be a lower-risk agent

than full agonist opioids, however it is clear that thismedication can be as susceptible to abuse as full-opioid agonists.

Abuse-deterrent opioid formulations, ofcourse, do not prevent users from simply consumingtoo much of a medication. These formulations mayhelp reduce the public health burden of prescriptionopioid abuse, but the evidence to date is inadequateto project whether this potential will actually beachieved.20

Case Study: Progress

At a follow-up visit 2 weeks later, Mr. Davidsonreports reduced pain and improved functioning. He

says his pain is now 3-4 on a 10-point scale. He can

now walk his dog twice daily, and is using the

computer keyboard without pain. He says his sleep

has improved as well. Mr. Davidson asks for a

higher dose of the opioid to see if I can get the pain

down to zero. Although seemingly reasonable, it is


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explained to Mr. Davidson that, in fact, zero pain

is an unrealistic goal for anyone, and that

increasing the dose to achieve that goal would likely

incur a range of side effects that would erode his

overall quality of life. Although initially

disappointed, Mr. Davidson acknowledged the

explanation and did not press the issue.

Periodic Review and Monitoring

If a trial of an opioid medication is deemedsuccessful and opioid therapy is continued, periodicreview and monitoring should be performed for theduration of treatment. The tests performed, questionsasked, and evaluations made should be tailored tothe patient as guided by the physicians clinicaljudgment. For example, a physical examination mayor may not be required at each follow-up visit.

Clinicians must evaluate progress against

agreed-upon treatment goals and assess for a widerange of potential adverse effects, ranging fromphysical side effects such as constipation orsedation, to behavioral side effects such as moodchanges, signs of drug craving or seeking, orimpaired function in various domains of dailyliving.16As part of routine practice, clinicians whoprescribe opioids should perform medicationreconciliation at each patient visit.39The AmericanMedical Association defines medicationreconciliation as making sense of a patientsmedications and resolving conflicts between

different sources of information to minimize harmand maximize therapeutic effects.39

The intensity and frequency of monitoring isdependent on an assessment of the patients risk forabuse, diversion, or addiction. Tools and techniquessimilar or identical to those used during an initialassessment of a patients risk can be used to re-assess or monitor risk on an on-going basis.2

States vary in their requirements forintervals at which follow-up visits are required whencontrolled substances such as opioid medications areprescribed. Although federal law allows for a 90-day

supply of prescriptions for patients receivingschedule II drugs (who are otherwise deemed safe tohave this amount), state law can vary from 30 daysto 6 months.2In cases where state and federal lawconflict, the most restrictive rule prevails.2

Relatively infrequent monitoring may beappropriate for low-risk patients on a stable dose ofopioids. More frequent or intense monitoring isappropriate for patients during the initiation of

therapy or if the dose, formulation, or opioidmedication is changed. Patients who may need morefrequent or intense monitoring include:1

Those with a prior history of an addictivedisorder, past abuse, or other aberrant use

Those in an occupations demanding mental

acuity Older adults

Patients with an unstable or dysfunctionalsocial environment

Those with comorbid psychiatric or medicalconditions

Daily or weekly monitoring may benecessary for patients at very high risk for adverseoutcomes.

Reviewing Functional Goals

A key part of periodic monitoring is acareful review of previously-agreed-upon functionalgoals. Patients should come to appointments readyto provide the evidence upon which an evaluation ofprogress can be made. This evidence should span asmany domains of a persons life as possible:personal and social relationships, employment,physical activities, health, hobbies, and spiritualactivities. Functional goals that are not attainedrequire investigation, possible adjustment, andencouragement that future progress is possible. If thegoals havebeen attained, clinicians should be

supportive and positive, while setting new goals tomotivate further progress.Functional goals related to physical activity

are sometimes not achieved by patients because theyreport that the agreed-upon activity hurts too much.16Such cases should be carefully evaluated before adecision is made to increase the dose of an opioidmedication. All patientseven those with end-stagediseasecan engage in somekind of physicalactivity at least sometime during the day. Themotions or activity may be extremely modest, yetthey may nonetheless serve as effective functional

goals. Patients with chronic pain often require suchmicro-level goals and controlled, gradually-increasing motion or activity over sustained periodsof time.

