Patient Outcomes in Dose Reduction or Discontinuation of Long-Term Opioid Therapy

Annals of Internal Medicine REVIEW
Patient Outcomes in Dose Reduction or Discontinuation of Long-Term

Opioid Therapy
A Systematic Review
Joseph W. Frank, MD, MPH; Travis I. Lovejoy, PhD, MPH; William C. Becker, MD; Benjamin J. Morasco, PhD;
Christopher J. Koenig, PhD; Lilian Hoffecker, PhD, MLS; Hannah R. Dischinger, BS; Steven K. Dobscha, MD; and
Erin E. Krebs, MD, MPH
Background: Expert guidelines recommend reducing or dis- including interdisciplinary pain programs, buprenorphine-
continuing long-term opioid therapy (LTOT) when risks out- assisted dose reduction, and behavioral interventions, were
weigh benets, but evidence on the effect of dose reduction on found. Study quality was good for 3 studies, fair for 13 studies,
patient outcomes has not been systematically reviewed. and poor for 51 studies. Many studies reported dose reduction,
but rates of opioid discontinuation ranged widely across inter-
Purpose: To synthesize studies of the effectiveness of strategies ventions and the overall quality of evidence was very low.
to reduce or discontinue LTOT and patient outcomes after dose Among 40 studies examining patient outcomes after dose re-
reduction among adults prescribed LTOT for chronic pain. duction (very low overall quality of evidence), improvement was
Data Sources: MEDLINE, EMBASE, PsycINFO, CINAHL, and the reported in pain severity (8 of 8 fair-quality studies), function (5 of
Cochrane Library from inception through April 2017; reference 5 fair-quality studies), and quality of life (3 of 3 fair-quality
lists; and expert contacts. studies).
Study Selection: Original research published in English that Limitation: Heterogeneous interventions and outcome mea-
addressed dose reduction or discontinuation of LTOT for sures; poor-quality studies with uncontrolled designs.
chronic pain. Conclusion: Very low quality evidence suggests that several
Data Extraction: Two independent reviewers extracted data types of interventions may be effective to reduce or discontinue
and assessed study quality using the U.S. Preventive Services LTOT and that pain, function, and quality of life may improve
Task Force quality rating criteria. All authors assessed evidence with opioid dose reduction.
quality using the GRADE (Grading of Recommendations Assess- Primary Funding Source: Veterans Health Administration.
ment, Development and Evaluation) system. Prespecied patient (PROSPERO: CRD42015020347)
outcomes were pain severity, function, quality of life, opioid with-
drawal symptoms, substance use, and adverse events.
Ann Intern Med. doi:10.7326/M17-0598 Annals.org
Data Synthesis: Sixty-seven studies (11 randomized trials and For author afliations, see end of text.
56 observational studies) examining 8 intervention categories, This article was published at Annals.org on 18 July 2017.
A pproximately 10 million U.S. adults are prescribed

long-term opioid therapy (LTOT) for chronic pain
despite inadequate evidence of long-term benet and
ing prescribed LTOT, 91% continued use of opioid
medications after the overdose (18). There is little evi-
dence to guide clinicians in the process of opioid ta-
growing evidence of harms (1, 2). No published studies pering, especially in primary care settings, where most
have compared LTOT (>1 year) versus placebo, no opi- opioid therapy is prescribed (19, 20). In addition, little
oid, or nonopioid therapies (2). In recent decades, a is known about the risks and benets of opioid taper-
dramatic increase in the prescription of opioid medica- ing. Potential risks include withdrawal symptoms, in-
tions has been accompanied by increases in opioid creased pain, and loss to follow-up (20). However,
overdose (3); more than 33 000 opioid overdose some patients report improvements in function and
deaths occurred in 2015 (4). Higher prescribed opioid quality of life after tapering (21). The effects of opioid
dose is associated with overdose risk (57) as well as tapering on patient outcomes have not been systemat-
incidence of opioid use disorder, depression, fracture, ically reviewed.
motor vehicle accident, and suicide (8 12). Dose re- To address these gaps, we systematically reviewed
duction or discontinuation, or opioid tapering, may de- the evidence on the effectiveness of strategies to re-
crease these risks, and expert guidelines recommend duce or discontinue LTOT prescribed for chronic pain
tapering when risks outweigh benets (13, 14).
Opioid tapering can be challenging for both pa-
tients and clinicians. In routine practice, discontinuation
of LTOT is uncommon, ranging from 8% to 35% in prior See also:
cohort studies (15, 16). In a survey of patients receiving
high-dose opioid medications for chronic pain, nearly Editorial comment . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
half reported wanting to cut down or stop, yet 80% Web-Only
were receiving high-dose opioids 1 year later (17).
CME/MOC activity
Among patients who had a nonfatal overdose while be-
Annals.org Annals of Internal Medicine 1
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REVIEW Outcomes in Dose Reduction or Discontinuation of Long-Term Opioid Therapy
and the effect of dose reduction or discontinuation of or addressed only reduction of interventional pain
LTOT on important patient outcomes. techniques.
Data Extraction and Quality Assessment
METHODS We developed an instrument for data extraction
based on prior systematic reviews conducted by the
A multidisciplinary team of investigators with ex-
investigators. Three investigators piloted the data ex-
pertise in pain and opioid management developed 2
traction instrument using a randomly chosen study,
key questions to address the study objectives. These
and the results were returned to the pool for formal
key questions assessed 1) the effectiveness of strate-
review. These investigators discussed difculties with
gies to reduce or discontinue LTOT, and 2) the effect of
the extraction instrument and reached consensus on
dose reduction or discontinuation of LTOT on prespeci-
minor modications. Using the nalized instrument, 2
ed patient outcomes of pain severity, pain-related
investigators independently extracted data on design,
function, quality of life, opioid withdrawal symptoms,
patient sample, setting, interventions, measures, and
substance use, or adverse events. We followed the
results from each study. When dose information was
PRISMA (Preferred Reporting Items for Systematic re-
not provided by the study, we used a standard algo-
views and Meta-Analyses) guidelines (22), and the
rithm for calculating morphine-equivalent doses
protocol is registered in the PROSPERO database
(MEDs) of opioid medications (23).
(CRD42015020347).
Two reviewers independently assessed study qual-
Data Sources and Searches ity (risk of bias in individual studies) using criteria de-
We searched MEDLINE, EMBASE, PsycINFO, veloped by the U.S. Preventive Services Task Force
CINAHL, and the Cochrane Library from inception (USPSTF), which facilitate rating of study quality as
through 19 April 2017. We consulted with a research good, fair, or poor (Appendix Table 2, available at
librarian to design a search strategy based on our key Annals.org). The investigators were blinded to each
questions. We developed a MEDLINE search strategy, other's ratings, and discrepancies were resolved by
which was also applied to other databases, using mul- consensus or by a third reviewer, if necessary. We did
tiple subject headings (where available) and text words not exclude studies on the basis of quality.
for key concepts of opioids, tapering, and pain. Data Synthesis
No language or year limits were applied. Within this We assessed the overall quality of the evidence
broader search, we identied potentially relevant sys- using a method developed by the GRADE (Grading of
tematic reviews and meta-analyses published since Recommendations Assessment, Development and
2005. The full electronic search strategy for MEDLINE is Evaluation) Working Group (24). GRADE provides ex-
presented in Appendix Table 1 (available at Annals plicit criteria that address study design, risk of bias, im-
.org). We examined reference lists from all included precision, inconsistency, indirectness, and magnitude
studies and from relevant systematic reviews and pub- of effect to rate the quality of evidence across studies.
lished expert guidelines. We also sought input from ex- This method rates the quality of the evidence from high
pert contacts. Records retrieved from each search strat- (very condent that the true effect lies close to that of
egy were organized using the EndNote bibliographic the estimate of effect) to very low (very little condence
management application (Clarivate Analytics). in the effect estimate) (Appendix Table 3, available at
Study Selection Annals.org). All authors iteratively discussed GRADE as-
Two investigators (J.W.F. and H.R.D.) indepen- sessments to achieve consensus. We present system-
dently reviewed abstracts identied by the search strat- atic review results organized by key question. We did
egy and, when necessary, the full text to determine in- not attempt meta-analyses because of heterogeneity
clusion. Discrepancies were resolved by consensus. We across studies and methodological limitations of the
included studies that involved adults (aged 18 years) studies.
who were prescribed LTOT for chronic pain (dened as Role of the Funding Source
pain lasting >3 months) and that addressed at least 1 The Veterans Health Administration's Substance
key question. Studies that did not report pain duration Use Disorder Quality Enhancement Research Initiative
were included if the average duration of opioid therapy funded the study through its Locally Initiated Projects
was more than 3 months. We did not require interven- program (QLP 59-046). The funding sources had no
tions to involve explicit goals or mandatory conditions role in the design and conduct of the study; collection,
of opioid dose reduction. Eligible study designs in- management, analysis, or interpretation of the data; or
cluded randomized trials, cohort studies, case control preparation, review, or approval of the manuscript.
studies, and case series. We excluded case reports and
cross-sectional studies, as well as studies that did not
describe the clinical intervention or report patient-level RESULTS
data. We also excluded studies that were not published Database searches identied 3522 abstracts, from
in English; involved nonhuman participants; addressed which 74 studies met criteria for full-text review. Seven-
only acute, surgical, postoperative, obstetric, or cancer teen additional articles were identied from reference
pain; involved only palliative or hospice care; evaluated lists and expert contacts. Of these 91 studies, 68 arti-
only illicit or nonmedical use of opioid medications; cles representing 67 studies met inclusion criteria
2 Annals of Internal Medicine Annals.org

Outcomes in Dose Reduction or Discontinuation of Long-Term Opioid Therapy REVIEW
(2592) (Appendix Figure, available at Annals.org). tually exclusive intervention types: interdisciplinary pain
These studies included 11 randomized controlled trials, programs, buprenorphine-assisted dose reduction, be-
8 controlled observational studies, and 48 uncontrolled havioral interventions, detoxication, ketamine-assisted
observational studies. Studies presented data on dose reduction, acupuncture, other outpatient pro-
12 546 patients (range, 5 to 1457 patients); 10 studies grams, and other interventional programs (Table 1). In-
conducted at a single center (32, 33, 36, 44 48, 70, 80) terventions occurred in outpatient settings, inpatient
and 2 studies each at 3 centers (37, 49, 50, 52, 63, 64) settings, or both in 42, 15, and 10 studies, respectively;
may have included data on individual participants in 5 studies were conducted in primary care settings.
more than 1 study. We categorized studies into 8 mu- Among 48 studies reporting baseline opioid dose for
Table 1. Effectiveness of Strategies to Reduce or Discontinue LTOT (n = 67 studies)
Studies, Participants, Description Results* Quality

n n Ratings
Interdisciplinary pain programs (28, 30, 32, 33, 36, 37, 42, 4450, 52, 54, 55, 58, 63, 64, 67, 69, 70, 74, 7781, 86, 88)
31 9915 Programs delivered interdisciplinary pain care with heterogeneity of Mean opioid discontinuation rate, Fair: 11
program components, personnel, and duration (range, 18 wk) 87% (range, 29%100%); 20 studies
21 outpatient studies, 8 inpatient studies, and 2 studies in both studies Poor: 20
settings studies
Opioid discontinuation mandatory in 22 studies; goal of dose
reduction in 5 studies
Mean program completion rate, 85% (range, 76%100%); 25
studies
Buprenorphine-assisted dose reduction (2527, 34, 35, 59, 71, 72, 75, 83)
10 470 Studies transitioned patients from LTOT to buprenorphine with Mean opioid discontinuation rate, Poor: 10
heterogeneity of induction protocol, dose, and duration of 91% (range, 33%100%); 6 studies
therapy studies
5 outpatient studies, 2 inpatient studies, and 3 studies in both
settings
4 studies included only patients who had successfully transitioned
to buprenorphine
Behavioral interventions (61, 65, 66, 76, 85, 90, 91)

6 238 Studies tested heterogeneous behavior-based and cognitive Mean opioid discontinuation rate, Good: 3
behaviorbased therapies, including CBT, meditation, and other 21% (range, 6%55%); 5 studies studies
CIH methods Poor: 3
All studies in outpatient settings; 3 of 6 in primary care settings studies
Goal of opioid discontinuation in 1 study; goal of dose reduction in
1 study
Other outpatient programs (3941, 73, 84)

