2016-CDC Guideline for Prescribing Opioids for Chronic Pain

7/25/2019 2016-CDC Guideline for Prescribing Opioids for Chronic Pain

1/22

Copyright 2016 American Medical Association. All rig hts reserved.

CDC Guideline for Prescribing Opioids for Chronic Pain

United States, 2016

Deborah Dowell, MD,MPH; TamaraM. Haegerich, PhD;Roger Chou, MD

IMPORTANCE Primary care clinicians find managing chronic pain challenging. Evidence of

long-term efficacy of opioids forchronic pain is limited. Opioiduse is associated with serious

risks, including opioid use disorder and overdose.

OBJECTIVE To provide recommendations aboutopioid prescribing for primary care clinicians

treating adultpatients with chronic pain outside of active cancer treatment, palliative care,

and end-of-life care.

PROCESS The Centers for Disease Control and Prevention (CDC) updated a 2014 systematic

review on effectiveness andrisks of opioids andconducted a supplementalreview on

benefits andharms, values andpreferences, andcosts. CDCused theGrading of

Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess

evidence type and determine the recommendationcategory.

EVIDENCE SYNTHESIS Evidence consisted of observational studies or randomized clinical trials

with notable limitations, characterized as low quality using GRADE methodology.

Meta-analysis wasnot attempted due to thelimited number of studies,variabilityin study

designs and clinical heterogeneity, and methodological shortcomings of studies. No study

evaluated long-term (1 year) benefit of opioids forchronic pain. Opioids were associated

with increased risks, including opioid use disorder, overdose, and death, with

dose-dependent effects.

RECOMMENDATIONS There are 12 recommendations. Of primary importance, nonopioid

therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits

for pain and function are expected to outweigh risks.Before starting opioids, clinicians should

establishtreatment goals with patients andconsider how opioids will be discontinued ifbenefits do notoutweigh risks. When opioids areused, clinicians should prescribe the lowest

effective dosage, carefully reassess benefits and risks when considering increasing dosage to

50 morphine milligram equivalentsor more per day, and avoidconcurrent opioids and

benzodiazepines whenever possible. Clinicians should evaluate benefits and harmsof

continued opioidtherapy with patients every 3 monthsor more frequently andreview

prescription drug monitoring program data, when available, for high-risk combinations or

dosages. For patients with opioid use disorder, clinicians should offer or arrange

evidence-based treatment, such as medication-assisted treatment with buprenorphine or

methadone.

CONCLUSIONS AND RELEVANCE The guideline is intended to improve communicationabout

benefits andrisks of opioids forchronic pain, improve safety and effectiveness of pain

treatment, and reduce risks associated with long-term opioid therapy.

JAMA. doi:10.1001/jama.2016.1464

Published onlineMarch 15, 2016.

Editorials

Author AudioInterview at

jama.com

Related articles and JAMA

Patient Page

Supplementalcontent at

jama.com

Related articles at

jamainternalmedicine.com,

jamapediatrics.com, and

jamaneurology.com

Author Affiliations: Division of

Unintentional InjuryPrevention,

National Center for InjuryPreventionand Control, Centers for Disease

Controland Prevention, Atlanta,

Georgia.

Corresponding Author: Deborah

Dowell, MD, MPH, Division of

Unintentional InjuryPrevention,

National Center for InjuryPrevention

and Control, Centers for Disease

Controland Prevention,

4770 BufordHwy NE,

Atlanta, GA 30341

([email protected]).

Clinical Review & Education

Special Communication

(Reprinted) E1


wnloaded From: http://jama.jamanetwork.com/ by a La Trobe University User on 03/15/2016
http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1910&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.19058&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2016.0664&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jamainternmed.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jamainternmed.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://ama-jps.ejpress.com/cgi-bin/prod.plex?jps_action=email_person_display&[email protected]&to_p_id=23401http://ama-jps.ejpress.com/cgi-bin/prod.plex?jps_action=email_person_display&[email protected]&to_p_id=23401http://ama-jps.ejpress.com/cgi-bin/prod.plex?jps_action=email_person_display&[email protected]&to_p_id=23401http://www.jamainternmed.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2016.0664&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2015.19058&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1910&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2016.1464&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464


2/22


The number ofpeople experiencing chronicpain is substan-

tial, with US prevalence estimated at 11.2% of the adult

population.1Patientsshouldreceiveappropriatepaintreat-

ment based on a careful consideration of the benefits and risks of

treatmentoptions. Opioidsare commonlyprescribed forpain, with

approximately3% to4% ofthe adult USpopulation prescribedlong-

term opioidtherapy.2 Evidence supportsshort-term efficacyof opi-

oids in randomized clinical trialslasting primarily 12 weeks or less,

3

and patients receivingopioid therapy for chronic painreport some

painrelief whensurveyed.4-6However,fewstudieshavebeencon-

ducted to rigorously assess the long-term benefits of opioids for

chronic pain (pain lasting >3 months) with outcomes examined at

least 1 yearlater.7Opioid painmedication usepresentsserious risks.

From 1999 to 2014, more than 165 000 persons died of overdose

relatedtoopioidpainmedicationintheUnitedStates. 8 In2013alone,

an estimated 1.9 millionpersonsabusedor weredependenton pre-

scription opioidpain medication.9Primarycarecliniciansreportcon-

cern aboutopioid pain medication misuse, find managingpatients

with chronic pain stressful, express concern about patient addic-

tion, and report insufficient training in prescribingopioids.10

The CDC Guideline for Prescribing Opioids for Chronic Pain

United States,2016, is intended forprimary careclinicians (eg, fam-

ily physicians, internists, nurse practitioners, and physician assis-

tants)whoaretreatingpatientswithchronicpain(ie,painconditions

that typicallylast>3 months or past thetime of normal tissueheal-

ing)in outpatientsettings. Theguideline is intendedto applyto pa-

tients18 years andolderwith chronic pain outside of activecancer

treatment,palliative care,and end-of-life care.Some of the recom-

mendations might be relevantfor acute care settings or other spe-

cialists,such as emergencyphysicians or dentists,but use in these

settings or by other specialists is notthe focus of the guideline.

Theguideline is intendedto improve communicationbetween

cliniciansand patients about therisksand benefitsof opioid therapy

forchronicpain, improve thesafetyand effectivenessof paintreat-

ment,andreducetherisksassociatedwithlong-termopioidtherapy,including opioid use disorder, overdose, and death. Clinical deci-

sion making should be based on a relationship between the clini-

cian and patient andan understanding of thepatientsclinicalsitu-

ation, functioning, and life context. The recommendations in the

guidelineare voluntary,rather thanprescriptive standards. Theyare

basedon emergingevidence,including observationalstudies or ran-

domizedclinicaltrials withnotablelimitations.Clinicians shouldcon-

sider thecircumstancesanduniqueneedsof each patientwhenpro-

viding care.ThisSpecial Communicationdetailsevidence reviewed

by and official recommendations issued by the Centers for Disease

Control and Prevention (CDC) and provides key highlights from a

more extensive guideline; the full guideline with detailed informa-

tionon disclosures and conflict of interest protocols, methods,sci-entificfindings,and recommendationrationalescanbe found in the

Morbidity and Mortality Weekly Report(MMWR).11

Guideline Development Process

Grading of Recommendations Assessment, Development,

and Evaluation Method

CDCused theCDC Advisory Committee on ImmunizationPractices

(ACIP) translation12 of the Grading of Recommendations Assess-

ment, Development, and Evaluation (GRADE) method for guide-

line development.13 Within the ACIP GRADE framework, the qual-

ityofabodyofevidencewasgraded,andtherecommendationswere

developedand placedinto categories (A or B) based onthe qualityof evidence, balance of benefits and harms, values and prefer-

ences, and resource allocation (Box 1).

CDCobtainedinputfrom experts,stakeholders,the public,peer

reviewers,and a federallychartered advisory committee in the de-

velopmentprocess.CDC drafted a set of recommendations and in-

vited subject matterexperts,primarycare professionalsocietyrep-

resentatives,and state agency representatives (Core Expert Group,

listed atthe endof thearticle)to provideindividual perspectives on

howCDC usedthe evidenceto developthe recommendations. CDC

asked experts toundergo a rigorous process toassess andmanage

possible conflicts of interest; full details on protocols and disclo-

suresarereportedintheMMWR.11CDCalsoengagedpartnersfrom

10 federal agencies and a Stakeholder Review Group of 18 organi-zations (listed at the end of the article) to provide comment. CDC

convened a constituent engagement webinar to obtain additional

perspectivesfrom constituents on thekey recommendations.Toob-

taincomments fromthe publicon thefull guideline,CDC published

anoticeinthe Federal Register(80 FR 77351) announcing theavail-

ability of theguidelineandthe supporting clinical andcontextualevi-

dence reviews for publiccomment. Per the final informationqual-

ity bulletin for peer review(https://www.whitehouse.gov/sites

/default/files/omb/memoranda/fy2005/m05-03.pdf),theguideline

was peer reviewed because it provides influential scientific

Box1. Interpretation of Recommendation Categories

and Evidence Type

Recommendation Categories

Recommendation categories are basedon evidence type, balance

between desirable and undesirable effects,values and

preferences,and resourceallocation (cost).