Managing Breakthrough Pain

Patients with chronic pain receiving a steadydose of an opioid medication may experienceepisodes of pain that break through the analgesic


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effects of the steady-state drug (regardless of theroute of administration).1Close monitoring ofbreakthrough episodes is key to helping patientsreduce pain and facilitate functioning. Providingpatients either paper or electronic pain diaries canhelp them track breakthrough episodes and spot

correlations between the episodes and variables inthe patients life. If specific triggers are identified,this may provide opportunities for changes that willreduce the prevalence of breakthrough episodeswithout recourse to increased reliance onmedication.20

Non-opioid methods of dealing withbreakthrough pain (i.e., cold or warmth, massage,yoga, acupuncture, meditation, electricalstimulation) might be considered prior to anyincreases in opioid medication; although researchevidence regarding many CAM (complementary and

alternative medicine) approaches is inconclusive. Ifa short-acting opioid preparation is prescribed forbreakthrough pain, clinicians should remind patientsabout the potentials problems of diversion andmisuse of these agents.

As with the management of the underlyingchronic pain condition, clinicians should use anagreed-upon set of functional goals as a way tomonitor, and if necessary, adjust, the use of as-needed opioid medications for breakthrough pain.

Monitoring Adherence

Trust is a necessary part of anypatient/clinician relationship, but studies suggest thatin the context of controlled substances, it is unwiseto rely on a patients word that medications arebeing consumed as prescribed.2Although the use ofmore objective ways to monitor adherence tomedication regimens is an imperfect science, suchmethods remain an essential component of periodicreview. Multiple objective methods to assessadherence exist, but there is no single bestapproach and all such methods have both advantagesand potential drawbacks.

Drug testing should be approached in aconsensual manner as part of an agreed-upontreatment plan and with the idea that such testingbenefits both the patient and the provider.2 Thepotential benefits of clinical drug testing include:2

Serving as a deterrent to inappropriate use

Providing objective evidence of abstinencefrom drugs of abuse

Monitoring response to treatment

Assisting with a diagnosis

Helping patients allay concerns by familymembers, employers, or law-enforcement

Demonstrating to regulatory authorities a

clinicians dedication to monitoring bestpractices

In the context of family practice settings,unobserved urine collection is usually an acceptableprocedure for drug testing. Prescribers, however,should be aware of the many ways in which urinespecimens can be adulterated. Specimens should beshaken to determine if soap products have beenadded, for example. The urine color should be notedon any documentation that accompanies thespecimen for evaluation, since unusually coloredurine could indicate adulteration. If possible, urine

temperature and pH should be measuredimmediately after collection.2

One way to reduce the risk of urine test falsepositives or false negatives is to develop arelationship with a single laboratory, becomefamiliar with its testing tools and threshold values,and use the same screening and confirmatory testsregularly to build familiarity with the range ofnormal results.2

Prescribers should be familiar with themetabolites associated with each opioid that may bedetected in urine, since the appearance of a

metabolite can be misleading.2A patient prescribedcodeine, for example, may test positive for morphinebecause morphine is a metabolite of codeine. Similarmisunderstandings may occur for patients prescribedhydrocodone who appear positive for hydromor-phone or oxycodone and oxymorphone.

Table 4: Urinary Analytes of Common Opioid Pain

Medications

Drug Urinary Analytes

Morphine MorphineHydromorphoneCodeine

Codeine CodeineMorphineHydrocodone

Hydrocodone HydrocodoneHydromorphone6-Hydrocodol

Oxycodone OxycodoneOxymorphoneHydrocodone

Source: Webster LR, and Dove B. Avoiding Opioid Abuse While Managing Pain. Lifesource.2007.