5 1169 2 studies of systemwide interventions in primary care, 2 studies of Mean opioid discontinuation rate, Poor: 5
outpatient specialty care, and 1 study of outpatient medical 20% (range, 12%44%); 3 studies
marijuana treatment studies
Goal of dose reduction in 3 studies
Other interventional programs (29, 56, 57, 87)

4 308 2 studies of an implantable device, 1 study of detoxication under Mean opioid discontinuation rate, Poor: 4
anesthesia, and 1 study of lidocaine infusion 70% (range, 33%79%); 3 studies
Goal of opioid discontinuation in 3 studies studies
Detoxication (31, 38, 62, 82)

4 200 Interventions supported opioid dose reduction with symptomatic Mean opioid discontinuation rate, Poor: 4
medications (e.g., clonidine and benzodiazepines) 91% (range, 91%100%); 3 studies
2 outpatient studies, 1 inpatient study, and 1 study in both settings studies
Ketamine-assisted dose reduction (51, 60, 68, 89)

4 168 Studies examined oral, intravenous, and subcutaneous Opioid discontinuation rates of Poor: 4
administration of ketamine 18% and 27% in 2 studies studies
1 outpatient study, 1 inpatient study, and 2 studies in both settings
Goal of opioid discontinuation in 1 study; goal of dose reduction in
3 studies
Acupuncture (43, 53, 92)

3 78 2 studies of electroacupuncture; 1 study of auricular acupuncture Opioid discontinuation rates of Fair: 2
1 outpatient study, 1 inpatient study, and 1 study in both settings 66% and 86% in 2 studies studies
Goal of opioid discontinuation in 2 studies Poor: 1
studies
CBT = cognitive behavioral therapy; CIH = complementary and integrative health; LTOT = long-term opioid therapy.
* Among studies reporting opioid discontinuation rates.
Among studies reporting program completion.

participants receiving LTOT, the mean daily dose We identied 40 studies that examined the effect
ranged from 29 to 556 mg MED. Study interventions of dose reduction or discontinuation of LTOT on pa-
had an objective of opioid discontinuation or dose re- tient outcomes (key question 2) (Table 3). These studies
duction in 43 and 12 studies, respectively; 12 studies included 5 randomized controlled trials, 6 controlled
reported on this outcome in secondary or exploratory observational studies, and 29 uncontrolled observa-
analyses. tional studies. None of the 40 studies were rated as
All included studies assessed the effectiveness of good-quality. For each of the 6 prespecied patient
strategies to reduce or discontinue LTOT (key question outcomes, the GRADE quality of evidence was very low
1). Study quality as assessed by the USPSTF criteria was (Table 2 and Appendix Table 4).
good for 3 studies, fair for 13 studies, and poor for 51 Thirty-six studies (8 fair-quality and 28 poor-quality)
studies. The GRADE quality of evidence to address the examined the effect of opioid dose reduction on pain
effectiveness of strategies to reduce or discontinue severity. The 8 fair-quality studies included 1 controlled
LTOT was very low (Table 2; Appendix Table 4, avail- and 6 uncontrolled observational studies of interdisci-
able at Annals.org). In the remainder of this section, we plinary pain programs and 1 uncontrolled observa-
highlight results from good- and fair-quality studies. tional study of acupuncture; all 8 studies reported im-
Descriptions of all included studies are available in Ap- proved pain after opioid dose reduction. The effect of
pendix Table 5 (available at Annals.org). dose reduction on pain-related function was assessed
Thirty-one studies (11 fair-quality and 20 poor- in 17 studies (5 fair-quality and 12 poor-quality). The 5
quality) presented data from 19 distinct interdisciplin- fair-quality studies were observational studies of inter-
ary pain programs. These programs were described as disciplinary pain programs (1 controlled and 4 uncon-
intensive multimodal treatment with an interdisciplinary
trolled); all 5 studies reported improved function after
team, typically organized around a biopsychosocial
opioid dose reduction. The effect of dose reduction on
model of chronic pain. The 11 fair-quality studies in-
quality of life was assessed in 12 studies (3 fair-quality
cluded 2 controlled and 9 uncontrolled observational
and 9 poor-quality). The 3 fair-quality studies were un-
studies. Ten fair-quality studies described programs
controlled observational studies of interdisciplinary
that mandated discontinuation as a condition of enroll-
pain programs; all reported improved quality of life af-
ment; in these programs, 87% of participants discontin-
ter opioid dose reduction. Opioid withdrawal symp-
ued opioid use at program completion (range, 74% to
toms were examined in 18 studies (3 fair-quality and 15
100%).
Six studies (3 good-quality and 3 poor-quality) with poor-quality); the reported incidence during opioid
238 total participants assessed the effectiveness of be- dose reduction ranged widely. Four poor-quality stud-
havioral interventions. The 3 good-quality studies were ies examined new-onset substance use. Eleven poor-
small randomized controlled trials; 2 were described as quality studies assessed adverse events; 5 assessed
pilot trials, and none were powered to detect clinically mortality outcomes, and 1 reported a single opioid-
meaningful differences in opioid dose reduction. The related overdose death.
rst good-quality trial compared a 4-month interactive
voice response intervention versus usual care among
patients with chronic pain (n = 51); a goal of opioid
DISCUSSION
dose reduction was optional. The intervention reduced
the mean opioid dose signicantly at 4-month (P = This systematic review identied 67 studies that
0.04) and 8-month (P = 0.004) follow-up compared with examined the effectiveness of strategies to reduce or
usual care (mean dose change was not reported) (65). discontinue LTOT among adults with chronic pain, in-
The second good-quality trial compared an 8-week cluding 3 small good-quality randomized trials, 1 fair-
group intervention based on mindfulness meditation quality randomized trial, and 12 fair-quality observa-
and cognitive behavioral therapy with usual care tional studies. Though many studies reported positive
among patients receiving LTOT (n = 35); the interven- dose reduction outcomes, the overall quality of the ev-
tion did not explicitly encourage dose reduction. The idence for effectiveness of all strategies to reduce or
mean change in the daily opioid dose from baseline to discontinue LTOT was very low due to methodological
26 weeks was 10.1 mg MED in the intervention group limitations across studies and an absence of adequately
compared with 0.2 mg MED in the control group (P = powered randomized trials. We identied 40 studies
0.8) (90). The third good-quality trial compared a 22- that assessed the effect of dose reduction or discontin-
week opioid taper support intervention (motivational uation of LTOT on important patient outcomes, 8 of
interviewing and pain self-management education de- which were fair-quality observational studies. The fair-
livered by a physician assistant) with usual care (n = 35); quality studies reported improvement in pain severity
opioid dose reduction was the primary outcome. The (8 of 8 studies), function (5 of 5 studies), and quality of
intervention reduced the mean opioid dose by 43% life (3 of 3 studies) after opioid dose reduction. How-
compared with 19% in the usual care group at 22 ever, the overall quality of the evidence was very low
weeks (P = 0.07) (76). The remaining 6 intervention for all 6 prespecied patient outcomes.
types were described in 30 studies (2 fair-quality and Common themes across intervention types can
28 poor-quality). provide insight into the program components that may

provide effective support for opioid tapering. In the 3 gies. Such care is consistent with expert guidelines for
good-quality trials of behavioral interventions and the management of LTOT and chronic pain (13, 14, 93). In
11 fair-quality studies of interdisciplinary pain pro- addition to the content of these interventions, the
grams, patients received multimodal care that empha- quantity of care provided is likely an important factor.
sized nonpharmacologic and self-management strate- Multidisciplinary care and close follow-up (at least
Table 2. Summary of Findings and Quality-of-Evidence Assessment

Summary of Findings Quality-of-Evidence Assessment (GRADE)
Outcome Studies, Participants, Study Study Results Risk of Inconsistency Indirectness Imprecision Quality
n n Design Quality Bias
Effectiveness of 67 12 546 RCT: 11 Good: 3 Multiple intervention Serious Not serious Serious Not serious Very
strategies CO: 8 Fair: 13 types examined, low
to reduce UO: 48 Poor: 51 with heterogeneity
or of patient
discontinue populations, study
LTOT completion, and
rates of opioid
reduction and
discontinuation
Effect of dose
reduction
or
discontinuation
on patient
outcomes
Pain severity 36 7674 RCT: 4 Good: 0 8 of 8 fair-quality Serious Not serious Not serious Not serious Very
CO: 6 Fair: 8 studies reported low
UO: 26 Poor: 28 improved pain 21
of 28 poor-quality
studies reported
improved pain, 4
reported no
change, and 3
reported worse
pain
Function 17 4809 RCT: 2 Good: 0 5 of 5 fair-quality Serious Not serious Not serious Not serious Very
UO: 14 Poor: 12 improved function
8 of 12
poor-quality
studies reported
improved function,
2 reported no
change, and 2
reported
decreased function
QOL 12 2880 RCT: 1 Good: 0 3 of 3 fair-quality Serious Not serious Not serious Not serious Very
UO: 11 Poor: 9 improved QOL
4 of 9 poor-quality
studies reported
improved QOL, 4
reported no
change, and 1
reported worse
QOL
Opioid 18 1147 RCT: 4 Good: 0 Rates of opioid Serious Serious Not serious Not serious Very
withdrawal CO: 0 Fair: 3 withdrawal low
symptoms UO: 14 Poor: 15 symptoms ranged
widely (0%100%);
4 of 18 studies
reported
withdrawal
symptoms in all
patients
Substance 4 204 RCT: 1 Good: 0 2 studies reported Serious Not serious Not serious Not serious Very
use CO: 0 Fair: 0 illicit substance use low
UO: 3 Poor: 4 (63% and 64%) (27,
71)
1 study reported
nonmedical use of
prescription
opioids (43%) (77)
1 study reported
illicit intravenous
opioid
administration
(<1%) (28)
Adverse 11 519 RCT: 2 Good: 0 5 of 11 studies Serious Not serious Not serious Not serious Very
events CO: 1 Fair: 0 assessed mortality low
UO: 8 Poor: 11 with 1
opioid-related
overdose in a
single study (75)
CO = controlled observational study; GRADE = Grading of Recommendations Assessment, Development and Evaluation; LTOT = long-term opioid
therapy; QOL = quality of life; RCT = randomized controlled trial; UO = uncontrolled observational study.