Category A recommendation: Applies to all persons;mostpatients should receive the recommended course of action.

Category B recommendation: Individual decision making needed;

differentchoiceswill be appropriate for different patients.

Clinicianshelp patients arrive at a decision consistent withpatient

values and preferences and specific clinical situations.

Evidence Type

Evidencetypeis based onstudydesign as well as a functionof

limitationsin studydesign or implementation,imprecision of

estimates,variability in findings, indirectness of evidence,

publicationbias, magnitudeof treatmenteffects, dose-response

gradient, and constellationof plausible biasesthat could

change effects.

Type 1 evidence: Randomized clinical trialsor overwhelming

evidence fromobservational studies.

Type 2 evidence: Randomized clinical trials with important

limitationsor exceptionallystrongevidencefrom observational

studies.

Type 3 evidence: Observational studies or randomized clinical

trialswith notable limitations.

Type 4 evidence: Clinical experience and observations,

observational studies withimportantlimitations, or randomized

clinical trialswith several majorlimitations.

Clinical Review & Education SpecialCommunication CDC Guideline for PrescribingOpioids for ChronicPain, 2016

E2 JAMA Publishedonline March 15, 2016 (Reprinted) jama.com


https://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2005/m05-03.pdfhttps://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2005/m05-03.pdfhttps://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2005/m05-03.pdfhttp://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464https://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2005/m05-03.pdfhttps://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2005/m05-03.pdf


3/22


information. In addition, the National Center for Injury Prevention

andControlBoardof ScientificCounselors(BSC),a federal advisory

committee, established an Opioid Guideline Workgroup (OGW) to

reviewtheguideline(membersoftheBSCandOGWarelistedatthe

endof the article).The OGWissued a reportof observations to the

BSC.At an in-personmeeting, theBSC consideredthe OGWreport,

deliberated on the draft guideline itself, and offered an additional

opportunity for public comment. The BSC voted unanimously tosupport the observations made by the OGW; that CDC adopt the

guideline recommendations that, according to the workgroups

report, had unanimous or majority support; and that CDC further

consider the guideline recommendations for which the group had

mixed opinions. At each stage, CDC reviewed and carefully

considered comments and revised the guideline.

Clinical Evidence Review

To inform the guideline development process, CDC updated a sys-

tematicreviewsponsoredbytheAgencyforHealthcareResearchand

Quality (AHRQ) on the effectiveness and risks of long-term opioid

treatmentofchronicpain7 thataddressedclinicalquestionsaboutef-

fectiveness of long-term opioid therapy for outcomes at least 1 year

later relatedto pain,function,andquality oflife.Theeffectiveness ofshort-term opioid therapy has been established previously. In ran-

domized clinical trials 12 weeks or shorter in duration, opioids were

moderatelyeffectiveforpainrelief,with smallbenefitsfor functional

outcomes; although estimates varied, based on uncontrolled stud-

ies,a high percentageof patients discontinued long-termopioid use

because of lack of efficacy and because of adverseevents.3 Opioids

have uniqueeffects such astoleranceand physical dependencethat

mightinfluenceassessmentsofbenefitovertime.Theseeffectsraise

questionsaboutwhetherfindingsonshort-termeffectivenessofopi-

oid therapy can be extrapolated to estimate benefits of long-term

therapyforchronicpain.Thus,itisimportanttoconsiderstudiesthat

provide data on long-term benefit. For opioid-related harms (over-

dose, fractures, falls, motor vehicle crashes), studies were includedwith outcomes measured at shorter intervals because such out-

comes canoccur early during opioidtherapy.

The review also considered evidence related to initiation and

titration, harms and adverse events, and risk mitigation. CDC up-

datedthe reviewwith morerecent studies.Because long-termopi-

oidusemaybeaffectedbyuseofopioidsforacutepain,CDCadded

a clinical questiononthe effectsof prescribingopioids foracutepain

on long-term use(Box 2).

CDCupdatedthesystematicliteraturesearchusingsearchterms

for opioid therapy, specific opioids, chronic pain, and comparative

study designs; assessed the overall strength of each body of evi-

dence using methodsdevelopedby theGRADEWorkingGroup; and

qualitativelysynthesized results. Completemethodsand datafor the

clinical evidence review, including information about data sources

and searches, study selection, data extraction and quality assess-

ment,datasynthesis,andupdatesearchyieldandnewevidencemay

be found inthe MMWR and associated online appendixes.11

Theupdatedreviewrevealedthatevidenceonlong-termopioid

therapy forchronicpain outside of end-of-life careremainslimited,

withinsufficient evidenceto determinelong-termbenefits,although

evidence suggests risk of serious harms that is dose-dependent.

Table 1 provides a summary of the evidence and thequalityratings

assigned.Fulldetailsonmethodologyandfindingsareavailableinthe

2014AHRQ report7 andthe MMWR report.11 The body of evidence

foreachclinical questionwascategorizedasevidencetype3 or4 (ob-

servational studies or randomized clinicaltrials withnotablelimita-

tionsor clinical experience andobservation).We highlightimportant

findings from thereview for each keyquestion(KQ)below.

KQ1:Effectivenessand Comparative Effectiveness

No study of opioid therapy vs placebo, no opioid therapy, or non-opioid therapy for chronic pain evaluated long-term (1 year) out-

comes related to pain, function, or quality of life. Most placebo-

controlled randomized clinical trials were 6 weeks or shorter in

duration.7

KQ2:Harms and Adverse Events

Long-term opioid therapy was associated with problematic pat-

terns ofopioiduse leadingto clinically significantimpairmentor dis-

tress. Varyingterminologyhas beenused to reflect thispattern, in-

cluding addiction (more informally), opioid abuse and opioid

dependence (perDiagnostic and Statistical Manual of Mental Dis-

orders [Fourth Edition][DSM-IV] or International Classification of Dis-

eases, Ninth Revision, Clinical Modification[ICD-9-CM]), and opi-

oid use disorder (perDSM-5). Such disorders are manifested bysimilar criteria, including unsuccessful efforts to reduce or control

useand useresulting in socialproblemsand a failure tofulfill major

roleobligationsatwork,school,orhome.Disordersaredifferentfrom

tolerance (diminished response to a drug with repeated use) and

physical dependence (adaptation to a drug that produces symp-

toms of withdrawal when the drug is stopped), both of which can

exist without a diagnosed disorder.

Long-termopioidtherapy wasassociated withan increased risk

of an opioid abuse or dependence diagnosis (as defined byICD-

9-CMcodes) vs no opioid prescription.14 In primary care settings,

prevalenceof opioid dependence(usingDSM-IVcriteria)rangedfrom

3%to 26%.15-17 Factorsassociated withincreasedrisk of misuse in-

cluded history of substance use disorder, younger age, major de-pression, and use of psychotropicmedications.16,18Opioiduse was

associated with a dose-dependent increased risk of fatal and non-

fatal overdose19,20 (Table 2). Otherrisks associated withopioiduse

includedcardiovascularevents,28,29endocrinologicharms,30,31and

road trauma.32

KQ3:Dosing Strategies

Initiationoftherapywithanextended-release/long-acting(ER/LA)opi-

oidwas associated with greaterrisk of nonfatal overdose than initia-

tion with animmediate-release opioidin 1 study, with riskgreatestin

thefirst2 weeks after initiation oftreatment.33Three studiesof vari-

ous ER/LA opioids found no clear differences related to pain or

function34-36;thereweremixedfindingsregardingthedifferencesbe-

tween methadone and morphine in overall risk for nonfatal or fatal

overdose,37-39 suggestingthat risks of methadone might vary in dif-

ferent settings. One study found no differences between more lib-

eral dose escalation and maintenance of current doses after 12

months40; evidence on other comparisons related to opioid dosing

strategieswas toolimited to determine effectson outcomes.