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Case Study: A Caution Light

After 3 weeks, the physician is given a message that

a young woman has called requesting an early refill

of Mr. Davidsons opioid because hes suffering.

This raises the physicians suspicions. He accesses

his state Prescription Drug Monitoring Program tosee if Mr. Davidson might be getting prescriptions

from another provider. He is not, and nothing

appears unusual. The physician calls Mr. Davidson

directly and Mr. Davidson confirms that he did ask

his granddaughter to call for the prescription

because he was having increased pain after playing

tennis for an hour. Mr. Davidson is advised to

temporarily use an OTC NSAID (not more than 600

mg) and is asked to return for an in-person visit

within a week. At that visit, a range of non-

pharmacological strategies are reviewed, with the

aim of providing additional pain relief and improvedfunction (i.e., post-exercise cold/warm treatments;

exercises to improve flexibility; massage; and the

use of an elbow brace to be used for tennis).

Using Prescription Drug Monitoring Programs(PDMPs)

PDMPs can serve an important clinicalmonitoring role. PDMPs use secure Internet sites tooffer point-of-care access to records of controlledsubstances from other prescribers and dispensingpharmacies. From these, clinicians can quickly glean

patterns of prescription drug use that can be helpfulin confirming or refuting suspicions of aberrantbehaviors. Information from a PDMP may also beclinically relevant in that it may reveal that a patientis being prescribed medications whose combinationsare contraindicated.

There is currently little uniformity,information-sharing, or cooperation among statePDMPs, but efforts are under way to improve thissituation. An advisory committee of the Council ofState Governments has endorsed the formation of aninterstate PDMP compact, and legislation to

accomplish this goal is currently being drafted.37

Bychecking PDMP data (particularly for high-riskpatients), clinicians can get a sense of the controlledsubstances that the patient has been receiving fromother prescribers and other pharmacies.38Individualsmay have perfectly acceptable reasons for multipleprescribing episodes, but the existence of such apattern should always trigger inquiry.

Common Issues Related to Opioid Pain

Medications

Preventing and Managing Opioid-Related SideEffects

Many patients treated with an opioid willexperience side effects, the most common of whichis constipation. Other possible effects include:2

Respiratory depression Sedation Urinary hesitancy or retention

Dry mouth Nausea/vomiting

Itching Sweating Hypogonadism

Myoclonus

Some side effects, such as sedation, maylessen over time after treatment initiation. Others,such as constipation, rarely become less problematic.Constipation is so common, in fact, that whenpatients use opioids and do not have constipation,clinicians should consider possible reasons rangingfrom rapid bowel transit time to diversion.Constipation requires proactive treatment, withstimulating laxatives prescribed at the time ofinitiating opioids, and frequent re-evaluation. Withthe exception of constipation, uncomfortable orunpleasant side effects may potentially be reduced

by switching to another opioid or route ofadministration (such side effects may also bealleviated with adjunctive medications).

Opioids and Pregnancy

Some data suggest an association betweenthe use of long-term opioid therapy duringpregnancy and adverse outcomes in newborns,including low birth weight and premature birth,though co-related maternal factors may play a role inthese associations and causality is not certain.1Higher doses of antenatal methadone in tolerant

mothers do not seem to increase complication rates.

1

Importantly, opioid withdrawal can be expected inup to half of newborns of opioid-dependentmothers.1If a mother is receiving long-term opioidtherapy at or near the time of delivery, a professionalexperienced in the management of neonatalwithdrawal should be available.1

Nonetheless, given the potential risks ofopioids during pregnancy, current American Pain


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Society-American Academy of Pain Medicine (APS-AAPM) guidelines suggest that clinicians shouldencourage minimal or no use of opioids duringpregnancy unless the potential benefits outweighrisks.1If opioid medications are prescribed,clinicians should thoroughly counsel pregnant

women about the potential risks and benefits, andclinicians should be prepared to anticipate andmanage risks to the patient and newborn.