Table 3. Studies of Effect of Dose Reduction or Discontinuation of LTOT on Patient Outcomes (n = 40 studies)
Study, Year (Reference) Study Intervention Type Sample Outcomes Assessed Quality
Design Size Rating
Pain Function Quality Opioid Substance Adverse
of Life Withdrawal Use Events
Heiwe et al, 2011 (43) UO Acupuncture 29 Fair
Hooten et al, 2009 (46) UO IPP 1241 Fair
Hooten et al, 2010 (47) UO IPP 109 Fair
Huffman et al, 2017 (50) CO IPP 1457 Fair
Kidner et al, 2009 (52) UO IPP 1226 Fair
Krumova et al, 2013 (54) UO IPP 102 Fair
Murphy et al, 2013 (63) UO IPP 705 Fair
Townsend et al, 2008 (80) UO IPP 373 Fair
Baron and McDonald, CO Buprenorphine-assisted 23 Poor
2006 (25)
Berland et al, 2013 (26) UO Buprenorphine-assisted 76 Poor
Blondell et al, 2010 (27) RCT Buprenorphine-assisted 12 Poor
Buckley et al, 1986 (28) UO IPP 173 Poor
Cowan et al, 2003 (30) UO IPP 104 Poor
Cowan et al, 2005 (31) RCT Detoxication 10 Poor
Cunningham et al, UO IPP 131 Poor
2016 (33)
Daitch et al, 2012 (34) UO Buprenorphine-assisted 104 Poor
Daitch et al, 2014 (35) UO Buprenorphine-assisted 35 Poor
Drossman et al, 2012 (38) UO Detoxication 39 Poor
Hanson et al, 2009 (39) CO Other outpatient program 200 Poor
Harden et al, 2015 (40) UO Other outpatient program 50 Poor
Hassamal et al, 2016 (42) UO IPP 5 Poor
Hooten et al, 2015 (48) RCT IPP 21 Poor
Kapural et al, 2010 (51) CO Ketamine-assisted 36 Poor
Kroening and Oleson, UO Acupuncture 14 Poor
1985 (53)
Lake et al, 2009 (55) UO IPP 267 Poor
Maani et al, 2011 (57) UO Other interventional program 6 Poor
Maclaren et al, 2006 (58) UO IPP 127 Poor
Malinoff et al, 2005 (59) UO Buprenorphine-assisted 95 Poor
Miller et al, 2006 (62) UO Detoxication 53 Poor
Nilsen et al, 2010 (66) UO Behavioral 11 Poor
Quinlan, 2012 (68) UO Ketamine-assisted 11 Poor
Rome et al, 2004 (70) UO IPP 356 Poor
Rosenblum et al, 2012 (71) UO Buprenorphine-assisted 12 Poor
Roux et al, 2013 (72) RCT Buprenorphine-assisted 43 Poor
Schwarzer et al, 2015 (74) CO IPP 32 Poor
Streltzer et al, 2015 (75) UO Buprenorphine-assisted 43 Poor
Taylor et al, 1980 (77) UO IPP 7 Poor
Tennant and Rawson, CO IPP 42 Poor
1982 (78)
Webster et al, 2016 (83) RCT Buprenorphine-assisted 39 Poor
Weimer et al, 2016 (84) UO Other outpatient program 516 Poor
CO = controlled observational study; IPP = interdisciplinary pain program; LTOT = long-term opioid therapy; RCT = randomized controlled trial;
UO = uncontrolled observational study.
weekly) were common attributes of evaluated pro- terventions delivered concurrent nonopioid pain man-
grams in good- and fair-quality studies. Such team- agement approaches that may have provided more
based, intensive support would require additional re- benet than LTOT. Second, opioid dose reduction may
sources to implement in primary care settings, where alleviate adverse effects of LTOT that can negatively
most opioid medications are prescribed (19). Given the affect function and quality of life, such as constipation,
heterogeneity across interventions and the overall poor fatigue, poor sleep, and depressed mood. Third, im-
quality of studies, data do not currently support assess- provement after opioid dose reduction may result from
ment of comparative effectiveness of the different mod- resolution of opioid-induced hyperalgesia, a paradoxi-
els of care or opioid tapering protocols used in in- cal response in which patients receiving opioids be-
cluded studies. come more sensitive to painful stimuli (94). Finally,
Although condence is limited by the very low given the observational nature of most studies, we can-
quality of evidence overall, ndings from this system- not exclude reverse causation (that is, patients success-
atic review suggest that pain, function, and quality of fully tapered opioids because pain severity decreased).
life may improve during and after opioid dose reduc- In the realm of opioid therapy, patient safety and pain
tion. Several potential mechanisms may underlie this relief have often been framed as conicting and mutu-
nding. First, in addition to tapering opioids, most in- ally exclusive goals. Evidence about benets of opioid

tapering for pain, function, and quality of life, if con- Table 4. Implications for Clinicians and Next Steps for
rmed by future high-quality studies, holds the poten- Research
tial to fundamentally alter the conversation about opi-
oid tapering. Implications for Clinicians Next Steps for Research
Three prior systematic reviews identied 11 ran- Discuss with patients receiving Researchers should seek consensus
domized or controlled studies of interventions for dose LTOT that pain severity, on the reporting of opioid dose
function, and quality of life reduction and denition of
reduction among patients prescribed opioid medica- may improve after opioid clinically meaningful dose
tions for chronic pain (2, 95, 96). All 3 reviews deter- tapering. reduction.
mined that the strength of evidence was insufcient to Consider referring patients to Innovative approaches to
draw conclusions. Our review extends these prior re- a multidisciplinary, recruitment and randomization
multimodal pain program, (such as trials with randomization
views by providing an updated and comprehensive as- when available, to support at the provider or facility level)
sessment of the literature, adding 2 recent good- opioid dose reduction. are needed to generate
quality randomized controlled trials and 11 fair-quality high-quality evidence on
outcomes.
observational studies. Whereas prior reviews assessed Consider team-based Future studies should examine
outcomes of opioid dose reduction, this is, to our strategies with close interventions that are feasible in
knowledge, the rst study to systematically review pa- follow-up to support busy primary care settings and
tient outcomes after dose reduction or discontinuation opioid tapering when scalable across multiple health
multidisciplinary programs systems.
of LTOT for chronic pain. are inadequately accessible.
The ndings of this systematic review should be Given inadequate evidence on Public health surveillance and
interpreted in the context of its limitations. First, there the risks of opioid tapering, large-scale observational studies
caution and close are needed to assess outcomes
was substantial heterogeneity of measures of opioid monitoring are warranted of efforts to reduce opioid
dose reduction and patient outcomes. Second, we cat- during and after. prescribing at health system and
egorized interventions into clinically relevant domains population levels.
according to the authors' descriptions of key compo- LTOT = long-term opioid therapy.
nents. There was substantial heterogeneity within do-
mains and overlap across some. Third, most of the in- assisted approaches (99) for supporting opioid
cluded studies examined voluntary participation in a tapering warrants further study. Fourth, in the context
clinical program or research intervention. The ndings of ongoing health system and population-level efforts
may therefore not be generalizable to patients for to reduce opioid use and prevent opioid-related harms
whom LTOT is reduced or discontinued involuntarily. (100 102), we identied no prospective studies of man-
Fourth, publication bias may have limited the evidence datory, involuntary opioid dose reduction among oth-
that was available for this review. Finally, new data may erwise stable patients. Finally, this review found insuf-
have emerged since April 2017 in this rapidly evolving cient evidence on adverse events related to opioid
area; 39 of the 67 studies included in this review were tapering, such as accidental overdose if patients re-
published since 2010, and 18 were published since sume use of high-dose opioids or switch to illicit opioid
2015. sources or onset of suicidality or other mental health
This systematic review highlights challenges and symptoms. Public health surveillance and large-scale
opportunities for future research (Table 4). First, mea- observational studies are needed to assess outcomes
surement and reporting of opioid dose reduction were of efforts to reduce opioid prescribing at the health
heterogeneous across studies, and consensus on what system and population levels, especially rare but im-
constitutes meaningful dose reduction is needed, in- portant adverse events, such as overdose and suicide.
cluding patients transitioning to buprenorphine. Sec- In conclusion, this systematic review identied mul-
ond, innovative strategies for recruitment and retention tiple strategies to reduce or discontinue LTOT for
will be required for future patient-level randomized tri- chronic pain and found very-low-quality evidence that
als of opioid tapering because patients' apprehension opioid dose reduction may improve pain, function, and
with regard to tapering may serve as a barrier to quality of life. In addition to discussing the goals and
participation (21). Such strategies might include ran- risks of opioid therapy, clinicians should consider dis-
domization of patients to active pain management in- cussing the potential benets of opioid tapering with
terventions with optional opioid dose reduction, ran- patients receiving LTOT. Informed by the multidisci-
domization to different protocols or tapering rates plinary care models among good- and fair-quality stud-
among motivated patients, or randomization at the ies, clinicians should consider referring patients to
level of the prescriber or facility. Given that loss to multidisciplinary pain programs, when available, or de-
follow-up was common in poor-quality studies in this veloping team-based approaches to support opioid ta-
review, evidence on effective strategies to enhance pa- pering in outpatient practice. Finally, given inadequate
tient engagement is also needed. Third, future research evidence on the risks of opioid tapering, caution and
should examine strategies that are likely to be feasible close monitoring are warranted during and after taper-
in busy primary care settings and scalable across health ing; consideration of overdose prevention strategies,
systems. Although 31 studies in this review examined such as naloxone, may be prudent (103). Together,
interdisciplinary pain programs, only 5 involved pri- these strategies are well-aligned with the broader goal
mary care settings. The effectiveness of less resource- of patient-centered, evidence-based, effective chronic
intensive team-based models (97, 98) or technology- pain care (104).

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Career Development Award IK2HX001516. Dr. Becker re- dependence among individuals with chronic noncancer pain: the
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Health Services Research and Development QUE15-460.
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89. Zekry O, Gibson SB, Aggarwal A. Subanesthetic, subcutaneous /jama.2014.7689
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Veterans Affairs; 2016. 2017.

Current Author Addresses: Dr. Frank: VA Eastern Colorado Author Contributions: Conception and design: J.W. Frank, T.I.
Health Care System, 1055 Clermont Street, Denver, CO Lovejoy, W.C. Becker, B.J. Morasco, S.K. Dobscha, E.E. Krebs.
80220. Analysis and interpretation of the data: J.W. Frank, T.I. Love-
Dr. Lovejoy: Center to Improve Veteran Involvement in Care, joy, W.C. Becker, B.J. Morasco, C.J. Koenig, H.R. Dischinger,
VA Portland Health Care System, 3710 SW U.S. Veterans Hos- S.K. Dobscha, E.E. Krebs.
pital Road, Mail Code R&D 66, Portland, OR 97239. Drafting of the article: J.W. Frank, T.I. Lovejoy, W.C. Becker,
Dr. Becker: VA Connecticut Healthcare System, 950 Campbell B.J. Morasco, C.J. Koenig, L. Hoffecker, H.R. Dischinger, S.K.
Avenue, Mail Stop 151B, West Haven, CT 06516. Dobscha, E.E. Krebs.
Dr. Morasco: Center to Improve Veteran Involvement in Care, Critical revision of the article for important intellectual con-
VA Portland Health Care System, 3710 SW U.S. Veterans Hos-
tent: J.W. Frank, T.I. Lovejoy, W.C. Becker, B.J. Morasco, C.J.
pital Road, Mail Code R&D 99, Portland, OR 97239.
Koenig, L. Hoffecker, H.R. Dischinger, S.K. Dobscha, E.E.
Dr. Koenig: Department of Communication Studies, San Fran-
Krebs.
cisco State University, 1600 Holloway Avenue, Humanities
Final approval of the article: J.W. Frank, T.I. Lovejoy, W.C.
Building, Room 282, San Francisco, CA 94132.
Dr. Hoffecker: Health Sciences Library, University of Colorado, Becker, B.J. Morasco, C.J. Koenig, L. Hoffecker, H.R. Disch-
12950 East Montview Boulevard, MS-A003, Aurora, CO inger, S.K. Dobscha, E.E. Krebs.
80045. Obtaining of funding: J.W. Frank, T.I. Lovejoy, W.C. Becker,
Ms. Dischinger: Oregon Health & Science University School of B.J. Morasco, S.K. Dobscha, E.E. Krebs.
Medicine, 3181 SW Sam Jackson Park Road, Portland, OR Administrative, technical, or logistic support: H.R. Dischinger.
97239. Collection and assembly of data: J.W. Frank, W.C. Becker, B.J.
Dr. Dobscha: Center to Improve Veteran Involvement in Care, Morasco, L. Hoffecker, H.R. Dischinger.
VA Portland Health Care System, 3710 SW U.S. Veterans Hos-
pital Road, Portland, OR 97239.
Dr. Krebs: Center for Chronic Disease Outcomes Research,
Minneapolis Veterans Affairs Health Care System, One Veter-
ans Drive, Minneapolis, MN 55417.
Appendix Table 1. Ovid MEDLINE Search Strategy
Concepts MeSH Terms Text Words

Opioid medications (exp analgesics, opioid/ or codeine/ or hydrocodone/ or morphine/ (Opioid* or opiate* or codeine or clonidine or morphine or
or oxycodone/) and tu.xs. hydrocodone or oxycodone).tw,kf,rn.
Dose reduction or (Taper* or wean* or (dose* adj1 reduc*) or detox* or
discontinuation withdraw* or discontinuat* or cessation or tolerance or
conversion or substitution).tw,kf,rn.
Chronic pain (pain/ or exp musculoskeletal pain/ or exp back pain/ or exp (pain).tw,kf,rn.
chronic pain/ or exp facial pain/ or exp headache/ or
metatarsalgia/ or neck pain/ or exp neuralgia/ or exp nociceptive
pain/ or pain, intractable/ or pain, referred/ or exp arthralgia/ or
eye pain/ or ank pain/ or glossalgia/ or exp headache/ or exp
pelvic pain/ or shoulder pain/) and dt.fs. or "Pain Measurement"/
or Pain Threshold/
Systematic reviews and meta-analysis/ ("systematic review" or "systematic reviews").ab,ti,kf. or
meta-analyses cochrane.mp. or medline.ab,ti,kf. or pubmed.ab,ti,kf. or
cinahl.ab,ti,kf. or embase.ab,ti,kf. or handsearch*.ab,ti,kf.
or (hand adj2 search*).ab,ti,kf. or (manual* adj2
search*).ab,ti,kf. or meta-analysis.ab,ti,kf. or
meta-analyses.ab,ti,kf. or met analy*.mp. or
metanaly*.mp. or meta-analysis/ or (technology adj1
assessment*).ab,ti,kf. or HTA.ab,ti,kf. or HTAs.ab,ti,kf. or
(technology adj1 overview*).ab,ti,kf. or (technology adj1
appraisal*).ab,ti,kf.
MeSH = Medical Subject Headings.
Annals.org Annals of Internal Medicine