KQ4:Risk Assessment and Risk MitigationStrategies

Evidence on the accuracy of risk assessment instruments for pre-

dicting opioid abuseor misuse wasinconsistentfor the Opioid Risk

CDC Guideline for PrescribingOpioids for Chronic Pain,2016 Special Communication ClinicalReview & Education

jama.com (Reprinted) JAMA Publishedonline March 15, 2016 E3


http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464


4/22


Tool41-43 and limited for other risk assessment instruments.41,44,45

No study evaluated the effectiveness of risk mitigation strategies.

KQ5: Effect of OpioidTherapyfor Acute Pain on Long-term Use

Studies examining patientswho underwent low-risk surgery or ex-

perienced low back pain from injury revealed that opioid therapy

prescribed for acutepain was associated with greater likelihood of

long-term use.46,47Comparedwithnoearlyopioiduseforacutelow

backpain,theadjustedoddsratioforreceiving5ormoreopioidpre-

scriptions from 30 to 730days after onset was 2.08 (95% CI,1.55-

2.78)for1 to140 morphine milligramequivalents(MME)perday and

increasedto6.14(95%CI,4.92-7.66)for450MMEormoreperday. 47

Box2. KeyQuestions forthe ClinicalEvidence Review

KeyQuestion1. Effectivenessand Comparative Effectiveness

a. In patients with chronic pain, what is theeffectivenessof

long-term opioid therapy vs placebo or no opioid therapy

for long-term(1 year) outcomes related to pain,function,

andquality oflife?

b. Howdoes effectivenessvary depending on: (1) the specific type

or causeof pain (eg,neuropathic, musculoskeletal [includinglow

back pain], fibromyalgia, sickle celldisease,inflammatory pain,

and headache disorders); (2) patient demographics (eg,age, race,

ethnicity, gender); and (3) patient comorbidities (includingpast

or current alcohol or substanceuse disorders, mental health

disorders, medical comorbidities, and highrisk foraddiction)?

c. In patientswithchronic pain, whatis thecomparativeeffectiveness

of opioidsvs nonopioid therapies (pharmacologicor

nonpharmacologic) on outcomes relatedto pain,function,

andqualityof life?

d. In patients withchronic pain,what is the comparative effective-

nessof opioids plus nonopioidinterventions(pharmacologic or

nonpharmacologic) vs opioids or nonopioidinterventionsalone

on outcomes related topain,function, quality oflife,and dosesof

opioids used?

KeyQuestion2. Harmsand AdverseEvents

a. In patientswithchronic pain, whatarethe risks ofopioids vs

placeboor noopioidon (1)opioidabuse, addiction,and related

outcomes;(2) overdose;and (3)otherharms, including

gastrointestinal-related harms,falls, fractures, motorvehicle

crashes, endocrinologic harms,infections,cardiovascular events,

cognitive harms,and psychologicalharms (eg, depression)?

b. How do harms vary depending on(1) thespecific type or cause of

pain (eg, neuropathic, musculoskeletal [includingback pain],

fibromyalgia, sickle cell disease, inflammatory pain,headache

disorders); (2) patient demographics; (3) patient comorbidities

(including past orcurrent substanceuse disorder orat high risk

foraddiction);and (4) thedoseof opioids used?

KeyQuestion3. Dosing Strategies

a. In patientswithchronic pain, whatis thecomparativeeffectivenessofdifferentmethodsfor initiatingand titrating opioidson

outcomes relatedto pain, function, andquality oflife;risk of

overdose,addiction,abuse, ormisuse; anddosesof opioidsused?

b. In patients withchronic pain,what is the comparative effective-

ness of immediate-release vs extended-release/long-acting

(ER/LA) opioids on outcomes related to pain,function, and

quality oflife;riskof overdose, addiction, abuse,or misuse; and

dosesof opioids used?

c. In patients with chronic pain, what is thecomparative effective-

ness ofdifferent ER/LAopioids on outcomes related to pain,

function,and quality oflife andriskof overdose, addiction,

abuse, or misuse?

d. In patients withchronic pain,what is the comparative effective-

nessof immediate-release plus ER/LAopioidsvs ER/LA opioids

aloneon outcomes related to pain, function, andqualityof life;risk ofoverdose,addiction, abuse,or misuse; anddosesof

opioids used?

e. In patients with chronic pain, what is thecomparative

effectivenessof scheduled, continuous vs as-needed dosing of

opioids onoutcomesrelatedto pain, function, andqualityof life;

risk ofoverdose, addiction, abuse,or misuse; anddoses of

opioids used?

f. In patients with chronic pain on long-termopioid therapy, what is

the comparative effectiveness of doseescalation vs dose

maintenanceor useof dose thresholds on outcomes related to

pain, function, andqualityof life?

g. In patients on long-termopioid therapy, whatis the comparative

effectivenessof opioid rotation vs maintenance of current opioid

therapy onoutcomesrelated to pain, function,and quality of life;

anddoses of opioids used?

h. In patients on long-termopioid therapy, whatis the comparative

effectivenessof different strategies for treating acute

exacerbationsof chronic pain on outcomesrelated to pain,

function,and quality of life?

i. In patients onlong-term opioidtherapy, what arethe effects of

decreasing opioid dosesor of tapering offopioids vs continuation

ofopioids onoutcomesrelated to pain, function,quality oflife,

and withdrawal?

j. In patients on long-term opioid therapy, what is the comparativeeffectivenessof different tapering protocolsand strategies on

measures related to pain,function,quality of life, withdrawal

symptoms, and likelihood of opioid cessation?

KeyQuestion4. RiskAssessment andRisk MitigationStrategies

a. In patients withchronicpain beingconsidered for long-term

opioid therapy, whatis the accuracyof instruments for predicting

riskof opioid overdose, addiction, abuse, or misuse?

b. In patients with chronic pain, what is theeffectivenessof useof

riskpredictioninstrumentson outcomes related to overdose,

addiction,abuse, or misuse?

c. Inpatientswith chronic pain prescribedlong-term opioid therapy,

whatis the effectiveness of risk mitigationstrategies, including

(1) opioid management plans, (2) patient education,(3) urine

drug screening, (4) use of prescription drug monitoring program

data,(5) use of monitoring instruments, (6) morefrequent

monitoring intervals, (7) pill counts, and(8) useof

abuse-deterrent formulations on outcomesrelated to overdose,

addiction,abuse, or misuse?

d. What is the comparative effectivenessof treatmentstrategies for

managing patients with addiction to prescription opioids on

outcomes related to overdose, abuse, misuse, pain,function, and

quality of life?

Key Question5. Effectof OpioidTherapy forAcute Pain

on Long-termUse

a. In patients with acute pain, what arethe effects ofprescribing

opioidtherapyvs not prescribingopioid therapy for acute pain on

long-termopioid use?

Keyquestions1-4 weredeveloped forthe Agency for Healthcare Researchand

Quality review.7






5/22
http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464


6/22


7/22


8/22


Ta

ble1.GRADER

at

ingso

fthe

Ev

iden

ce

for

the

Key

Cli

nic

alQ

ues

tionsa

(con

tin

ue

d)

Outcome

Studies

Limitations

Inconsistency

Imprecision

Typeo

f

Eviden

ce

b

OtherFactors

EstimatesofEffec

torFindings

RiskAssessmentandRiskMitigationStrategies(KeyQuestion4)

Diagnosticaccuracyofinstrumentsfor

predictingriskforopioidoverdose,

addiction,

abuse,

ormisuseamong

patientswithchronicpainbeing

consideredforlong-

term

opioidtherapy

OpioidRiskTool

3studiesofdiagnostic

accuracy

(n=496);

newforupdate:


accuracy

(n=320)

Serious

limitations

Veryserious

inconsistency

Serious

imprecision

4

None

identified

Basedonacutoff

scoreof>4(orunspecified),

5studies(2fair-q

uality

,3poor-quality)

reportedsensitivitythatrangedfrom

0.2

0-

0.9

9andspecificitythatrangedfrom

0.1

6-

0.8

8.

Screenerandopioidassessment

forpatientswithpain

,version1


accuracy

(n=203)

Veryserious

limitations

No

inconsistency

Serious

imprecision

3

None

identified

Basedonacutoff

scoreof8

,sensitivitywas

0.6

8andspecifici

tywas0

.38in1study,

fora

positivelikelihood

ratioof1

.11anda

negativelikelihoo

dratioof0

.83

.Basedon

acutoffscoreof>

6,

sensitivitywas0

.73

in1study.

Screenerandopioidassessmentfor

patientswithpain:revised

Newforupdate:


accuracy

(n=320)

Veryserious

limitations

No

inconsistency

Serious

imprecision

3

None

identified

Basedonacutoff

scoreof>3orunspecified

,

sensitivitywas0.25and0

.53andspecificity

was0

.62and0

.73in2studies,

forlikelihood

ratioscloseto1.