Driving and Work Safety

Driving while using opioid medicationsremains a controversial issue. Particularly at theinitiation of therapy, opioid medications may causesleepiness, clouded thinking, decreased concen-tration, slower reflexes, or incoordination, all ofwhich may pose a danger to the patient and otherswhen driving or operating machinery.1On the other

hand, a number of epidemiologic studies failed toshow an association between long-term opioid useand motor vehicle accidents, fatalities, or citationsfor impaired driving.1Since at least some of thecognitive and motor-impairing effects of opioidsresolve with steady use and a consistent dose, someactivities or driving may be allowable at thediscretion of the clinicians medical judgment and inthe absence of signs of impairment.

Current APS-AAPM guidelines recommendthat all patients who are initially prescribed opioidmedications, or those who have their dose increased,

be advised not to drive or engage in potentiallydangerous work or other activities.1There is noconsensus on exactly how long they should abstainfrom driving. Patients should be educated about theincreased risk of impairment when starting opioidtherapy, when increasing doses, and when takingother drugs or substances (such as, alcohol,benzodiazepines, or even some cold remedies) thatmay exacerbate cognitive and motor impairment.Clinicians should be aware that certain professions(i.e., school bus drivers and pilots) may be subject torestrictions in the use of opioid medications.1

Clinicians should check with their state medicalsociety or the Federation of State Medical Boards toobtain up-to-date information in this regard.

Screening for Endocrine Function

Both male and female patients on long-termopioid therapy are at risk for hypogonadism, thus theendocrine function of all patients should be assessed

at the start of long-term opioid therapy and at leastannually thereafter. The symptoms of hypogonadismin both genders may include fatigue, mood changes,decreased libido, loss of muscle mass, andosteoporosis. Although there are insufficient data torecommend routine endocrine screening of

asymptomatic patients, current guidelines dorecommend such testing for patients exhibiting anyof the aforementioned signs and symptoms.1

Opioid Rotation

Opioid rotation means switching from oneopioid to another in order to better balance analgesiaand side effects. Rotation may be needed because ofa lack of efficacy (often related to tolerance),bothersome or unacceptable side effects, increaseddosing that exceeds the recommended limits of thecurrent opioid (e.g., dose limitations of co-compounded acetaminophen), or inability to absorbthe medication in its present form (i.e., if there is achange in the patients ability to swallow, switch toa formulation that can be absorbed by a differentroute such as transdermal.)20

Because of the large number of variablesinvolved in how any given opioid will affect anygiven patient, opioid rotation must be approachedcautiously, particularly when converting from animmediate-release formulation to an ER/LAproduct.20An equianalgesic chart should be usedwhen changing from one opioid to another or fromone route of administration to another. Such chartsmust be used carefully, however. A high degree ofvariation has been found across the various chartsand online calculator tools, and may account forsome overdoses and fatalities.41The optimal dose fora specific patient must be determined by carefultitration and appropriate monitoring, and cliniciansmust be mindful that patients may exhibitincomplete cross-tolerance to different types ofopioids because of differences in the receptors orreceptor sub-types to which different opioids bind.2

In some cases, because of the risk ofpotential harm during the time of rotating from onechronic opioid regimen to another, it may be wise toinitially use lower doses of an ER/LA opioid thanmight be suggested by equianalgesic charts, whiletemporarily liberalizing, as needed, the use of ashort-acting opioid. This would then be followed bygradual titration of the LA opioid to the point where


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the as-needed short-acting opioid is incrementallyreduced, until no longer necessary.