Appendix Table 2. USPSTF Quality Rating Criteria for Appendix Table 3. GRADE Criteria for Assessing Quality
RCTs and Cohort Studies of Evidence*
Criteria Initial quality of a body of evidence

Initial assembly of comparable groups: Randomized trial = high
RCTsadequate randomization, including concealment and whether Observational study = low
potential confounders were distributed equally among groups Any other evidence = very low
Cohort studiesconsideration of potential confounders with either
restriction or measurement for adjustment in the analysis; Decrease GRADE if
consideration of inception cohorts Serious (1) or very serious (2) risk of bias
Maintenance of comparable groups (includes attrition, crossovers, Serious (1) or very serious (2) inconsistency
adherence, contamination) Serious (1) or very serious (2) indirectness
Important differential loss to follow-up or overall high loss to follow-up Serious (1) or very serious (2) imprecision
Measurements: equal, reliable, and valid (includes masking of outcome Likely (1) or very likely (2) publication bias
assessment)
Clear denition of interventions Increase GRADE if
Important outcomes considered Large (+1) or very large (+2) effect
Analysis: adjustment for potential confounders for cohort studies, or Evidence of a dose response gradient (+1)
intention-to-treat analysis for RCTs (i.e., analysis in which all participants All plausible confounders would reduce a demonstrated effect (+1) or
in a trial are analyzed according to the intervention to which they were would suggest a spurious effect if no effect was observed (+2)
allocated, regardless of whether or not they completed the
intervention)
Signicance of the 4 levels of evidence
High = We are very condent that the true effect lies close to that of the
Denition of ratings based on above criteria estimate of the effect
Good Moderate = We are moderately condent in the effect estimate: The true
Meets all criteria: Comparable groups are assembled initially and effect is likely to be close to the estimate of the effect, but there is a
maintained throughout the study (follow-up at least 80%); reliable and possibility that it is substantially different
valid measurement instruments are used and applied equally to the Low = Our condence in the effect estimate is limited: The true effect
groups; interventions are spelled out clearly; important outcomes are may be substantially different from the estimate of the effect
considered; and appropriate attention to confounders in analysis. Very low = We have very little condence in the effect estimate: The true
Fair effect is likely to be substantially different from the estimate of effect
Studies will be graded fair if any or all of the following problems occur,
without the important limitations noted in the poor category below: GRADE = Grading of Recommendations Assessment, Development
Generally comparable groups are assembled initially but some and Evaluation.
question remains whether some (although not major) differences * From reference 24.
occurred in follow-up; measurement instruments are acceptable
(although not the best) and generally applied equally; some but not all
important outcomes are considered; and some but not all potential
confounders are accounted for.
Poor
Studies will be graded poor if any of the following major limitations
exists: Groups assembled initially are not close to being comparable or Appendix Figure. Study ow diagram.
maintained throughout the study; unreliable or invalid measurement
instruments are used or not applied at all equally among groups
(including not masking outcome assessment); and key confounders are Abstracts identified and screened for
Excluded (n = 3448)
given little or no attention. eligibility (n = 3522)
Not published in English: 7
RCT = randomized controlled trial; USPSTF = U.S. Preventive Services Nonhuman participants: 57
Task Force. Nonadult participants: 26
Nonclinical setting: 110
Nonpain outcome: 276
Cancer-related pain: 448
Acute, surgical, or interventional
pain: 1166
Nonopioid therapies only: 210
Not related to opioid tapering:
443
Not original data: 599
No outcome data: 32
Other: 74
Articles retrieved for full-text review
(n = 74)
Excluded (n = 23)
No original data: 2
No long-term opioid use: 5
No tapering outcomes: 4
Intervention not described: 8
Acute pain: 1
Nonmedical use: 3
Articles identified from reference

lists and expert contacts (n = 17)
Articles included in analysis

(n = 68)
Annals of Internal Medicine Annals.org

Appendix Table 4. Derivation of GRADE Score*
Outcome Initial Adjustment Reason for Adjustment Final

GRADE GRADE
Score Score
Effectiveness of strategies to reduce or discontinue LTOT 2 1 Risk of bias; indirectness Very low
Effect of dose reduction or discontinuation on patient outcomes
Pain severity 2 1 Risk of bias Very low
Function 2 1 Risk of bias Very low
Quality of life 2 1 Risk of bias Very low
Opioid withdrawal symptoms 2 1 Risk of bias; inconsistency Very low
Substance use 2 1 Risk of bias Very low
Adverse events 2 1 Risk of bias Very low
GRADE = Grading of Recommendations Assessment, Development and Evaluation; LTOT = long-term opioid therapy.
* Reference 24. See Appendix Table 3 for criteria for assigning GRADE score for quality of evidence.
Annals.org Annals of Internal Medicine

Appendix Table 5. Characteristics of Studies Evaluating the Effectiveness of Strategies to Reduce or Discontinue LTOT for Chronic Pain
Study, Year Design Setting, Years, Country, Sample Characteristics Baseline Opioid Intervention Program Control Program Patient Results Quality
(Reference) and Funding Source Use and Dose Goal of Dose Condition Completion and Outcomes Rating*
(MED) Reduction Study Follow-up (KQ2)
Annals of Internal Medicine

Baron and RCS Inpatient psychiatric facility 23 patients referred by 100% Optional hospitalization Yes Yes 100% (23/23) Yes 100% discontinued opioid Poor
McDonald, with outpatient PCP for opioid Mean, 556 mg Ibuprofen only (n = 7) completed medications
2006 (25) follow-up discontinuation Median, 360 mg or ibuprofen plus program 21/23 reported improved
March 2004-May 2006 Mean age: 50.7 y buprenorphine taper Range, 14-180 d pain severity (P < 0.001)
United States Female: 30% (n = 16) Signicant pain reduction
Funding NR Pain duration: NR compared to baseline
(mean NRS, 8.0 vs. 3.3;
P < 0.001)
No signicant difference
in pain severity
reduction between
treatment groups
Berland et al, RCS Two inpatient settings 76 consecutive patients 100% Inpatient opioid Yes No 100% (76/76) Yes 100% discontinued opioid Poor
2013 (26) 2009-2010 with chronic pain Median, 400 mg discontinuation and completed medications
United States Median age: 48 y buprenorphine program At follow-up, 54% on
Funding NR Female: 58% initiation with Range, 0-25 mo buprenorphine, 26%
Pain duration: NR outpatient follow-up 7 (9%) lost to resumed opioid, and
follow-up 10% not on opioids
67% reported improved
pain, and 60% reported
improved function vs.
baseline
Blondell et al, RCT Multidisciplinary outpatient 12 patients prescribed 100% Inpatient opioid Yes Yes 42% (5/12) Yes 100% discontinued opioid Poor
2010 (27) pain management opioids for chronic Dose NR discontinuation and completed medications
program pain with opioid buprenorphine program 0/6 patients in taper
Dec. 2007-Apr. 2008 dependence Mean initiation with 10/12 (83%) at 6 mo group and 5/6 in
United States age: 45 y outpatient follow-up maintenance group
NIAAA Female: 50% with buprenorphine completed intervention
Pain duration: NR tapering (n = 6) or At 6 mo, 8/10 patients on
steady dose (n = 6) buprenorphine, and
protocol 2/10 resumed opioid
medications
At 6 mo, 6/10 reported
improved pain, 8/10
reported improved
function vs. baseline
At 6 mo, 6/10 reported
alcohol and/or illicit
drug use
Buckley et al, RCS Inpatient multidisciplinary 173 consecutive patients 71% (124/173) on 1 wk inpatient opioid Yes No 94% (116/124) Yes 116/124 (94%) Poor
1986 (28) pain center with chronic pain opioid or tapering using completed discontinued opioid
Jan. 1981-June 1982 Mean age: 46 y sedative blinded pain cocktail program medications
United States Female: 45% medication Effects on pain and
Funding NR Mean pain duration: 6.8 Mean, 253 mg function NR
y 4 patients experienced
withdrawal symptoms
or adverse event
Caraway et al, RCS Pain management center 99 patients with 90% (89/99) Implantation of Yes No 99% (98/99) at 6 mo No 68% (67/98) and 74% Poor
2015 (29) Dates NR implantable drug Dose NR intrathecal drug 13% (13/99) (73/98) discontinued

United States delivery system for 6 delivery system and completed 5 y opioids at 1 and 6 mo
Funding NR mo use for 6 mo follow-up postimplantation,
Mean age: 67 y respectively
Female: 68% For all patients, pain
Mean pain duration: decreased by 2.1 points
81% with >5 y at 1 mo (P < 0.001) and
1.9 points at 6 mo (P <
0.001) vs. baseline
Continued on following page
Annals.org
Annals.org
Appendix Table 5Continued
Cowan et al, RCS Outpatient pain clinic 104 patients on opioid 100% Multidisciplinary No No Mean treatment Yes 57% (59/104) Poor
2003 (30) 1995-1999 medications for 92% with dose outpatient pain duration, 14.1 mo discontinued opioid
United Kingdom chronic pain 60 mg including medications
Funding NR Mean age: 55 y nonpharmacologic, Among patients who
Female: 61% pharmacologic, and stopped opioids, 66%
Mean pain duration: interventional (52/78) reported
10.5 y modalities worsening pain and
50% (39/78) reported a
decrease in function; no
patients reported
improved pain and 3%
reported improved
function
17% (13/78) reported
opioid withdrawal
symptoms; 2 patients
reported addiction to
opioids
Cowan et al, RCT Outpatient pain clinic 10 patients with chronic 100% Double-blind, Yes Yes 100% (10/10) Yes 100% discontinued Poor
2005 (31) Dates NR pain on long-acting Mean, 40 mg placebo-controlled, completed trial opioids during 60-h
United Kingdom morphine for 30 d crossover study abstinence period
Janssen-Cilag, Napp Mean age: 56 y comparing 60-h Patients reported
Pharmaceuticals Female: 40% periods of cessation increased pain and
Mean pain duration: vs. morphine increased interference
13.5 y continuation with general activity
and enjoyment of life at
end of 60-h abstinence
period (all P < 0.05)
3/10 (30%) reported
withdrawal symptoms
Crisostomo et al, RCS Outpatient 383 consecutive patients 58% (146/253) 3-wk intensive Yes No 84% (322/383) No Proportion of patients Poor
2008 (32) multidisciplinary pain with cLBP Mean, 61 mg multidisciplinary pain 81% (309/383) at 3 using opioid
rehabilitation center Mean age: 47 y rehabilitation wk medications decreased
Jan. 2000-April 2006 Female: 62% program using 79% at discharge vs.
United States Mean pain duration: 8.9 cognitive behavioral admission
Unfunded y model and Signicant improvements
incorporating opioid in pain severity and
discontinuation physical function
among all patients
Cunningham et al, RCS Outpatient 131 consecutive patients 42% (55/131) 3-wk intensive Yes No 100% (131/131) Yes 100% (55/55) Poor
2016 (33) multidisciplinary pain with bromyalgia who Mean, 99 mg; multidisciplinary pain completed discontinued opioid
rehabilitation center completed program range, 5-600 mg rehabilitation program medications
Jan. 2006-Dec. 2012 Mean age: 46 y program using Patients taking opioids at
United States Female: 81% cognitive behavioral baseline had signicant
Funding NR Mean pain duration: model and improvements in pain
11.6 y incorporating pain (mean NRS, 5.2 vs. 7.2;
medication P < 0.001), pain
discontinuation interference (mean MPI,
45.0 vs. 55.2; P < 0.001)

and QOL (mean SF-36,
42.9 vs. 33.3; P < 0.001)

at program completion
vs. baseline
Opioid withdrawal
symptoms (peak COWS
score) not signicantly
different based on
opioid dose (P = 0.22)
or duration
of use (P = 0.8)