Briefriskinterview

Newforupdate:


accuracy

(n=320)

Veryserious

limitations

No

inconsistency

Serious

imprecision

3

None

identified

Basedonahigh-riskassessment

,sensitivity

was0

.73and0

.83andspecificitywas0

.43

and0

.88in2stud

ies,

forpositivelikelihood

ratiosof1

.28and

7.1

8andnegativelikelihood

ratiosof0

.63and

0.1

9.

Effectivenessofriskprediction

instrumentsonoutcomesrelated

tooverdose,

addiction,

abuse,

ormisuseinpatientswith

chronicpain

Outcomesrelatedtoabuse

None

NA

NA

NA

Insuffi

cient

NA

Noevidence.

Effectivenessofriskmitigation

strategies,

includingopioid

managementplans,

patienteducation,

urinedrugscreening,

useof

prescriptiondrugmonitoringprogram

data

,useofmonitoringinstruments

,

morefrequentmonitoringintervals

,

pillcounts

,anduseofabuse-

deterrent

formulations,

onoutcomesrelated

tooverdose,

addiction,

abuse,

ormisuse


None

NA

NA

NA

Insuffi

cient

NA

Noevidence.

Comparativeeffectivenessoftreatment

strategiesformanagingpatientswith

addictiontoprescriptionopioids


None

NA

NA

NA

Insuffi

cient

NA

Noevidence.

(continued)






9/22


Contextual Evidence Review

CDCconducted a contextual evidence review to assist in develop-

ing the recommendations by providing an assessment of the bal-

ance ofbenefitsand harms,values andpreferences, andcost, con-

sistent with the GRADE approach (Box 3). Rapid review methods

wereused to streamlinethe process andobtainevidencequickly(eg,

by limitingdatabase searchesand summarizingstudy qualitybased

on author reports rather thanapplying objectivequalityratingpro-tocols). Full details on methodology, including data sources and

searches, inclusion criteria, study selection,and dataextraction and

synthesis, and findings are available in theMMWRreport.11 In this

article, we summarize benefits and harms of nonopioid therapies

found in theclinicalliterature and harms of opioidtherapy, includ-

ingadditional studies notincludedin theclinicalevidencereview (eg,

studies not restricted to patients with chronic pain).

Severalnonpharmacologicand nonopioid pharmacologictreat-

ments were found to be effective for chronic pain in studies rang-

ing in duration from 2 weeks to 6 months48-66 (Table 3). For ex-

ample,cognitivebehavioral therapy (CBT)had smallpositive effects

on disability and catastrophic thinking.66 Exercise therapy re-

duced pain and improved function in chronic low back pain54; im-

provedfunction andreducedpainin osteoarthritisof theknee51and

hip52; andimproved well-being, fibromyalgiasymptoms,andphysi-

cal function in fibromyalgia.48 Multimodal and multidisciplinary

therapies helped reduce pain and improve function more effec-

tively than single modalities.55,67 Multiple guidelines recom-

mended acetaminophen as first-line pharmacotherapy for

osteoarthritis68-73 or for low back pain74 and nonsteroidal anti-

inflammatory drugs (NSAIDs)as first-line treatmentfor osteoarthri-

tis or low back pain70,74; first- and second-line drugs for neuro-

pathic pain include anticonvulsants (gabapentin or pregabalin),

tricyclicantidepressants,and serotonin-norepinephrinereuptakein-

hibitors (SNRIs).75-78 Nonsteroidal anti-inflammatory drugs have

been associated with hepatic, gastrointestinal, renal, and cardio-

vascular risks.63,73,79

Opioid-relatedoverdose riskwas dose-dependent, withhigher

opioid dosagesassociatedwithincreasedoverdoserisk(Table2).19-27

Compared with dosages of1 to


10/22


riskstratificationand mitigation strategies foridentifyingrisky opioid-

taking behaviors and prescribing practices, such as checking pre-

scription drug monitoring program (PDMP) data95 and urine drug

testing,96 as well as co-prescription of naloxone.97 In addition,

methadoneand buprenorphine foropioid use disorder were found

to increase retentionin treatmentand to decrease illicit opioiduseamong patients with opioid use disorder, and some studies sug-

gestthat effectivenessis enhanced whenpsychosocial treatments

are used in conjunction with medication-assisted therapy.98-102

Recommendations

The guideline includes 12 recommendations (Box 5). GRADE

recommendation categories were based on the following

assessment:

Noevidenceshowsalong-termbenefitofopioidsinpainandfunc-

tion vsno opioids forchronicpainwithoutcomesexaminedat least

1 yearlater (withmost placebo-controlledrandomizedclinical trials

6 weeks in duration).

Extensive evidence shows the possible harms of opioids (includ-

ing opioid use disorder, overdose, and motor vehicle injury).Extensive evidence suggests some benefits of nonpharmaco-

logic and nonopioid pharmacologic therapy, with less harm.

Determining When to Initiate or Continue Opioids

forChronic Pain

1. Nonpharmacologic therapy and nonopioid pharmacologic

therapy are preferred for chronic pain. Clinicians should consider

opioid therapy only if expected benefits for both pain and func-

tionareanticipatedtooutweighriskstothepatient.Ifopioidsare

used, they should be combined with nonpharmacologic therapy

Table 2. RelationshipBetween Doseand Overdose

Source Topic Population Primary Outcomes Key Findings

Bohnertet al,27 2016a

Matched case-control studyexamining associationbetween opioid dosage andfatal overdose

Veterans Health Administrationpatients with chronic painreceiving opioid therapy,2004-2009

Unintentional fatal opioidoverdose

24% of controls had dosages >50 MME/d, but59% of cases had dosages above this level.

Bohnertet al,22 2011a

Case-cohort studyexamining the associationbetween prescribed opioid

dosage in MME/d and risk ofopioid overdose death

Veterans Health Administrationpatients receiving opioid therapyfor pain, 2004-2005

Fatal opioid overdose Among patients with chronic pain, receiving20-


11/22


and nonopioid pharmacologic therapy, as appropriate. (Recom-

mendationcategory: A; evidence type: 3)

Nonpharmacologictherapy (such as exercisetherapy andCBT)

shouldbeusedtoreducepainandimprovefunctioninpatientswith

chronic pain. Aspects of these approaches canbe used even when

there is limited accessto specialtycare. For example, primary care

clinicians can encourage patients to take an active role in the care

plan and support patientsin engagingin exercise. Nonopioidphar-

macologic therapy (such as NSAIDs, acetaminophen, anticonvul-sants, andSNRIs)should be usedwhen benefits outweighrisks and

should be combinedwith nonpharmacologictherapy. Opioids should

not be consideredfirst-line or routine therapy for chronic painout-

side of activecancer, palliative, andend-of-lifecare, given small to

moderate short-termbenefits,uncertainlong-termbenefits, andpo-

tential for serious harms; althoughevidence on long-termbenefits

of nonopioid therapies is also limited, these therapies are also as-

sociated with short-term benefits, and risks are much lower. This

doesnotmean that patients shouldbe requiredto sequentially fail

nonpharmacologic and nonopioid pharmacologic therapy before

proceedingto opioid therapy. Rather, expected benefits specific to

the clinical context should be weighed against risks before initiat-

ing therapy. In someclinicalcontexts (eg, headache, fibromyalgia),expectedbenefitsof initiatingopioidsare unlikelyto outweighrisks

regardless of previous nonpharmacologic and nonopioid pharma-

cologictherapiesused. Inother situations(eg, seriousillnessin a pa-

tientwithpoorprognosisforreturntopreviousleveloffunction,con-

traindicationsto other therapies,and clinicianand patientagreement

that the overriding goal is patient comfort), opioids might be ap-

propriateregardless of previoustherapies used.If opioidsare used,

theyshouldbe combinedwithnonpharmacologic therapyand non-

opioid pharmacologic therapy, as appropriate, to provide greater

benefits to patients.

2. Before starting opioid therapy for chronic pain, clinicians

should establish treatment goals with all patients, including real-

istic goals for pain and function, and consider how opioid

therapy will be discontinued if benefits do not outweigh risks.