Managing Non-Adherent Patients

Patients who begin to exhibit aberrant drug-related behaviors or non-adherence to a prescription

should be monitored more strictly than compliantpatients. Suspicion that a patient is non-adherentshould prompt a thorough investigation of thesituation, including an honest evaluation of thepatient/provider relationship. The way cliniciansinteract with patients can affect the relationship (forbetter or worse) and influence treatment outcomes.20A clinicians negative reactions to non-adherencemight include anger at the patient, disappointmentand sadness at the apparent betrayal of trust, or fearthat the patients behavior could expose the providerto legal jeopardy.20

Before accusing a patient of not adhering toa prescribed regimen, clinicians should assess thesituation fully. Possible reasons for non-adherenceinclude:

Inadequate pain relief Misunderstanding of the specifics of the

prescription

Misunderstandings related to lack of fluencywith English

Attempts to stretch a medication in orderto save money

Cultural or familial pressure not to take a

medication Stigma about taking a pain medication

Overmedication and fears about addiction Misunderstanding of a prescription by a

caregiver who has taken responsibility fordaily apportioning of medications

Confusion between two medications thatlook very similar to each other

The use of patientprovider agreementsand/or informed consent documents can helpclinicians navigate the uncertainties that can arise in

cases of real or apparent non-adherence, and mayhelp make the process less confrontational.Consultation with an addiction medicine specialistor psychiatrist may be necessary if addiction issuspected or if a patients behavior becomes soproblematic that it jeopardizes the clinician/patientrelationship.

Case Study: Stable Improvement

After a slight dose adjustment of the gabapentin, Mr.

Davidson reports continued functional progress and

acceptable levels of pain. He has increased his level

of physical activity and reports that his mood and

general health are better as a result. He states hewould like to try to taper his use of the opioid, and

he is given clear and specific instructions for how to

do that.

Treatment Termination

Reasons for discontinuation of an opioidanalgesic can include the healing of or recoveryfrom an injury, medical procedure, or condition;intolerable side effects; lack of response; ordiscovery of misuse of medications. Regardless ofthe reason, termination should be accomplished so as

to minimize unpleasant or dangerous withdrawalsymptoms by tapering the opioid medication slowly,or by carefully changing to a new formulation.Opioid discontinuation poses a host of potentialwithdrawal symptoms including nausea, vomiting,myalgia, headaches, abdominal pain, and sweating.Benzodiazepine withdrawal can be potentially life-threatening.

Approaches to weaning range from a slow10% reduction per week to a more aggressive 25 to50% reduction every few days.1In general, a slowertaper will produce fewer unpleasant symptoms of

withdrawal. Of note, clonidine can be used todiminish some opioid withdrawal symptoms at adose of 0.1 0.2 mg orally every 6 hours or with atransdermal patch at 0.1 mg/24 hours.52

In general, opioid therapy must bediscontinued or re-evaluated whenever the risk oftherapy is deemed to outweigh the benefits beingprovided. A clinician may choose to continue opioidtreatment with intensified monitoring, counseling,and careful documentation if it is deemed in the bestinterest of the patient. This requires, however,careful consideration and a well-documented risk

management plan that addresses the greaterresources necessary for opioid continuationfollowing evidence of misuse.

If termination of the provider/patientrelationship is deemed necessary, clinicians mustensure that the patient is transferred to the care ofanother provider and ensure that the patient hasadequate medications to avoid unnecessary risk,such as from uncontrolled or potentially dangerous


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withdrawal.17Practitioners can be held accountablefor patient abandonment if medical care isdiscontinued without justification or adequateprovision for subsequent care.

Methadone

Methadone has recently received growingattention and concern because it is frequentlyinvolved in unintentional overdose deaths.42Thesedeaths have escalated as methadone has increasinglybeen used as an analgesic drug for chronic pain.43Atone time, methadone had been used almostexclusively in opioid maintenance therapy programsto treat addiction. Its relatively long plasmaelimination half-life compared to its relatively shortanalgesic half-life makes it optimal for maintenance,allowing for once-daily dosing. But methadone onlyexerts potent analgesic effects in the early phase of

its elimination half-life, and this, along with the factthat it is among the least expensive opioids, has ledto a dramatic increase in its use for alleviatingchronic non-cancer pain.1