Daitch et al, RCS Interventional pain 104 patients with chronic 100% Outpatient conversion Yes No Mean treatment Yes Study excluded patients Poor
2012 (34) management practice pain, converted to Mean, 180 mg to sublingual duration, 10.3 mo who continued to use
Dec. 2007-July 2010 buprenorphine for buprenorphine Range, 2-42 mo opioid medications or
United States 60 d did not continue
Unfunded Mean age: 49 y buprenorphine 60 d

Female: 42% Signicant reduction in
Pain duration: NR pain severity after
conversion to
buprenorphine vs.
baseline (mean NRS,
2.3-point reduction; P <
0.01)
Nonsignicant change in
QOL
Daitch et al, RCS Interventional pain 35 patients with chronic 100% Outpatient conversion Yes No Mean treatment Yes Study excluded patients Poor
2014 (35) management practice pain, on high-dose Mean, 550 mg to sublingual duration, 6 mo who continued to use
July 2010-April 2011 opioid medications buprenorphine opioid medications or
United States converted to did not continue
Funding NR buprenorphine for buprenorphine 60 d
60 d Signicant reduction in
Mean age: 49 y pain severity (mean
Female: 40% NRS, 7.2 to 3.5; P <
Pain duration: NR 0.01) and QOL (mean
QOL scale, 6.1 to 7.1; P
< 0.01) after conversion
to buprenorphine vs.
baseline
Darchuk et al, RCS Outpatient 449 patients with chronic 56% (253/449) 3-wk intensive Yes No 92% (411/449) No 94% (239/253) Fair
2010 (36) multidisciplinary pain pain and functional Mean, 112 mg multidisciplinary pain completed discontinued opioid
rehabilitation center impairment rehabilitation program medications at
Oct. 2004-April 2006 Mean age: 46 y program using 72% (292/411) discharge
United States Female: 79% cognitive behavioral completed 6-mo 15% (44/292) reported
Unfunded Mean pain duration: 9.9 model and follow-up opioid use at 6-mo
y incorporating opioid follow-up
discontinuation Signicant improvements
in pain severity and
general activity at 6-mo
follow-up vs. admission
for all patients (P <
0.001 for all
comparisons)
Dersh et al, RCS Outpatient 1323 consecutive Most patients Intensive physical Yes No 91% (1200/1323) No Opioid discontinuation Poor
2008 (37) interdisciplinary patients with chronic, Dose NR reactivation and completed required for program
functional restoration disabling pain/disability program completion but not
program occupational spinal management with 100% (1200/1200) specically reported
1994-1999 disorders mandatory opioid completed 1-y Opioid use at 1-y
United States Mean age: 42 y discontinuation follow-up follow-up NR
Unfunded Female: 38% Among all patients, 80%
Mean disability duration: (955/1200) returned to
19 mo work and 74%
(891/1200) currently
employed at 1-y
follow-up
Drossman et al, RCS Inpatient gastroenterology 39 patients with severe 100% Inpatient opioid Yes No 97% (38/39) Yes 100% decreased opioid Poor
2012 (38) consult service; chronic abdominal Mean, 75 mg discontinuation with completed dose; 90% (35/39)

outpatient pain on opioid consult service (n = program discontinued opioids at
gastroenterology clinic medications 34) or outpatient 64% (25/39) program completion
Nov. 2008-Nov. 2011 Mean age: 40 y discontinuation (n = completed 3-mo 66% (24/36) resumed
United States Female: 92% 5), both guided by follow-up opioids at an average of
Pzer and Salix Mean pain duration: 15 y multimodal protocol 97 d posttreatment
Pharmaceuticals (range, 1-416 d)
51% (20/39) reported
30% reduction in pain
severity after
discontinuation vs.
baseline
82% reported opioid
withdrawal symptoms
Annals.org
Annals.org
Hanson et al, Case Specialty gastroenterology 100 cases on opioid for 50% (50/100) 1 visit in IBD clinic No Yes 76/200 (38%) Yes Of patients who returned Poor
2009 (39) control clinic at a tertiary care IBD-related pain at Dose NR returned for 1 for follow-up, 56%
referral center initial visit; 100 follow-up visit (22/39) discontinued
Jan. 1999-Dec. 2002 matched controls opioid medications
United States Median age: 37.4 y Patients who had
Mayo Foundation for Female: 64% discontinued opioids
Medical Education and Mean disease duration: were more likely to
Research 6.2 y report none-to-mild
pain (73% vs. 18%) vs.
those who continued
opioids
Harden et al, RCS Single integrated health 50 patients with chronic 100% Routine clinical care Yes No 100% (50/50) Yes 94% (47/50) decreased Poor
2015 (40) care system pain on opioid 64% with dose with dose reduction completed opioid dose at 12 mo;
Jan. 2010-Jan. 2013 medications >200 mg implemented by 12-mo follow-up 13% (6/50)
United States Mean age: 54 y primary care discontinued opioid
Funding NR Female: 12% providers, the pain medications
Pain duration: NR service, or the Mean opioid dose
pharmacist-run pain reduction of 46% at 12
management clinic mo
68% of patients either
experienced no change
or less pain at 12 mo vs.
baseline
Haroutounian et al, PCS Outpatient pain clinic 206 patients with 35% (73/206) Cannabis treatment Yes No 85% (176/206) No 44% (32/73) discontinued Poor
2016 (41) June 2010-Jan. 2013 treatment resistant Median, 60 mg (smoked or edible), (encouraged completed 6-mo opioids at 6 mo (P <
Israel chronic pain supervised by pain to attempt follow-up 0.01)
Unfunded Mean age: 51.2 y management dose Among patients still
Female: 38% physician with dose reduction) receiving opioids at
Pain duration: NR titration by protocol follow-up, median dose
decreased from 60 mg
to 45 mg MED
Among all participants,
pain severity improved
at 6 mo vs. baseline
(S-TOPS, 75.0 vs. 83.3;
P < 0.01)
Hassamal et al, RCS Outpatient 5 patients with cLBP 100% Interdisciplinary, Yes No 100% completed Yes No patients (0/5) Poor
2016 (42) interdisciplinary opioid scheduled for spine Mean, 238 mg outpatient program follow-up 1 mo discontinued opioids;
reduction program surgery involving opioid postop mean dose decreased
Dates NR Mean age: 58 y dose reduction, from 238 mg MED at
United States Female: 80% medication admission to 157 mg
Funding NR Mean opioid duration: management, and MED preop and 139
10 y nonpharmacologic mg MED postop
therapies (CBT, PT, Improvements in pain
OT) (mean NRS, 5.0 vs. 7.6),
pain interference
(mean, 67.7 vs. 72.4),
and satisfaction with
participation in social
roles (mean, 39.4 vs.
32.8) at 1 mo postop vs.
admission

Heiwe et al, RCS Inpatient and outpatient 29 patients with chronic 100% Opioid discontinuation Yes No 66% (19/29) Yes 66% (19/29) of patients Fair

2011 (43) academic dependency pain on opioid 10% (3/29) taking with counseling and completed discontinued opioid
center medications strong opioids optional auricular program medications
Feb-June 2006, Aug Mean age: 44 y acupuncture and PT 97% (28/29) At follow-up, 32% (6/19) of
2006-April 2007 Female: 86% completed data completers and 78%
Sweden Mean pain duration: 11 y collection at (7/9) of noncompleters
Funding NR mean follow-up on opioids
of 2.1 y Among completers, pain
severity (median NRS,
4.0 vs. 5.0) and
withdrawal symptoms
improved at 2-y
follow-up vs. baseline

Hooten, 2007 (44) PCS Outpatient 159 consecutive patients 38% (61/159) 3-wk intensive Yes No 89% (142/159) No 93% (57/61) of patients on Poor
multidisciplinary pain with bromyalgia Dose NR multidisciplinary pain completed opioids discontinued at
rehabilitation center Mean age: 45 y rehabilitation program program completion
Jan. 2002-Dec. 2003 Female: 86% program using Among all patients, pain

United States Funding NR Mean pain duration: 9.9 cognitive behavioral severity and physical
y model and function improved
incorporating opioid signicantly at program
discontinuation completion vs.
admission (P < 0.01)
Hooten et al, RCS Outpatient 33 consecutive male 32% (21/66) 3-wk intensive Yes No 88% (29/33) of male No 95% (20/21) discontinued Fair
2007 (45) multidisciplinary pain patients with Mean, 64 mg for multidisciplinary pain patients opioid medications
rehabilitation center bromyalgia; 33 men rehabilitation completed Among all patients, pain
Jan. 2002-June 2005 matched female Mean, 39 mg for program using program severity and physical
United States patients women cognitive behavioral function improved
Funding NR Mean age: 47 y model and signicantly at program
Female: 50% incorporating opioid completion vs.
Mean pain duration: discontinuation admission (P < 0.01);
10.4 y these changes did not
differ signicantly by
sex
Hooten et al, RCS Outpatient 1241 consecutive 50% (622/1241) 3-wk intensive Yes No 85% (1057/1241) Yes Proportion of patients Fair
2009 (46) multidisciplinary pain patients with chronic Mean, 118 mg multidisciplinary pain completed using opioid
rehabilitation center pain rehabilitation program medications decreased
Sept. 2003-Feb. 2007 Mean age: 46 y program using from 50% at discharge
United States Female: 75% cognitive behavioral to 2% at admission
Unfunded Mean pain duration: 9.9 model and Pain severity at program
y incorporating opioid completion was
discontinuation signicantly higher
among patients who
continued to use
opioids vs. those who
discontinued opioid
medications (mean MPI
pain subscale, 43.4 vs.
37.0; P = 0.01)
Hooten et al, PCS Outpatient 109 patients with chronic 100% 3-wk intensive Yes No 93% (101/109) Yes 98% (99/101) of program Fair
2010 (47) multidisciplinary pain pain on opioid Mean, 192 mg multidisciplinary pain completed completers
rehabilitation center medications 30 mg rehabilitation program discontinued opioids
March 2007-July 2008 MED for >1 mo program using For 91 patients
United States Mean age: 46.5 y cognitive behavioral completing data
Foundation for Anesthesia Female: 57% model and collection, pain severity
Education and Research Mean pain duration: 9.9 incorporating opioid signicantly improved
y discontinuation at program completion
vs. baseline (mean MPI
pain subscale, 41 vs.
51; P =.002)
Mean opioid withdrawal
score was 4.5 at
program completion
Hooten and Warner, RCT Outpatient 21 patients with chronic 100% 15-d course of Yes Yes 86% (18/21) Yes 95% (20/21) of study Poor
2015 (48) multidisciplinary pain pain on opioid Mean, 98 mg varenicline (n = 10) completed study completers
rehabilitation center medications 60 mg vs. placebo (n = 11) discontinued opioids
June 2011-May 2012 MED in context of 3-wk Opioid withdrawal
United States Median age: 49.0 y in intensive symptoms decreased