Clinicians should continueopioid therapy only if there is clinically

meaningful improvement in pain and function that outweighs

risks to patient safety.(Recommendation category: A; evidence

type: 4)Before opioid therapy is initiated for chronic pain, clinicians

should determine how effectiveness will be evaluated and should

establish treatment goals with patients. Clinicians seeing new

patients already receiving opioids should establish treatment

goals for continued treatment. Goals should include improvement

in both pain relief and function. However, there are some clinical

circumstances under which reductions in pain without improve-

ment in physical function might be a more realistic goal (eg, dis-

eases typically associated with progressive functional impairment

or catastrophic injuries such as spinal cord trauma). Experts noted

that function can include emotional and social as well as physical

dimensions. In addition, experts emphasized that mood has

important interactions with pain and function. Clinicians may use

validated instruments such as the 3-item Pain average, interfer-

ence with Enjoyment of life, and interference with General activ-

ity (PEG) Assessment Scale103 to track patient outcomes. Clini-

cally meaningful improvement has been defined as a 30%

improvement in scores for both pain and function.104 Because

depression, anxiety, and other psychological comorbidities often

coexist with and can interfere with resolution of pain, clinicians

should use validated instruments to assess for these conditions

and ensure that treatment for these conditions is optimized.

3. Before starting and periodically during opioid therapy,

clinicians should discuss with patients known risks and realistic

benefits of opioid therapy and patient and clinician responsibili-

ties for managing therapy. (Recommendation category: A;

evidence type: 3)Cliniciansshouldensurethatpatientsareawareofpotentialben-

efitsof,harms of, andalternativesto opioids before startingor con-

tinuing opioid therapy. Clinicians are encouraged to haveopen and

honest discussions withpatientsto inform mutual decisionsabout

whether to start or continue opioid therapy. Important consider-

ations include the following:

Be explicit and realistic about expected benefits of opioids, ex-

plainingthat whileopioidscan reduce painduringshort-term use,

there is no good evidence that opioids improve pain or function

with long-term useand that complete reliefof pain is unlikely.

Emphasize improvement in function as a primary goal and that

function canimprove even when pain is stillpresent.

Advise patients about serious adverse effects of opioids, includ-ing potentially fatal respiratory depressionand development of a

potentially serious lifelong opioid use disorder.

Advise patients about common effects of opioids, suchas consti-

pation, dry mouth, nausea, vomiting, drowsiness, confusion, tol-

erance, physical dependence, and withdrawal symptoms when

stopping opioids.

Discuss effects that opioids may have on ability to safely operate

a vehicle, particularlywhenopioids areinitiated, whendosagesare

increased,orwhenothercentralnervoussystemdepressants,such

as benzodiazepines or alcohol, are used concurrently.

Box3. Key Areas forthe Contextual Evidence Review

Effectiveness of alternativetreatments, including

nonpharmacologic (eg, cognitivebehavioral therapy, exercise

therapy, interventionaltreatments, multimodal pain treatment)

and nonopioidpharmacologictreatments (eg,acetaminophen,

nonsteroidal anti-inflammatory drugs, antidepressants,

anticonvulsants), including studies of any duration.

Benefitsand harms of opioid therapy (including additionalstudies not included in the clinical evidence review,such as

studies thatwere not restrictedto patients withchronicpain,

evaluatedoutcomesat any duration, performed ecological

analyses, or used observationalstudy designs other thancohort

and case-cohort control studies) related to specific opioids, high-

dosetherapy, co-prescriptionwith other controlled substances,

duration of use,special populations, and potential usefulness of

riskstratificationor mitigationapproaches; in addition to

effectiveness of treatments associated with addressing potential

harms of opioid therapy (opioid use disorder).

Clinician and patient values and preferences related to opioids

and medicationrisks, benefits,and use.

Resource allocation, including costs and economicefficiency of

opioid therapy and riskmitigationstrategies.

Clinical guidelines relevant to opioidprescribing to complementthe Centers for DiseaseControl and Prevention recommendations

(eg, guidelines on alternative treatments, guidelines with

recommendations relatedto specificclinician actionssuch as

urine drugtesting or opioid tapering protocols).






12/22


Table 3. Effectiveness and Harms of Nonpharmacologicand Nonopioid Pharmacologic Treatmentsa

Sou rce Topic or Inter ve nti on Par ticipants or Population Primar y Ou tcome s Key Findings St udy Qu ality

Buschet al,48

2007

Exercise training vsuntreated control ornonexercise intervention

Systematic review of 33 RCTswith fibromyalgia patients

Global well-being,selected signs andsymptoms, andphysical function

Exercise training improves globalwell-being and physical function.Supervised aerobic exercise traininghas beneficial effects on physicalcapacity and fibromyalgiasymptoms.

Four studies wereclassified as highquality, 15 asmoderate quality, and14 as low quality

Chaparro

et al,49

2014

Noninjectable opioids vs

placebo or other treatments

Systematic review of 15 RCTs

with patients with chronic lowback pain

P ai n O ne t ri al found t ra ma do l si mi la r t o

celecoxib for pain relief. Two trialsdid not find a difference betweenopioids and antidepressants for painor function.

Low- to

moderate-qualityevidence

Collinset al,50

2000

Antidepressants vs placebo;anticonvulsants vs placebo

Systematic review of 19 RCTs fordiabetic neuropathy orpostherpetic neuralgia

Pain For diab etic neu rop athy, the NN Tfor 50% pain relief was 3.4 forantidepressants (12 trials, 10evaluated TCAs and 3 SSRIs) and2.7 for anticonvulsants (3 trials).For postherpetic neuralgia, the NNTwas 2.1 for antidepressants (3studies evaluating TCAs) and 3.2 foranticonvulsants (1 study evaluatinggabapentin).

The mean and medianquality score forincluded studies was4 on a scale of 1-5

Fransenet al,51

2015

Exercise vs nonexercisegroup (active or notreatment)

Systematic review of 54 RCTs orquasi-randomized trials for kneeosteoarthritis

Reduced joint painor improvedphysical functionand quality of life

Exercise reduced pain, improvedfunction, and improved quality oflife immediately after treatment; instudies providing posttreatmentfollow-up data, improved pain and

function were sustained for 2-6 mo.

High-quality evidencefor reduced pain andimproved quality oflife andmoderate-quality

evidence for improvedfunction

Fransenet al,52

2014

Exercise vs nonexercisegroup (active or notreatment)

Systematic review of 10 RCTs orquasi-randomized trials for hiposteoarthritis

Reduced joint painand improvedphysical functionand quality of life

Exercise reduced pain and improvedfunction immediately aftertreatment; in studies providingposttreatment follow-up data,improved pain and function weresustained for at least 3-6 mo.

High-quality evidencefor reduced pain andimproved function

Huseret al,53

2013

Duloxetine vs placebo;milnacipran vs placebo

Systematic review of 10 RCTs forfibromyalgia patients

Benefits andharms

Duloxetine and milnacipran reducedpain by a small amount comparedwith placebo.

Risk of bias inincluded studies waslow

Haydenet al,54

2005

Exercise therapy vs notreatment, otherconservative treatments

Systematic review consisting of61 RCTs for low back pain

Pain, function Exercise therapy reduces pain andimproves function with smallmagnitudes of effect. Effectivenessof exercise therapy appears to begreater in populations visiting ahealth care provider compared withthe general population.

Only a small numberof studies rated ashigh quality; potentialpublication bias

Lee et al,55

2014

CIM therapies vs single

self-care CIM, nonself-careCIM, usual care/notreatment, othermultimodal program, orother control

Systematic review of 26 RCTs for

management of chronic pain

Pain symptoms Integrative multimodal therapies

resulted in positive, but sometimesmixed, effects on pain symptomscompared with active controls orsingle self-care modalities. Morestudies are needed to make strongconclusions about effectiveness.

Large majority of

poor quality, includingweaknesses inrandomization andallocationconcealment

Lunnet al,56

2014

Duloxetine vs placebo orother controls

Systematic review of 18 RCTs forneuropathic pain, chronic painconditions without identifiedcause, or fibromyalgia

Benefits andharms ofduloxetine

Duloxetine at 60 mg and 120 mgdaily, but not lower dosages, wereeffective in reducing pain indiabetic peripheral neuropathy painand in fibromyalgia.

Moderate-qualityevidence for diabeticneuropathy;lower-qualityevidence forfibromyalgia; somerisk of bias

Mooreet al,57

2009

Pregabalin vs placebo orany active control

Systematic review of 25double-blind RCTs forpostherpetic neuralgia, painfuldiabetic neuropathy, centralneuropathic pain, or fibromyalgia

Analgesic efficacyand associatedadverse events

Pregabalin was effective in patientswith postherpetic neuralgia,diabetic neuropathy, centralneuropathic pain, and fibromyalgiaat doses of 300 mg, 450 mg, and600 mg (but not at 150 mg) daily.NNTs were generally 6 formoderate benefit in postherpeticneuralgia and diabetic neuropathybut 7 for fibromyalgia.