Methadone has unique pharmacokinetic andpharmacodynamic characteristics that addsubstantial risk to its use. Although its chemicalstructure is different from classic opioids such asmorphine, methadone acts on the same set of opioidreceptors, though with different affinities for thevarious opioid receptor subtypes.20In addition,methadone possess non-opioid receptor effects that

may explain some of its potential special efficacy.These varied effects across opioid receptors, alongwith its non-opioid properties, have garneredmethadone the reputation of being a broadspectrum opioid.20For a number of reasons,however, methadone must be titrated very carefullyin order to avoid overdose. These reasons include:20

An analgesic half-life much shorter than itselimination half-life (leading toaccumulation)

Metabolism by a group of liver enzymes thatdiffer from those associated with most other

opioids, hence leading to unexpected drug-drug interactions

Significant genetic variations in the liverenzymes that metabolize methadone, whichcontribute to the unpredictability ofmethadones effects and side effects

Metabolism may be affected by cigarettesmoking (which accelerates elimination) and

alcohol consumption (which can augmentmethadone toxicity acutely and acceleratemetabolism with chronic use)

The APS/AAPM guidelines recommend astarting dose in most opioid-naive patients of 2.5 mg

every 8 hours, with dose increases occurring nomore frequently than weekly.1 The lowest possibledose titration should be followed even in opioid-tolerant patients because methadone appears to bemore potent in patients who have been using higherdoses of the pre-switch opioid. The total daily doseof methadone on the first day of treatment shouldnot ordinarily exceed 30-40 mg/d regardless of priorexposure.44In older patients or those with renal orhepatic comorbidities, lower starting doses, lessfrequent dosing, and more cautious dose titration arerecommended. Because of its long half-life andvariable pharmacokinetics, methadone is notrecommended to treat breakthrough pain or as an as-needed medication.

When rotating from another opioid tomethadone, extreme caution must be used whenreferring to equianalgesic conversion tables. Theconsensus recommendations from an expert panelsuggest a 75 to 90% decrementin the equianalgesicdose from conventional conversion tables when aswitch is made from another opioid to methadone.45

Because the risk of overdose is particularlyacute with methadone, patients should be educatedabout these risks and counseled to use methadoneexactly as prescribed. They should also be warnedabout the dangers of mixing unauthorized substanceswith their medication. Benzodiazepines, inparticular, pose a threat. Death investigations oftenfind that benzodiazepines have been used incombination with methadone and other opioids.42Other respiratory depressants, including alcohol,pose similar risks. Dosing should, therefore, beconservative and cautious until patients demonstratethe ability to tolerate and use the drug safely.

In 2006, the FDA issued a public healthadvisory warning that methadone can cause seriouscardiac conduction disturbances, including QTinterval prolongation and Torsades de Pointes, apotentially fatal ventricular arrhythmia.46It appearsthat methadone-related corrected QT (QTc) intervalprolongation and cardiac arrhythmias can occur atany dose but are more likely at higher doses or withconcomitant use of drugs that interact withmethadone or that themselves prolong QTc.


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Although uncommon, the cardiac arrhythmias thatcan be induced by methadone can be lethal if notdetected. The cardiac health of patients who arecandidates for methadone should be assessed, withparticular attention paid to any history of heartdisease or arrhythmias.47An initial ECG may be

advisable prior to starting methadone, particularly ifa patient has a specific cardiac disease or cardiacrisk factors or is taking agents that may interact withmethadone.45

Required Patient Education

Thorough patient education about the safeuse, storage, and disposal of opioid medications isan essential part of best practices opioidprescribing. This education can be partiallyintegrated into standard patient/provider agreementsor informed consent documents. As with other

patient-directed materials, education must beprovided in a language and at a reading level(typically 6th-7thgrade) appropriate for a clinicianspatient population. Examples of effective patienteducation can be found at websites, such asOpioids911-Safety (www.opioids911.org).