Mayo Foundation varenicline group, multidisciplinary pain over time in 5/7
46.0 y in placebo rehabilitation patients in the
group program and opioid varenicline group and
Female: 28% discontinuation (n = 4/11 patients in the
Mean pain duration: 5.8 10) placebo group
y Both groups experienced
signicant
improvements in pain
severity at program
completion vs. baseline
(median MPI pain
subscale, 10 vs. 31; P =
0.001)
Annals.org
Annals.org
Huffman et al, RCS Outpatient 120 patients who 100% 3-4 wk interdisciplinary Yes No 82% (558/682) No 82% (459/558) of program Poor
2013 (49) interdisciplinary chronic completed program, Mean, 111 mg chronic pain completed completers
pain rehabilitation discontinued opioid rehabilitation program discontinued opioid
program medications and program including Among patients medications by
Jan. 2007-Dec. 2010 returned 12-mo PT/OT, who discontinued program completion
United States follow-up survey psychotherapy, opioids, 26% 23% (27/120) resumed an
Funding NR Mean age: 49.5 y education, and (120/459) opioid (including
Female: 67% medication completed buprenorphine and
Pain duration: NR management 12-mo follow-up tramadol) at 1 y
including opioid
discontinuation
Huffman et al, RCS Outpatient 1457 patients with 28% (413/1457) 3-4 wk interdisciplinary Yes Yes 82% (1194/1457) Yes 87% (654/754) Fair
2017 (50) interdisciplinary chronic chronic pain who on high-dose chronic pain completed discontinued opioids,
pain rehabilitation participated in (100 mg) rehabilitation program 4% (30/754) discharged
program program 36% (528/1457) program including Outcome data on buprenorphine 10%
2007-2010 Mean age: 46.3 y on low-dose PT/OT, available for 46% (77/754) continued
United States Female: 62% (<100 mg) psychotherapy, (544/1194) at 6 full-agonist opioids
Funding NR Pain duration: NR Mean, 177 mg education, and mo and 39% Among patients who
medication (461/1194) at 12 discontinued opioids,
management mo 31% (128/417) resumed
including opioid opioid use during
discontinuation 12-mo follow-up
Pain and function
improved at discharge,
6 mo, and 12 mo vs
admission; these effects
did not differ across
opioid groups
Kapural et al, RCS Outpatient pain clinic 18 consecutive patients 100% Intravenous ketamine Yes Yes 61% (11/18) Yes Among 11 patients who Poor
2010 (51) Dates NR on LTOT who Mean, 153 mg infusions, 3 100% (36/36) completed 3 infusions,
United States received ketamine intervention h/treatment, 3-6 completed 8 mo 18% (2/11)
Unfunded infusions group weekly infusions follow-up discontinued opioids;
18 sex-matched controls Mean, 190 mg opioid dose decreased
Mean age: 46 y control following last infusion
Female: 44% (mean MED, 184 mg to
Mean pain duration: 9 y 92 mg; P = 0.02) but
was not signicant at 6
mo (mean, 140 mg
MED; P = 0.3). 7/11
decreased opioid dose
at 6 mo vs. baseline
Pain severity improved at
6 mo in 4/7 vs. baseline
Kidner et al, RCS Outpatient, 1226 consecutive 48.6% (596/1226) Outpatient, Yes No 78% (954/1226); Yes 74% (441/596) of patients Fair
2009 (52) interdisciplinary patients with a chronic 23% 30 mg, 10% interdisciplinary 74% in opioids on opioids at baseline
functional restoration disabling 31-60 mg, 12% functional restoration group vs. 81% in discontinued opioid
program occupational >60 mg program no opioids medications
Dates NR musculoskeletal incorporating opioid group (P < 0.01) Program completers on
United States disorder discontinuation 78% (954/1226) opioids at baseline
NIMH Mean age: 43.7 y Program duration NR completed reported improved pain
Female: 51% 12-mo follow-up (mean NRS, 4.9 vs. 6.6)
Mean disability duration: and disability (mean

13.3 y ODI, 24 vs. 42) at
discharge vs. admission

Kroening and RCS Inpatient pain 14 patients with chronic 100% Inpatient medication Yes No 86% (12/14) Yes 86% (12/14) discontinued Poor
Oleson, 1985 (53) management service pain on opioid Mean, 73 mg management and completed study opioid medications;
Dates NR medications methadone opioid dose tapering none resumed opioid at
United States Mean age: 45.8 y over 2-7 d with follow-up 6-15 mo later
Funding NR Female: 36% electroacupuncture, while completing a pain
Mean pain duration: 9.3 naloxone management program
y administration, and Per authors, pain
nerve blocks completely, or greatly,
alleviated at follow-up
21% (3/14) experienced
opioid withdrawal
symptoms

Krumova et al, RCS Inpatient pain 102 consecutive patients 100% 3 wk inpatient opioid Yes No 100% (102/102) Yes 76% (78/102) Fair
2013 (54) management service with chronic pain on Mean, 367 mg tapering with completed discontinued opioid
Jan. 2001-Dec. 2006 opioid medications pharmacologic program medications; 24%
Germany Mean age: 51 y management of 95% (97/102) (24/102) reduced dose
Funding NR Female: 46% withdrawal completed data by an average of 82%;
Mean opioid duration: symptoms and collection 6-12 42% (31/73) resumed
3.6 y outpatient mo after program opioid medications at
multidisciplinary completion follow-up

follow-up Pain severity improved at
program completion vs.
baseline (mean NRS,
5.4 vs. 7.1; P < 0.001)
At 6-12 mo, pain severity
(mean NRS, 5.9 vs. 7.1;
P < 0.001) and
pain-related disability
(mean PDI, 30.4 vs.
37.7; P < 0.001) were
improved vs. baseline
Lake et al, 2009 (55) RCS Inpatient, comprehensive 283 consecutive patients 48% (127/267) Inpatient, Yes No 94% (267/283) Yes All patients discontinued Poor
headache treatment admitted for inpatient Dose NR comprehensive completed opioid medications.
center headache treatment headache treatment program (mean 81% (103/127) achieved
Dates NR Mean age: 40 y involving medication length of stay, moderate to
United States Female: 79% withdrawal, 13.0 d) signicant pain
Funding NR Pain duration: NR medication improvement at
management and discharge
nonpharmacologic
therapies
Levine et al, PCS Outpatient academic 132 consecutive patients NR 3-wk trial of No No 48% (55/123) with No 55% (11/20) DNRS Poor
2017 (56) neurosurgical pain with chronic pain Mean, 253 mg percutaneous opioid data at 12 patients decreased
center treated with trial of stimulation followed mo dose and 15% (3/20)
July 2011-Oct. 2013 spinal cord by permanent increased dose; 46%
Canada stimulation implantation of SCS (16/35) SCS patients
No external funding Mean age: 47.3 y or DNRS if trial decreased dose and
Female: 54% successful 31% (11/35) increased
Mean pain duration: 6.8 dose
y Among all participants,
47% of DNRS patients
and 51% of SCS
patients achieved >50%
pain reduction
Maani et al, RCS Inpatient burn center in 6 patients with chronic 100% Ultrarapid opioid Yes No 100% (6/6) Yes 33% (2/6) discontinued Poor
2011 (57) military medical center pain related to burn Mean, 218 mg detoxication under completed opioid medications
Mar. 2008-Feb. 2009 injury anesthesia program Mean opioid medication
United States Mean age: 31 y use decreased from
Funding NR Female: 0% 218 mg MED
Mean pain duration: 1.8 preintervention to 22
y mg MED
postintervention (range,
0.175 mg)
There were no adverse
events during the
detoxication
procedure, and 1
patient was readmitted
within 1 wk of discharge
Maclaren et al, RCS Outpatient 127 consecutive patients 55% (70/127) 4-6 wk outpatient No No 76% (146/193) Yes Of 70 patients on opioids Poor

2006 (58) multidisciplinary with chronic pain Mean, 29 mg multidisciplinary completed at admission, 14 (20%)
rehabilitation program related to work injury functional restoration program decreased dose and 10
2001-2003 Mean age: 40.6 y program 88% (127/145) (14%) discontinued
United States Female: 47% completed 6-mo during treatment.
Funding NR Mean pain duration: 1.9 follow-up Among patients on
y opioids at baseline,
pain severity (mean
MPQ, 18 vs. 23; P <
0.025) and pain-related
function (mean PDI, 30
vs. 49; P < 0.025)
improved These effects
did not differ
signicantly between
patients decreasing
opioid dose vs. patients
maintaining opioid
dose
Annals.org
Annals.org
Malinoff et al, PCS Outpatient setting 95 consecutive patients 100% Outpatient conversion Yes No 94% (89/95) Yes 94% discontinued LTOT Poor
2005 (59) Dec. 2003-Oct. 2004 referred by pain Dose NR to sublingual completed and initiated
United States clinics for buprenorphine program buprenorphine, and
Funding NR detoxication from Mean follow-up, 8.8 none of these patients
LTOT mo returned to opioid
Mean age: 51.3 y Range, 2.4-16.6 mo medications
Female: 48% 86% reported substantial
Mean opioid duration: improvement in pain
8.8 y severity during
follow-up
Most patients reported
improved functional
status
6 patients discontinued
treatment during
detoxication due to
side effects; no patients
died or were
hospitalized
Marchetti et al, RCS Inpatient and outpatient 51 patients who 49% (25/51) Intravenous and oral Yes No Median treatment No 62% of patients on opioid Poor
2015 (60) pain management underwent Dose NR ketamine for up to 3 duration, 3 mo achieved at least a 30%
center Mean age: 46 y mo with opioid dose dose reduction
2007-2012 Female: 67% reduction and Among all patients, 44%
France Pain duration: NR pharmacologic (24/55) achieved at
Funding NR management of least a 50% reduction in
withdrawal pain severity; 51%
symptoms showed adverse effects
Mehl-Madrona et al, PCS Rural primary care practice 42 patients on long-term 100% GMVs provided No Yes 50% (42/84) No In GMV group, 19% (8/42) Poor
2016 (61) Dates NR opioids who Mean, 82 mg education about attended discontinued opioids,
United States completed 6 mo of nonpharmacologic program for >6 and 43% (18/42)
Coyote Institute, Inc. group medical visits pain care and taught mo reduced opioid dose;
42 matched controls multiple mean opioid dose
Mean age: 45 y complementary/ decreased in GMV
Female: 60% alternative medicine group (82.1 to 32.4 mg;
Mean pain duration: 9.1 techniques. Visits led P < 0.001).
y by family physician, In treatment-as-usual
nurse, and behavioral group, 1/42 decreased
health specialist. opioid dose.
Among all GMV
participants, pain
severity (mean NRS,
0.19; P < 0.01) and
QOL (mean MYMOP2,
1.42; P < 0.01)
improved vs. baseline
Miller et al, RCS Inpatient addiction 53 patients with chronic 100% Inpatient Yes No Program Yes Study included only Poor
2006 (62) treatment setting pain and prescription Dose NR discontinuation of completion NR patients who
2001-2003 opioid dependence opioid medications discontinued opioid
United States who completed with pharmacologic medications
Unfunded program management of Pain severity improved
Mean age: 45 y withdrawal signicantly at program
Female: NR symptoms with completion vs. baseline
Mean opioid duration: diazepam and (mean NRS, 3.4 vs. 5.5;
3.7 y clonidine P = 0.01)

Murphy et al, RCS Inpatient chronic pain 705 patients admitted to 37% (221/600) of 3-wk, inpatient Yes No 85% (600/705) Yes 100% (221/221) Fair
2013 (63) rehabilitation program pain program program interdisciplinary pain completed discontinued opioid

July 2006-Mar. 2011 Mean age: 50.1 y completers) program using program medications at program
United States Female: 20.2% Mean, 61 mg cognitive behavioral discharge. Baseline
VHA Mean pain duration: 13 y model and opioid use signicantly
incorporating pain more common among
medication non-completers (55%
discontinuation vs. 37%)
Among patients on
opioids at baseline,
pain severity (mean
NRS, 6.5 vs. 7.0; P <
0.001) and function
(mean POQ-ADL, 13 vs.
16; P < 0.001) improved
at program completion
vs. baseline

Murphy et al, RCS Inpatient chronic pain 324 patients with chronic 35% (114/324) 3-wk, inpatient Yes No 100% (324/324) No 100% discontinued opioid Fair
2016 (64) rehabilitation program pain who completed Mean, 63 mg interdisciplinary pain completed study medications at program
Aug. 2006-Apr. 2011 program and 3-mo program using discharge. At 3-mo
United States follow-up cognitive behavioral follow-up, 17%
Unfunded Mean age: 52 y model and reported opioid use.