Studies all had Oxfordquality scores basedon randomization,blinding, andreporting of dropout3 (out of maximumof 5)

Mooreet al,58

2014

Gabapentin vs placebo Systematic review of 37 RCTs forneuropathic pain or fibromyalgia

Analgesic efficacyand adverseeffects

Gabapentin was significantly moreeffective than placebo in reducingpain in diabetic neuropathy andpostherpetic neuralgia. Evidencewas insufficient for otherconditions.

Second-tierevidence (some riskof bias, but adequatenumbers in the trials)

(continued)






13/22


Table 3. Effectiveness and Harms of Nonpharmacologic and NonopioidPharmacologic Treatmentsa (continued)

Sou rce Topic or Inter vention Par ticipants or P opu latio n Primar y Outcomes Ke y Findings Study Quality

Roelofset al,59

2008

NSAIDs and COX-2 inhibitorsvs control

Systematic review of 65 RCTs fornonspecific low back pain

Acute low backpain

NSAIDs are more effective thanplacebo for acute and chronic lowback pain without sciatica, but havemore adverse effects. NSAIDs arenot more effective thanacetaminophen but had moreadverse effects. No type of NSAIDs,

including COX-2 inhibitors, wasfound to be more effective thanother NSAIDs.

Mixed high- andlow-quality studies

Saartoet al,60

2010

Antidepressants vs placeboor other controls

Systematic review of 61 RCTs forneuropathic pain

Pain TCAs and venlaf axine have lowNNTs (3.6 and 3.1, respectively) forat least moderate pain relief.

Study quality limitedby insufficientreporting detail

Salernoet al,61

2002

Antidepressants vs placebo Systematic review of 9 RCTs forchronic back pain

Back pain Antidepressants were associatedwith small but significantimprovement in pain severity;improvements in function were notsignificant. Most (6) studiesevaluated TCAs.

Moderate-qualitystudies

Staigeret al,62

2003

Antidepressants vs placebo Systematic review of 7 RCTs inpatients with chronic low backpain

Back pain Four of 5 studies evaluating TCAand tetracyclic antidepressantsfound significant improvement inchronic low back pain. Otherantidepressants studied (2 studiesevaluating SSRIs and 1 evaluatingtrazodone) did not show significant

pain improvement.

Mixed quality (qualityscores ranged from11-19 out of 22)

Trelleet al,63

2011

NSAIDs vs other NSAIDs orplacebo

Meta-analysis of 31 RCTscomparing any NSAID with otherNSAID or placebo for any medicalcondition

Myocardialinfarction, stroke,cardiovasculardeath, death fromany cause

Compared with placebo, NSAIDswere associated with increased riskof myocardial infarction, stroke,and cardiovascular death.

Generally high

Welschet al,64

2015

Opioids (includingtramadol) vs nonopioids(including acetaminophen,NSAIDs/COX-2 inhibitors,mexiletine, anticonvulsants,antidepressants, and musclerelaxants)

Systematic review of 10 RCTs inpatients with neuropathic pain,low back pain, or osteoarthritis

Efficacy (includingvarious painmeasures),tolerability, andsafety

There was no significant differencebetween opioids and nonopioidanalgesics in pain reduction;nonopioids were superior to opioidsin improving physical function andwere better tolerated. Whenpatients from tramadol trials(n randomized = 2788) wereremoved from results of the review,results for pain and function forpatients receiving opioids(morphine) compared withalternative drugs(n randomized = 223) had wide,

overlapping confidence intervals.Improved tolerability for alternativedrugs vs morphine remainedsignificant.

One study had a high,2 studies a moderate,and 7 studies a lowstudy quality

Wiffenet al,65

2014

Carbamazepine vs placeboor other active control

Systematic review consisting of10 RCTs in adults with chronicneuropathic pain or fibromyalgia

Pain relief Carbamazepine provided better painrelief than placebo for trigeminalneuralgia, diabetic neuropathy, andpoststroke pain for 4 weeks.Dizziness and drowsiness werecommonly reported withcarbamazepine. In 4 studies, 65% ofpatients receiving carbamazepine vs27% receiving placebo experienced1 adverse event. In 8 studies, 3%of patients receiving carbamazepinewithdrew because of adverse events(vs 0% taking placebo).

Third-tier evidence(trials involving smallnumbers ofparticipants;considered likely tobe biased, withoutcomes of limitedclinical utility, orboth)

Williamset al,66

2012

Cognitive behavioraltherapy or behavioral

therapy

Systematic review of 42 RCTs forpatients with nonmalignant

chronic pain except headache

Pain, disability,mood, and

catastrophicthinking

Cognitive behavioral therapy wasfound to have small to moderate

effects on pain, disability, mood,and catastrophic thinkingimmediately after treatment whencompared with usual treatment ordeferred cognitive behavioraltherapy, but only effects on moodpersisted at follow-up. Behavioraltherapy had a positive effect onmood immediately after treatment.

Mean quality of studydesign, 15.8 out of

26 (SD 4.3; range,9-24 out of 26)

Abbreviations: CIM,complementary and integrativemultimodal; COX-2,cyclooxygenase 2; NNT, number needed to treat; NSAID, nonsteroidalanti-inflammatory

drug;RCTs, randomizedclinical trials;SSRIs, selective serotonin reuptake inhibitors;TCA, tricyclic antidepressants.

a Allthe studies in this table were included in thecontextual evidencereview.






14/22


Discussincreased risks foropioiduse disorder, respiratory depres-sion, and death at higher dosages, along with the importance of

taking only theamount of opioids prescribed.

Reviewincreasedrisks forrespiratorydepressionwhen opioidsare

taken withbenzodiazepines, other sedatives,alcohol, illicit drugs

such as heroin, or other opioids.

Discuss risks to household members and other individuals if opi-

oids are intentionally or unintentionally shared with others for

whom they are notprescribed, includingthe possibility that oth-

ersmightexperienceoverdoseatthesameoratlowerdosagethan

prescribedforthepatientandthatyoungchildrenaresusceptible

to unintentional ingestion. Discuss storage of opioids in a secure,

preferably locked location and options for safe disposal of un-

used opioids.

105

Discuss the importance of periodic reassessment to ensure opi-

oids are helping to meet patient goals andto allow opportunities

for opioid discontinuation and consideration of additional non-

pharmacologic and nonopioid pharmacologic treatment options

if opioids arenot effectiveor areharmful.

Discuss planned use of precautions to reduce risks,including use

ofPDMP information andurine drugtesting.Consider includingdis-

cussion of naloxone use for overdose reversal.

Consider whether cognitive limitationsmight interfere withman-

agementofopioidtherapy(forolderadultsinparticular),andifso,

determine whether a caregivercan responsibly co-managemedi-

cation therapy. Discuss theimportance of reassessing safer medi-

cationuse with both thepatient andcaregiver.

Opioid Selection, Dosage, Duration, Follow-up,

and Discontinuation

4.When startingopioidtherapy forchronicpain,cliniciansshould

prescribeimmediate-releaseopioids instead of extended-release/

long-acting (ER/LA) opioids.(Recommendation category: A; evi-

dence type: 4)

Clinicians should not initiate opioid treatmentwith ER/LA opi-

oids and should not prescribe ER/LA opioids for intermittent use.

In general, avoiding the use of immediate-release opioids in com-

bination with ER/LA opioids is preferable.

When anER/LAopioid is prescribed, usinga product with pre-

dictable pharmacokinetics and pharmacodynamics is preferred to

minimize unintentional overdose risk.Methadoneshouldnotbe thefirstchoice foran ER/LAopioid. Only

clinicianswho arefamiliar withmethadones uniquerisk profileand

who are prepared to educate and closely monitor their patients

including risk assessment for QT prolongation and consideration

of electrocardiographic monitoringshould consider prescribing

methadone for pain.

Because dosing effects of transdermal fentanyl are often misun-

derstood by both clinicians and patients, only clinicians who are

familiarwith thedosingand absorption propertiesof transdermal

fentanyl andare prepared to educate their patients about itsuse

should consider prescribingit.