Safe use of opioid medications means thatpatients carefully follow clinician instructions,including special directions about timing of dosesand whether to administer the medication with foodor without. Clinicians should be mindful of anyphysical limitations (i.e. poor eyesight) that a patient

might have that could interfere with accurate andtimely administration of prescribed opioids.

Here are some key ideas to convey topatients about proper use:48

Read the prescription container label eachtime to check dosage

Never use medicines after expiration date Never share medicines with others Do not take a pain medicine with alcohol or

other sedatives

Do not take a pain medicine to promotesleep

Never break, chew, or crush medicines,particularly ER/LA opioid medications

For transdermal products, external heat,fever, and exertion can increase absorption,leading to a potentially fatal overdose

Transdermal products with metal foilbackings are not safe for use in MRIscanners

Do not use transdermal products if they arebroken or torn

Safe Storage

Patients need to be reminded that evenchildren or close relatives can be tempted to use pain

medications they have not been prescribed. Opioidsare often obtained by teens, for example, from un-secured medicine cabinets of family and friends.

If possible, opioid pain medications shouldbe stored in a locked cabinet or other secure storageunit. Storage areas should be cool, dry, and out ofdirect sunlight. Remind patients not to storemedications in their car, to keep medications in theoriginal containers, and to avoid storing medicationsin the refrigerator or freezer unless specificallydirected to do so by a healthcare provider orpharmacist.

Proper Disposal

The Office of National Drug Control Policycurrently recommends that unused opioid painmedications be flushed down a toilet.49If flushingmedicines is not allowed in your state, instructpatients to follow the instructions of a pharmacist fordisposal or to mix the medicines with an undesirablesubstance, such as used coffee grounds, put themixture into a disposable container with a lid or asealable bag, and place it in the trash.

Before they are thrown out, personal

information, including the prescription number,should be removed from empty medicationcontainers. Patients should also be encouraged to useany drug take-back programs available in the localcommunity. [Note: the Drug EnforcementAdministration maintains up-to-date information onnational take-back programs, as well as ways to finddrug collection sites in any given locale.Information can be accessed at: www.deadiversion.usdoj.gov/drug_disposal/takeback/index.html.]

Take-Home Naloxone

In the future it may become more commonto provide patients and their caregivers withpreparations of the opioid antagonist medicationnaloxone as a way to reverse the complicationsassociated with accidental overdose. In 2014, theFDA approved a new hand-held auto-injector fornaloxone (Evzio) that can be obtained with aprescription and used by family members orcaregivers to treat a person known or suspected to


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have had an opioid overdose.50Numerous studiesand community initiatives have attested to the safety,convenience, and effectiveness of providingintranasal naloxone to patients who may be at risk ofovermedication or overdose.51This includes patientswho:

Receive prescriptions of more than 50 mg ofmorphine equivalent/day

Are being rotated from one opioid to anotherwhen there may be incomplete cross-tolerance

Are opioid nave and who have beenprescribed methadone or who are rotatedfrom another opioid to methadone

Are released after emergency medical careinvolving opioid intoxication or poisoning

Have a suspected history of substance abuse,dependence, or nonmedical opioid use.

Have known or suspected concurrent heavyalcohol use

Have a respiratory infection or illness May have difficulty accessing emergency

medical services

Efforts are underway in several states tomake intranasal and/or injectable naloxone morewidely available to the public and to train health careand emergency service providers in its use.42

Dealing With Opioid Overdose

Because respiratory depression is the mostserious potential harm from opioids, it is incumbenton clinicians to fully inform patients of this fact andeducate them (and their home caregivers, if possible)on recommended steps to take in an emergency.Respiratory depression might occur because apatient takes more than the prescribed amount, eitherintentionally or unintentionally, or because thepatient was mistakenly given too much medicationby a caregiver. Point out that respiratory depressiontypically takes some time to develop, hence therewill be early warning signs of overdose including:

Intoxicated behaviorconfusion,slurred speech, stumbling

Feeling dizzy or faint

Acting very drowsy or groggy

Unusual snoring, gasping, or snortingduring sleep

Difficulty waking up from sleep orstaying awake

Patients and their caregivers should becounseled to immediately call 911 or an emergencyservice if they observe any of these warning signs. Ifnaloxone has been provided for the patient, it shouldbe administered immediately, which will reverserespiratory depression and should allow the patient

to begin breathing more normally. If a person hasstopped breathing, artificial respiration/cardio-pulmonary resuscitation (CPR, including rescuebreathing) should be begun immediately untilemergency help arrives.