Female: 21% incorporating pain There was no difference
Mean pain duration: medication in follow-up opioid use
12.2 y discontinuation by sex (P = 0.83)
Among all patients, both
males and females
reported improved pain
(P < 0.05) and
pain-related
interference (P < 0.05)
at discharge vs.
admission
Naylor et al, RCT Integrative medicine clinic 51 patients with chronic 63% (32/51) 4-mo TIVR to support No (optional Yes 100% (51/51) No 21% (3/14) TIVR patients Good
2010 (65) Feb. 2003-July 2004 pain who had 54% (14/26) in self-monitoring and goal completed study discontinued opioids at
United States completed 11-wk pain TIVR group skill-building (n = 26) reinforced 8 mo; 3 additional
NIDA, NIAAA, NIAMS coping skills training 72% (18/25) in vs. standard care (n = by TIVR) control patients
Mean age: 46 y control group 25) initiated opioids at 8
Female: 86% Mean, 80 mg mo
Mean pain duration: At 8 mo, opioid dose
11.2 y decreased in the TIVR
group (P = 0.05) and
increased signicantly
in the control group (P
=0.045)
Nilsen et al, PCS Outpatient, 11 patients with chronic 100% 6 one-hour Yes No 100% (11/11) Yes 55% (6/11) patients Poor
2010 (66) multidisciplinary pain pain and Mean, 36 mg physician-led CBT completed discontinued opioids;
clinic problematic opioid sessions during 8-wk program 45% (5/11) remained
Sept. 2003-May 2005 medication use period with gradual 100% (11/11) off codeine at 3 mo
Norway Mean age: 43 y tapering with goal of completed data Mean opioid dose
Funding NR Female: 81.8% discontinuation collection at 3 mo decreased by 81%
Mean pain duration: 7.2 posttreatment (P <
y 0.01)
Pain severity (mean NRS,
5.4 vs. 6.2; P > 0.05),
function (mean SF-36
physical function
0.07), and QOL (mean
SF-36 general health
subscale 48 vs. 34; P =
0.15) did not differ at 3
mo vs. baseline
All patients reported
withdrawal symptoms
Nissen et al, RCS Inpatient, multidisciplinary 288 patients with chronic 83% (239/288) Inpatient, No No 100% (288/288) No Opioid dose decreased at Poor
2001 (67) pain center pain Mean, 89 mg multidisciplinary pain completed discharge vs. admission
Jan.-Dec. 1998 Mean age: NR program program (36.9 mg MED vs. 88.7
Australia Female: NR mg MED; P < 0.001);
Funding NR Pain duration: NR proportion of patients
taking an opioid
decreased (58% at

discharge vs. 83% at
admission; P < 0.05).
Quinlan, 2012 (68) RCS Inpatient setting 11 patients with chronic 100% 5-d subanesthetic Yes No 73% (11/15) Yes 100% discontinued Poor
Dates NR pain on opioid Dose NR infusion of ketamine completed data opioids initially; 27%
Australia medications to assist with opioid collection (3/11) remained off
Funding NR Mean age: NR discontinuation opioids at 6 mo
Female: NR 64% (7/11) reported
Pain duration: NR decreased pain severity
postprocedure
36% (4/11) reported
feeling much better at
6 mo
2 patients experienced
adverse events
Annals.org
Annals.org
Ralphs et al, PCS Inpatient pain 108 patients with chronic 100% 4-wk residential Yes Yes 100% (108/108) No At discharge, 89% of the Fair
1994 (69) management program pain on opioid Mean, 36 mg multidisciplinary pain completed "cocktail" group
Dates NR medications program with program discontinued opioids
United Kingdom Mean age: 48.6 y voluntary opioid 76% (82/108) vs. 68% of the PCR
Institutional support Female: 58% dose reduction completed 6 mo group (P < 0.05)
Mean pain duration: Nonrandom selection follow-up At 6 mo, abstinence rates
10.2 y of PCR (n = 63) vs. were equivalent with
"cocktail reduction 55% of patients
method" (n = 45) remaining off opioids
Among all patients, pain
severity and
pain-related
impairment did not
differ between groups
at discharge
Rome et al, RCS Outpatient 356 consecutive patients 38% (135/356) 3-wk intensive Yes No 86% (305/356) Yes 98% (132/135) of patients Poor
2004 (70) multidisciplinary pain with chronic pain Mean, 78 mg multidisciplinary pain completed discontinued opioids by
rehabilitation center Mean age: 44.3 y rehabilitation program program discharge
Jan. 2002-Dec. 2002 Female: 74.2% program using 77% (274/356) Patients on opioids at
United States Mean pain duration: 7.8 cognitive behavioral completed data admission reported
Funding NR y model and collection at signicant
incorporating pain admission and improvement in pain
medication discharge severity (MPI subscale
discontinuation mean difference, 8.4; P
< 0.001), interference
(MPI subscale mean
difference, 12.5; P <
0.001), and perceived
life control (MPI
subscale mean
difference, 9.1; P <
0.001) at program
completion vs.
admission
Rosenblum et al, PCS Outpatient pain 12 patients with chronic 100% Outpatient conversion Yes No 33% (4/12) Yes 33% (4/12) patients Poor
2012 (71) management center pain on opioid Mean, 142 mg to sublingual completed completed transition to
July 2008-Feb. 2010 medications who had buprenorphine/ program buprenorphine
United States exhibited 1 aberrant naloxone Pain severity (mean BPI
NIDA behaviors subscale, 3.4 vs. 6.6; P
Mean age: 50 y < 0.01) and interference
Female: 42% (mean BPI subscale, 2.9
Mean opioid duration: vs. 6.0) decreased vs.
8.5 y baseline
83% (10/12) experienced
an adverse effect,
including 7 who
stopped treatment as a
result; 1 patient was
hospitalized due to
withdrawal symptoms
and increased pain
Roux et al, 2013 (72) RCT Inpatient psychiatric 43 patients prescribed 100% 7-wk inpatient study Yes Yes 72% (31/43) Yes 72% (31/43) completed Poor
setting opioids for chronic Median, 60 mg involving conversion completed the 7-wk study
Dates NR pain and opioid to program Pain severity was reduced
United States dependence buprenorphine/ 58% (25/43) on

NIDA Mean age: 48 y naloxone at each of 3 completed data buprenorphine/

Female: 36% blinded doses in collection naloxone vs.
Median opioid duration: random order preadmission ratings
5y (median MPQ, 21 vs.
38; P < 0.001)
Opioid withdrawal
symptoms were
reported in 83% of
study sessions
Schneider and Kirsh, RCS Outpatient pain practice 197 patients with chronic 95% prescribed Treatment for 1 y by a No No 100% (197/197) No 15% (29/197) decreased Poor
2010 (73) Dates NR pain treated by a long-acting single physician completed 1 y opioid dose during
United States single pain specialist opioid during trained in internal of follow-up follow-up; 2% (3/197)
Funding NR for 1 y follow-up medicine, addiction Mean follow-up, 4.7 discontinued opioids in
Mean age: 49 y Mean, 180 mg medicine, and pain y setting of aberrant
Female: 67% management behaviors.
Pain duration: NR


Schwarzer et al, RCS Inpatient pain 18 patients admitted for 56% (18/32) 3 wk inpatient opioid Yes Yes 100% (32/32) Yes 100% (18/18) patients in Poor
2015 (74) management program opioid withdrawal Mean, 175 mg tapering with completed OG discontinued
Nov. 2011-Dec. 2012 (OG); pharmacologic program opioids; 1/18 resumed
Germany 14 matched controls management of low-dose opioids.
Funding NR with no prior opioid withdrawal In the OG, there was a
use symptoms and nonsignicant decrease
Mean age: 23 y outpatient in average pain at
Female: 50% multidisciplinary discharge vs. baseline
Pain duration: NR follow-up (mean NRS, 6.6 vs. 7.2;
P = 0.22)
Central apnea was found
in 50% (9/18) OG
patients at baseline,
and resolved in all
patients at discharge.
Streltzer et al, RCS Outpatient psychiatric pain 43 consecutive patients 100% Outpatient conversion Yes No 100% (43/43) Yes 100% (43/43) Poor
2015 (75) clinic prescribed opioids for 93% (40/43) on to sublingual completed discontinued opioid
Jan. 2006-Dec. 2010 chronic pain and dose 120 mg buprenorphine program medications
United States transitioned to Treatment duration 44% (19/43) maintained
Funding NR sublingual ranged from 1-85 buprenorphine
buprenorphine mo treatment; 7% (3/43)
Median age: 50 y discontinued opioids
Female: 30% 23% (10/43) resumed
Pain duration: NR opioid medications,
dropped out, or were
transferred to a
licensed opioid
treatment program
1 patient died of an
overdose several
months after
discontinuing
buprenorphine
Sullivan et al, RCT Outpatient 35 patients with chronic 100% 22-wk outpatient Yes Yes 72% (13/18) No Opioid dose reduction Good
2017 (76) multidisciplinary pain pain on opioid Mean, 226 mg tapering support completed 80% favored intervention but
center medications including psychiatric of intervention was not signicant
May 2013-Sept. 2015 Mean age: 54 y consultation and sessions (adjusted mean
United States Female: 71% weekly visits with PA 89% (31/35) difference = 42.9 mg
NIDA Mean pain duration: for motivational completed 22-wk MED; P = 0.09) at 22 wk
13.8 y interviewing and pain data collection 39% (7/18) in intervention
self-management and 12% (2/17) in usual
training (n = 18) vs. care reduced opioid
usual care (n = 17) dose by 50% at 22 wk;
1 patient in each group
discontinued opioids
22% (4/18) in intervention
and 47% (8/17) in usual
care did not reduce
dose at 22 wk

Among all participants,
signicant differences
favoring the
intervention were found
for pain interference,
pain self-efcacy and
opioid-related
problems
Annals.org
Annals.org
Taylor et al, RCS Inpatient pain 7 patients with chronic 100% Inpatient detoxication Yes No 100% (7/7) Yes 100% discontinued Poor
1980 (77) management program pain on opioid Dose NR from analgesic completed opioids over an average
Dates NR medications medications, program of 3.7 d (range, 1-6 d);
United States Mean age: 49 y education on 86% (6/7) 50% (3/6) patients
Public Health Service Female: 57% relaxation and completed 6 mo reported taking an
Research Grant Mean pain duration: supportive therapy follow-up opioid at 6 mo
15.6 y Pain severity reduced at
6-mo follow-up vs.
baseline (mean 6-point
NRS, 1.44 vs. 2.89; P <
0.001)
50% (3/6) reported
increased activity at 6
mo
1 patient died in motor
vehicle accident during
6 mo follow-up
Tennant and RCS Multidisciplinary outpatient 42 patients with chronic 100% 21-d detoxication with Yes Yes 24% (5/21) in D/C Yes 24% (5/21) in D/C group Poor
Rawson, 1982 (78) pain program pain on opioid Mean, 123 mg pharmacologic group and 95% discontinued opioid
Jan. 1979-Sept. 1981 medications management of (20/21) in D/M medications; 95%
United States Mean age: 38.8 y withdrawal group completed (20/21) in D/M group
Funding NR Female: 50% symptoms followed initial 21-d phase requested maintenance
Mean opioid duration: by nonrandom on opioid medications
8.2 y assignment to (P < 0.001)
psychotherapy (D/C) At 90 d, 10% (2/21)
(n = 21) vs. patients in each group
psychotherapy plus abstinent from opioids;
optional opioid 2 additional patients in
maintenance (D/M) D/M group
(n = 21) discontinued opioids by
180 d
Signicant pain emerged
. . . for a majority of
patients
Thieme et al, RCT Hospital for rheumatic 61 patients with NR 5-wk inpatient, Yes Yes 97% (61/63) No Intervention patients Poor
2003 (79) disorders bromyalgia Dose NR group-based completed study reported a signicant
Dates NR Mean age: 47.3 y operant pain 97% (61/63) with 6- reduction in opioid
Germany Female: 100% treatment program and 15-mo medication use (effect
Funding NR Mean pain duration: consisting of follow-up size not reported; P <
16.5 y medication reduction 0.001) vs. PT
and education (n = Among all intervention
40) vs. 5-wk inpatient, patients, there was
PT program plus signicant
antidepressant improvement in pain
medication (n = 21) severity (mean MPI
subscale, 3.2 vs. 4.4; P
< 0.001) and
interference (mean MPI
subscale, 2.8 vs. 4.4; P
< 0.001) at 15 mo vs.
baseline
Townsend et al, RCS Outpatient 373 consecutive patients 57.1% (213/373) 3-wk intensive Yes No 91.2% (340/373) Yes 93% (176/190) Fair