5. When opioids are started, clinicians should prescribe the

lowest effective dosage. Clinicians should use caution whenpre-scribing opioids at any dosage, should carefully reassess evi-

dence of individual benefits and risks when considering increas-

ingdosageto 50 morphine milligramequivalents(MME) or more

per day, and shouldavoid increasing dosage to 90 MMEor more

perdayor carefullyjustify a decisionto titrate dosage to90 MME

or more perday. (Recommendation category: A; evidence type:3)

Clinicians should start opioids at the lowest effective dosage,

use caution when increasing opioid dosages, and increase dosage

bythe smallest practical amount.Before increasingtotalopioiddos-

age to50 MME ormore perday, clinicians shouldreassess whether

Table 4. MorphineMilligram Equivalent Doses

for CommonlyPrescribed Opioidsa

Opioidb Conversion Factor

Codeine 0.15

Fentanyl transdermal, g/h 2.4

Hydrocodone 1

Hydromorphone 4

Methadone, mg/d

1-20 4

21-40 8

41-60 10

61-80 12

Morphine 1

Oxycodone 1.5

Oxymorphone 3

Tapentadolc 0.4

a Adapted fromVonKorffM, Saunders K, RayGT, etal. Clin J Pain.

2008;24:521-527, and Interagency Guideline on PrescribingOpioids for Pain.

WashingtonState Agency Medical Directors Group. http://www

.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf.Accessed

February 19,2016.b Alldosesare in mg/d except forfentanyl, whichis g/h. Multiply thedaily

dosagefor each opioidby theconversionfactor to determinethe dose in

morphine milligram equivalents(MME). For example, tablets containing

hydrocodone,5 mg,and acetaminophen,300 mg,taken 4 times a daywould

contain a total of 20mg of hydrocodone daily, equivalent to 20MME daily;

extended-release tablets containingoxycodone, 10 mg, and taken twicea day

would containa total of 20mg of oxycodonedaily, equivalent to 30 MME

daily.

c Tapentadol is a -receptor agonist and norepinephrine reuptake inhibitor.

Morphine milligram equivalents are basedon degreeof -receptoragonist

activity, butit is unknown if this drug is associatedwithoverdosein thesame

dose-dependentmanner as observed withmedications thatare solely

-receptor agonists.

Box4. CautionsAbout Calculating MorphineMilligram

Equivalent Doses

Equianalgesicdose conversionsare only estimates and cannot

accountfor individualvariability in geneticsand pharmacokinetics.

Do not use the calculateddose in morphinemilligramequivalents

(MME) to determinethe doses to usewhenconvertingone

opioidto another;when converting opioids, thenew opioidis

typically dosed at substantially lower thanthe calculatedMMEdoseto avoid accidental overdosedue to incomplete

cross-tolerance and individual variabilityin opioid

pharmacokinetics.

Use particular caution with methadonedose conversions

because the conversion factor increasesat higher doses.

Useparticular caution with fentanylbecauseit is dosedin g/h

instead ofmg/d,and itsabsorptionis affectedby heat and

other factors.




http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdfhttp://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdfhttp://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.jama.com/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jama.2016.1464http://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdfhttp://www.agencymeddirectors.wa.gov/Files/2015AMDGOpioidGuideline.pdf


15/22


opioids are meetingthe patients treatmentgoals.If a patients opi-

oid dosagefor all sources of opioids combined reaches or exceeds

50 MME per day, clinicians should implement additional precau-

tions, including increased frequency of follow-up and considering

offering naloxone. Clinicians should avoid increasing opioid dos-

ages to 90 MME or more per day or should carefully justify a deci-

sionto increasedosageto 90MME ormore per day based onindi-vidualizedassessmentofbenefitsandrisksandweighingfactorssuch

as diagnosis, incremental benefits for pain and function relative to

harmsas dosagesapproach90 MMEper day, other treatments and

effectiveness, and recommendations based on consultation with

pain specialists. If patients do not experienceimprovement in pain

and functionat 90 MME ormoreper day, or ifthere are escalating

dosage requirements,cliniciansshoulddiscuss other approaches to

painmanagementwith thepatient,consider workingwith patients

to taper opioids to a lower dosageor to taper anddiscontinue opi-

oids, and consider consulting a pain specialist.

Established patients already prescribed high dosages of

opioids (90 MME/d), including patients transferringfromothercli-

nicians, should be offered the opportunity to reevaluate their con-

tinueduse ofopioids athighdosages inlightof recentevidence re-

garding the association of opioid dosage and overdose risk. For

patients who agree to taper opioids to lower dosages, clinicians

should collaboratewith thepatient on a tapering plan.6.Long-termopioiduse oftenbegins withtreatment ofacute

pain. When opioids areused foracutepain, clinicians shouldpre-

scribe thelowest effectivedoseof immediate-releaseopioidsand

should prescribe no greater quantity than needed for the ex-

pected duration of pain severe enoughto require opioids. Three

days orlesswilloftenbe sufficient; more than 7 days willrarelybe

needed. (Recommendation category: A; evidence type:4)

Acute pain can often be managed without opioids. When

diagnosis and severity of nontraumatic, nonsurgical pain are rea-

sonably assumed to warrant the use of opioids, clinicians should

Box5. Centersfor Disease Control and Prevention Recommendations for Prescribing Opioids for Chronic PainOutsideof Active Cancer,

Palliative, and End-of-Life Care

DeterminingWhen to Initiateor Continue Opioids for Chronic Pain

1. Nonpharmacologic therapy and nonopioidpharmacologictherapy

are preferred forchronic pain.Clinicians should consider opioid

therapy only if expectedbenefits for both pain andfunctionare

anticipated to outweigh risksto thepatient.If opioids areused, they

should be combinedwith nonpharmacologic therapy and nonopioid

pharmacologic therapy, as appropriate.

2. Before starting opioid therapy forchronic pain,clinicians should

establishtreatment goalswith all patients,includingrealisticgoals

for pain andfunction, andshould considerhow therapy will be

discontinued if benefits do not outweigh risks. Cliniciansshould

continueopioid therapy onlyif there is clinicallymeaningful

improvement in pain and function thatoutweighs risksto

patient safety.

3. Before starting and periodically during opioid therapy, clinicians

should discuss withpatients known risksand realisticbenefitsof

opioid therapy and patient and clinician responsibilitiesfor

managing therapy.

Opioid Selection,Dosage, Duration,Follow-up,and Discontinuation

4. Whenstartingopioid therapy for chronic pain,clinicians should

prescribeimmediate-release opioids instead of extended-release/

long-acting (ER/LA) opioids.

5. Whenopioids are started, clinicians should prescribe the lowest

effective dosage. Cliniciansshould use caution whenprescribing

opioids at any dosage, should carefullyreassessevidence of

individual benefits and riskswhen increasing dosage to 50 morphine

milligram equivalents (MME) or moreper day, and should avoid

increasing dosageto 90 MME or more perday or carefullyjustifya

decision totitrate dosageto 90 MMEor more perday.

6.Long-termopioid useoften beginswithtreatment of acute pain.

When opioids areusedfor acute pain,clinicians shouldprescribe the

lowest effectivedose of immediate-release opioids and should

prescribeno greater quantity thanneeded forthe expected duration

ofpain severe enoughto require opioids. Threedaysor less willoftenbe sufficient; more than 7 days will rarelybe needed.

7. Cliniciansshould evaluate benefits and harms with patients within

1 to4 weeks ofstartingopioid therapy for chronic pain orof dose

escalation. Cliniciansshould evaluate benefits and harmsof

continuedtherapywith patients every 3 months or morefrequently.

If benefits do not outweighharms of continuedopioid therapy,

clinicians should optimize therapiesand workwith patients to taper

opioids to lower dosages orto taperand discontinue opioids.

AssessingRisk andAddressing Harmsof Opioid Use

8. Before starting and periodically during continuation of opioid

therapy, cliniciansshould evaluate riskfactors foropioid-related

harms. Cliniciansshould incorporate intothe management plan

strategies to mitigate risk, including considering offeringnaloxone

whenfactorsthat increase riskfor opioid overdose, suchas history

of overdose, history of substanceuse disorder, higher opioid

dosages (50 MME/d), or concurrent benzodiazepineuse

are present.

9.Clinicians should review the patientshistoryof controlled

substanceprescriptionsusing state prescription drug monitoring

program (PDMP) data to determinewhetherthe patient is receiving

opioiddosagesor dangerouscombinations that puthim orher at

high riskfor overdose. Cliniciansshould review PDMPdata when

starting opioid therapy for chronic pain and periodically duringopioid therapy forchronic pain,rangingfrom everyprescriptionto

every 3 months.

10.When prescribingopioids forchronic pain,clinicians should use

urinedrug testing before starting opioid therapy and consider urine

drug testing at least annually to assess for prescribedmedications as

well as other controlled prescription drugsand illicit drugs.

11. Cliniciansshould avoidprescribing opioid pain medicationand

benzodiazepinesconcurrently whenever possible.

12. Clinicians should offer or arrange evidence-basedtreatment

(usually medication-assistedtreatment with buprenorphineor

methadonein combination withbehavioral therapies) for patients

with opioid use disorder.