Conclusions

This monograph has summarized bestpractices for the responsible prescribing of opioidpain medications for chronic non-cancer pain. Moredetailed information on many of these topics isavailable from the resources listed to the right. The

treatment of pain is a dynamic and evolving field,and clinicians should periodically refresh theirknowledge through reading, attending seminars orother events, or by taking additional CME courses.

Clinicians face the competing demands ofrelieving pain while minimizing potential harm toboth patients and society. The steps and proceduresdescribed in this monograph provide a roadmap andstructure by which clinicians can achieve these twingoals without incurring undue burdens of time orenergy. Pharmacovigilance simply means thatprescribers apply basic principles of prudent

medicine to the needs of patients in pain. Andbecause the evidence base for current guidelinesremains sub-optimal, clinicians retain a great deal oflatitude in deciding how that vigilance is bestdeployed on a day-to-day basis.


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Table 5: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics (ER/LA opioid

analgesics)

Avinza Morphine Sulfate ERCapsules, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, and 120 mg

Dosing Interval Once a day

Key Instructions Initial dose in opioid non-tolerant patients is 30 mg. Titrate using a minimum of 3-day intervals.

Swallow capsule whole (do not chew, crush, or dissolve).

May open capsule and sprinkle pellets on applesauce for patients who can reliably swallowwithout chewing; use immediately.

Maximum daily dose: 1600 mg due to risk of serious renal toxicity by excipient, fumaricacid.

Specific Drug Interactions Alcoholic beverages or medications containing alcohol may result in the rapid release andabsorption of a potentially fatal dose of morphine.

PGP inhibitors (e.g. quinidine) may increase the absorption/exposure of morphine sulfateby about two-fold.

Use in Opioid-TolerantPatients

90 mg and 120 mg capsules are for use in opioid-tolerant patients only.

Product-Specific SafetyConcerns

None

Butrans BuprenorphineTransdermal System, 5 mcg/hr, 10 mcg/hr, 20 mcg/hr

Dosing Interval One transdermal system every 7 days

Key Instructions Initial dose in opioid non-tolerant patients when converting from less than 30 mg morphineequivalents, and in mild to moderate hepatic impairment - 5 mcg/hr dose.

When converting from 30 mg to 80 mg morphine equivalents - first taper to 30 mgmorphine equivalent, then initiate with 10 mcg/hr dose.

Titrate after a minimum of 72 hours prior to dose adjustment.

Maximum dose: 20 mcg/hr due to risk of QTc prolongation.

Applicationo Apply only to sites indicated in the Full Prescribing Information.o Apply to intact/non-irritated skin.o Skin may be prepped by clipping hair, washing site with water onlyo Rotate site of application a minimum of 3 weeks before reapplying to the

same site.o Do not cut.

Avoid exposure to heat.

Dispose of used/unused patches by folding the adhesive side together and flushing downthe toilet.

Specific Drug Interactions CYP3A4 Inhibitors may increase buprenorphine levels.

CYP3A4 Inducers may decrease buprenorphine levels.

Benzodiazepines may increase respiratory depression.

Class IA and III antiarrythmics, other potentially arrhythmogenic agents, may increase riskfor QTc prolongation and torsade de pointe.

Use in Opioid-TolerantPatients

Butrans 10 mcg/hr and 20 mcg/hr transdermal systems are for use in opioid-tolerant patientsonly.

Drug-Specific SafetyConcerns

QTc prolongation and tors

rems section no self-assessment

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