2008 (80) multidisciplinary pain with chronic pain Mean, 99 mg multidisciplinary pain completed discontinued opioids by
rehabilitation center Mean age: 44.5 y rehabilitation program program completion

Jan. 2005-Feb. 2006 Female: 79.1% program using 70% (238/340) 14% (33/238) of patients
United States Mean pain duration: 9.4 cognitive behavioral completed 6-mo were taking opioids at
Institutional Small Grant y model and follow-up 6-mo follow-up
Research Award incorporating pain Among patients on
medication opioids at admission,
discontinuation there was improvement
in pain severity (mean
MPI subscale, 39 vs. 49;
P = 0.002) and pain
interference (mean MPI
0.002) at 6-mo


Vines et al, 1996 (81) RCS Multidisciplinary functional 23 patients with chronic 100% 4-wk intensive No No 52% (12/23) with No 70% (16/23) discontinued Poor
rehabilitation program pain on opioid Dose NR outpatient pain data collection at opioids by follow-up
July 1992-June 1993 medications rehabilitation program 3-11 mo after program
United States Mean age: 46 y program completion completion
Funding NR Female: 74% 100% (23/23) from Among all patients, pain
Mean pain duration: 9.2 3-11 mo severity (mean NRS, 4.3
y vs. 8.7) and activity
(mean days per week
with decreased activity,
2.6 vs. 6.7) improved at
Wang et al, PCS Outpatient orthopedic 1) 35 patients with cLBP 35.7% (35/98) Outpatient opioid Yes No 57% (20/35) in No 91% (32/35) discontinued Poor
2011 (82) surgery clinic on opioids; 2) 35 Mean, 107 mg tapering by 50% group 1 at 6 mo opioids by day 21
Dates NR patients with cLBP not every 3 d with 54% (19/35) in 15% (3/20) of patients
Germany on opioids; 3) 28 symptomatic support group 2 at 6 mo were taking an opioid
Institutional support healthy controls with doxepin 79% (22/28) in medication at 6-mo
Mean age: 47.7 y group 3 follow-up
Female: 54%
Mean pain duration: 8.8
y
Webster et al, RCT Inpatient clinical trial 39 patients with chronic 85% (33/39) on Double-blind, Yes Yes 94% (31/33) in Yes 92% (36/39) completed Poor
2016 (83) setting pain on opioids 80-160 mg MED placebo-controlled, 80-160 mg MED both 24-h treatment
Dates NR (80-220 mg MED) 15% (6/39) on crossover study group groups
United States Mean age: 42.3 y 161-220 mg comparing 24-h 83% (5/6) in In the 80-160 mg MED
Endo Pharmaceuticals Female: 54% MED periods of full opioid 161-220 mg MED group, 2 patients
Pain duration: NR agonist vs. buccal group experienced opioid
buprenorphine, both withdrawal (COWS
at 50% of baseline 13); 1 patient in both
opioid dose groups and 1 patient
with full agonist only
In the 80-160 mg MED
group, 56% and 41%
experienced an adverse
event during
buprenorphine and full
agonist, respectively
Weimer et al, RCS Academic primary care 516 patients on 100% Opioid Dosing Yes No 97% (112/116) at 28 Yes 37% (41/112) patients Poor
2016 (84) practice long-term opioid Mean, 263 mg in Limitation Policy (i.e., mo reduced opioid dose
May 2011-August 2013 medications high-dose mandatory dose below 120 mg MED;
United States Mean age: 59 y (>120 mg) reduction below 120 12% (13/112)
Professional society grant Female: 63% group (n = 116) mg MED) and discontinued opioids.
Pain duration: NR provider education Mean opioid dose
intervention decreased from 263 mg
to 199 mg (P < 0.001).
Among patients who
reduced dose, pain
(mean NRS, 5.4 vs. 5.6)

and QOL (mean NRS,
5.1 vs. 5.7) did not
change signicantly
postintervention vs.
preintervention
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Whitten and PCS Rural primary care practice 22 patients with chronic 100% 6-wk group CBT No No 34% (27/80) of No 18% (4/22) discontinued Poor
Stanik-Hutt, June-Nov. 2010 pain on opioid Mean, 69 mg program located eligible patients opioids
2013 (85) United States medications within primary care enrolled Among all patients, there
Funding NR Mean age: 61 y practice, cofacilitated 81% (22/27) were nonsignicant
Female: 5% by psychotherapist completed improvements in pain
Mean pain duration: and nurse program (mean BPI subscale, 4.9
20/22 with 10 y practitioner vs. 5.6; P = 0.11) and
physical function (mean
SF-36 PC, 32 vs. 29; P =
0.1) at 6 wk vs. baseline
Williams et al, RCT Multidisciplinary pain 121 patients with chronic 63% (27/43) of IP Cognitive behavioral Yes Yes 93% (40/43) for IP No 50% (21/42) discontinued Poor
1996 (86) management program pain Mean age: 50.0 y group programs consisting group opioids at 1 mo.
Dates NR Female: 53% 67% (30/45) of OP of exercise, goal 82% (37/45) for OP At 1 y, 80% (24/30) and
United Kingdom Mean pain duration: 8.1 group setting, education, group 55% (17/31) not using
Institutional support y 50% of WLC and opioid 1-y follow-up: opioids in IP and OP
Mean, 30 mg for IP discontinuation 78% (31/40) for IP groups, respectively (P
group Random assignment to group < 0.05). IP but not OP
Mean, 22 mg for 4-wk IP vs. 8-wk OP 78% (29/37) for OP group achieved a
OP group vs. waiting list control group signicant dose
reduction at 1 y.
Pain severity did not
improve signicantly in
either treatment group
vs. control at 1 mo (not
stratied by opioid
dose reduction)
Multiple measures of
function improved
signicantly in both
treatment groups vs.
control at 1 mo and 1 y
Williams and Stark, RCS Inpatient neurology unit 71 patients with chronic 80% (57/71) on Inpatient medication Yes No 93% (66/71) No 76% (45/57) discontinued Poor
2003 (87) Dates NR daily headache codeine; 47% discontinuation and completed opioid at 6 mo
Australia admitted for inpatient and 31% on 7-10 d lidocaine protocol follow-up (P < 0.001).
Funding NR treatment other and infusion and 87% (62/71) Of those who were still
Mean age: 44 y injectable medication completed 6 mo using codeine-based
Female: 87% opioids management follow-up medications, the mean
Mean pain duration: 5.5 23 mg among weekly dose decreased
y codeine users by 22%.
Pain outcomes not
stratied by opioid
dose reduction.
Younger et al, PCS Inpatient pain 12 patients with chronic 100% 7-14 d inpatient pain Yes No 100% (12/12) No 58% (7/12) discontinued Poor
2008 (88) rehabilitation program pain on opioid Mean, 33 mg rehabilitation completed opioid therapy; 2
Dates NR medications Median, 194 mg program with opioid program patients greatly
United States Mean age: 47.9 y detoxication using reduced high-dose
Arthritis Foundation, Female: 42% blinded pain cocktail therapy (i.e., 400 mg
NIGMS, NINDS Pain duration: NR MED)
Among all patients, pain
severity and opioid
withdrawal ratings did
not signicantly change
at discharge vs.

admission

Zekry et al, 2016 (89) PCS Inpatient pain 70 patients 73% (51/70) Subanesthetic, Yes No NR No Mean opioid dose Poor
management center Mean age: 49 y Mean, 216 mg subcutaneous 74% (52/70) decreased from 216 mg
2007-2012 Female: 37% ketamine infusion completed MED to 89 mg MED
Australia Pain duration: NR with or without follow-up posttreatment (59%
Funding NR subsequent reduction, P <0.005).
sublingual ketamine, Among patients continued
pharmacologic on ketamine lozenges,
management of 31% discontinued
withdrawal opioids at follow-up (3
symptoms mo-2 y).
Pain outcomes not
stratied by opioid
dose reduction


Zgierska et al, 2016 RCT Outpatient primary care 35 patients with cLBP on 100% 8 weekly, 2-h group No Yes 100% completed No Between-group difference Good
(90, 91) Jan. 2013-Oct. 2013 30 mg/d MED for >3 Mean, 148 mg sessions (meditation, trial in opioid dose change
United States mo CBT) and 30 favored intervention but
NIAAA, institutional Mean age: 51.8 y min/day, 6 d/wk of was not signicant (9.9
support Female: 80% at-home practice mg/d; P = 0.8).
Mean pain duration: plus usual care (n = Within-group opioid
14.2 y 21) vs. waitlist control dose reduction was not
receiving usual care signicant in either
(n = 14) group at 26 wk.
Proportion on >200 mg
MED decreased in the
intervention group
(29% to 20%) but not
control (21% to 23%) at
26 wk; opioid
discontinuation NR
The meditation-CBT
group reduced pain
severity vs. controls at
26 wk (P = 0.045)
Zheng et al, RCT Outpatient pain 35 patients with chronic 100% 6-wk intervention of No Yes 74% (26/35) No At week 8, opioid dose Fair
2008 (92) management center pain on opioid Mean, 376 mg twice-weekly REA (n completed 6-wk signicantly decreased
2005-2006 medications = 17) vs. SEA (n = 18) treatment period in both groups vs.
Australia Mean age: 49.7 y 66% (23/35) baseline (39% in REA
Institutional support Female: 49% completed 20-wk vs. 26% in SEA); the
Mean pain duration: study between-group
16.3 y difference was not
signicant
Average pain improved
signicantly in both
groups at week 8 vs.
baseline
No signicant group
differences in pain
severity or QOL at week
8
BPI = Brief Pain Inventory; CBT = cognitive behavioral therapy; cLBP = chronic low back pain; COWS = Clinical Opiate Withdrawal Scale; DNRS = dorsal nerve root stimulator; GMV = group
medical visit; IBD = inammatory bowel disease; IP = inpatient program; KQ = Key Question; LTOT = long-term opioid therapy; MED = morphine-equivalent dose; MPI = Multidimensional Pain
Inventory; MPQ = McGill Pain Questionnaire; MYMOP2 = My Medical Outcome Prole, 2nd version; NIAAA = National Institute on Alcohol Abuse and Alcoholism; NIAMS = National Institute of
Arthritis and Musculoskeletal and Skin Diseases; NIDA = National Institute on Drug Abuse; NIGMS = National Institute of General Medical Sciences; NIMH = National Institute of Mental Health;
NINDS = National Institute of Neurological Disorders and Stroke; NR = not reported; NRS = numerical rating scale; ODI = Oswestry Disability Index; OG = opioid withdrawal group; OP = outpatient
program; OT = occupational therapy; PA = physician assistant; PCP = primary care provider; PCR = patient-controlled dose reduction; PCS = prospective cohort study; PDI = Pain Disability Index;

POQ-ADL = Pain Outcomes Questionnaire-Activities of Daily Living; PT = physical therapy; QOL = quality of life; RCS = retrospective cohort study; RCT = randomized controlled trial; REA = real
electroacupuncture; SCS = spinal cord stimulator; SEA = sham electroacupuncture; SF-36 = 36-Item Short Form Health Survey; S-TOPS = Treatment Outcomes in Pain Survey-Short Form; TIVR =
therapeutic interactive voice response; VHA = Veterans Health Administration; WLC = wait-list control.
* See Appendix Table 2 for U.S. Preventive Services Task Force Quality Rating Criteria.
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Patient Outcomes in Dose Reduction or Discontinuation of Long-Term

A pproximately 10 million U.S. adults are prescribed

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Table 1. Effectiveness of Strategies to Reduce or Discontinue LTOT (n = 67 studies)

Studies, Participants, Description Results* Quality

Behavioral interventions (61, 65, 66, 76, 85, 90, 91)

Other outpatient programs (3941, 73, 84)

Other interventional programs (29, 56, 57, 87)

Detoxication (31, 38, 62, 82)

Ketamine-assisted dose reduction (51, 60, 68, 89)

Acupuncture (43, 53, 92)

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Table 2. Summary of Findings and Quality-of-Evidence Assessment

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Appendix Table 1. Ovid MEDLINE Search Strategy

Concepts MeSH Terms Text Words

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Criteria Initial quality of a body of evidence

Articles identified from reference

Articles included in analysis

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Outcome Initial Adjustment Reason for Adjustment Final

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