Allrecommendations are categoryA (apply to allpatientsoutside of active

cancer treatment, palliative care, andend-of-lifecare) except recommendation

10 (designated categoryB, withindividualdecision making required);detailed

ratings of theevidencesupportingthe recommendations are providedin the

full guideline publication.11






16/22


prescribe no greater quantity than needed for the expected dura-

tion of pain severe enoughto require opioids, often 3 days or less,

unless circumstances clearly warrant additional opioid therapy.

More than 7 days will rarely be needed. Postsurgical pain is out-

side the scope of this guideline but has been addressed

elsewhere.106 Clinicians should not prescribe additional opioids to

patients just in case pain continues longer than expected. Clini-

cians should reevaluate the subset of patients who experiencesevere acute pain that continues longer than the expected dura-

tion to confirm or revise the initial diagnosis and to adjust man-

agement accordingly. Clinicians should not prescribe ER/LA

opioids for the treatment of acute pain.

7. Clinicians should evaluate benefits and harms with

patients within 1 to 4 weeks of starting opioid therapy for

chronic pain or of dose escalation. Clinicians should evaluate

benefits and harms of continued therapy with patients every 3

months or more frequently. If benefits do not outweigh harms

of continued opioid therapy, clinicians should optimize other

therapies and work with patients to taper opioids to lower dos-

ages or to taper and discontinue opioids. (Recommendation

category: A; evidence type: 4)

Cliniciansshould evaluate patients to assessbenefits andharms

of opioids within1 to 4 weeks of startinglong-term opioidtherapy

or of doseescalation, consider follow-up intervalswithin the lower

end of this range when ER/LA opioids are started or increased or

when total daily opioid dosage is 50 MME per day or greater, and

strongly consider shorter follow-up intervals (within 3 days) when

starting or increasing the dosage of methadone. Clinicians should

regularlyreassess all patients receivinglong-termopioid therapy,in-

cluding patients who are new to the clinician but taking long-term

therapy, at least every 3 months and reevaluate patients exposed

togreater risk ofopioid usedisorderor overdose(eg,patients with

depressionor other mental health conditions, history of substance

use disorder or overdose, taking50 MME/d, taking other central

nervous system depressants) more frequently.Atfollow-up,cliniciansshoulddeterminewhether opioidscon-

tinueto meettreatment goals, includingsustainedimprovementin

pain and function, whether the patient has experienced common

or serious adverse events or has early warning signs of serious ad-

verse eventssuch asoverdose (eg,sedation,slurred speech) oropi-

oid usedisorder (eg,difficulty controlling use),whetherbenefitsof

opioids continueto outweighrisks, andwhetheropioid dosage can

be reduced or opioids canbe discontinued.

Cliniciansshouldwork withpatientsto reduce opioid dosageor

to discontinue opioids when possible if clinically meaningful im-

provements in pain and function are not sustained, if patients are

takinghigh-risk regimens(eg, dosages50MME/doropioidscom-

bined with benzodiazepines) without evidence of benefit, if pa-tientsbelieve benefits no longer outweigh risks or request dosage

reduction or discontinuation, or if patientsexperience overdoseor

other serious adverse events or warning signs of serious adverse

events.

When opioidsarereducedor discontinued,a taper slow enough

to minimize symptoms and signs of opioid withdrawal should be

used. A decrease of10% ofthe original dose per week is a reason-

able starting point; tapering plans may be individualized based on

patientgoalsandconcerns.Slowertapers(eg,10%permonth)might

be appropriateandbettertolerated,particularlywhen patients have

been taking opioids for years. More rapid tapers might be needed

for patients who have overdosed on their current dosage. Clini-

ciansshouldaccess appropriateexpertiseif consideringtapering opi-

oids duringpregnancy because of possible risk tothe pregnant pa-

tient and to the fetus if the patient goes into withdrawal. Primary

care clinicians should collaborate withmental health clinicians and

with other specialists as needed to optimize nonopioid pain man-

agement,as well as psychosocial support foranxietyrelated tothetaper.

Assessing Risk and Addressing Harms of Opioid Use

8. Before starting and periodically during continuation of opioid

therapy, clinicians should evaluate risk factors for opioid-related

harms. Clinicians should incorporate into the management plan

strategies to mitigate risk, including considering offering nalox-

one when factors that increase risk for opioid overdose, such as

historyof overdose, historyof substance usedisorder,higher opi-

oiddosages(50MME/d), or concurrent benzodiazepine use,are

present. (Recommendation category: A; evidence type: 4)

Certain risk factors can increase susceptibility to opioid-

associated harms. Clinicians should avoid prescribing opioidsto pa-

tients with moderate or severe sleep-disordered breathing when-ever possible. During pregnancy, clinicians and patients together

should carefully weigh risks and benefits when making decisions

about whether to initiateopioid therapy. Clinicians caring for preg-

nantwomenreceivingopioidsshouldarrangefor delivery at a facil-

ity prepared to evaluate and treatneonatal opioid withdrawal syn-

drome. Clinicians should use additional caution and increased

monitoringto minimizerisks of opioidsprescribedfor patientswith

renal or hepatic insufficiency, patients 65 years and older, and pa-

tientswith anxiety or depression. Cliniciansshould ensurethat treat-

ment for depression and other mental health conditions is opti-

mized, consulting with behavioral health specialists when needed.

If clinicians consider opioid therapy for patients with drug or alco-

hol usedisorders or for patients with prior nonfataloverdose, theyshould discuss increasedrisks foropioid use disorder andoverdose

with patients, carefully consider whether benefits of opioids out-

weighincreased risks, andincreasefrequencyof monitoring opioid

therapy.

Clinicians should consider offeringnaloxone whenprescribing

opioids to patientsat increasedrisk of overdose, includingpatients

with a history ofoverdose, patients with a history ofsubstance use

disorder, patientstaking benzodiazepineswith opioids,patientsat

risk ofreturningto a high dose towhichtheyare nolonger tolerant

(eg, patients recently released from prison), and patients taking

higherdosages of opioids (50 MME/d). Practices should provide

education on overdose prevention and naloxone use to patients

receiving naloxone prescriptions and to members of their

households.

9.Clinicians should review the patientshistoryof controlled

substance prescriptions using state prescription drug monitor-

ingprogram(PDMP)data to determinewhether thepatient is re-

ceiving opioid dosages or dangerous combinations that put him

orherathighriskforoverdose.CliniciansshouldreviewPDMPdata

whenstartingopioidtherapyforchronicpainandperiodicallydur-

ingopioid therapy forchronic pain, ranging from every prescrip-

tion to every 3 months.(Recommendation category: A; evidence

type: 4)






17/22


Clinicians should review PDMPdata for opioids and other con-

trolledmedicationspatientsmighthavereceivedfromadditional pre-

scribers to determinewhether a patient is receivinghigh total opi-

oiddosages ordangerous combinations (eg,opioids combined with

benzodiazepines)thatput himor herat high risk for overdose. Ide-

ally, PDMP data should be reviewed before every opioid prescrip-

tion. This is recommendedin allstates withwell-functioningPDMPs

and where PDMP access policies make this practicable (eg, clini-cianand delegate access permitted), but it is notcurrentlypossible

in states without functional PDMPs or in those that do not permit

certain prescribers to access them.

If patients are found to have high opioid dosages, dangerous

combinationsof medications, or multiplecontrolledsubstancepre-

scriptions written by different clinicians,severalactions canbe taken

to augment clinicians abilities to improve patient safety:

Clinicians should discuss information from the PDMP with their

patient and confirm that the patient is aware of the additional

prescriptions.

Clinicians should discuss safety concerns,including increasedrisk

forrespiratory depressionand overdose,with patientsfound tobe

receiving opioids from more than 1 prescriber or receiving medi-

cations that increase risk when combined with opioids (eg, ben-

zodiazepines).

Clinicians should avoid prescribing opioids and benzodiazepines

concurrently whenever possible. Clinicians should communicate

with others managing the patient to discuss the patients needs,

prioritizepatient goals, weighrisksof concurrentbenzodiazepine

and opioid exposure, and coordinate care.

Clinicians should calculatethe total MME/d for concurrentopioid

prescriptions. If patientsare found to be receivinghigh total daily

dosagesof opioids,clinicians should discuss their safety concerns

with the patient, consider tapering to a safer dosage, and con-

sider offering naloxone.

Cl

2016-CDC Guideline for Prescribing Opioids for Chronic Pain

Documents

Transcript of 2016-CDC Guideline for Prescribing Opioids for Chronic Pain