Published March 22, 2022

NEJM Evid 2022; 1 (4)

DOI: 10.1056/EVIDra2200038

REVIEW ARTICLE

Opioid Use Disorder Diagnosis and Management

Sarah E. Wakeman, M.D.1,2,3

Abstract C. Corey Hardin, M.D., Ph.D.,

Editor
The last twenty years have seen a staggering increase in opioid-related morbidity and
mortality. Although the consequences of untreated OUD are significant, OUD is a treat-
able illness. Here Wakeman reviews the epidemiology of OUD, its complications, screen-
ing, diagnosis, treatment, and harm reduction interventions.

Introduction

U
ntreated opioid use disorder (OUD), combined with dynamic shifts in opioid
supply, contamination of the illicit drug supply, and limited access to effective
OUD treatment has resulted in a staggering increase in opioid-related morbidity
and mortality. Between 1999 and 2019, nearly 841,000 people died in the United States
from an overdose, predominantly driven by opioid-related drug poisoning.1 During the
12-month period ending in June 2021, an estimated 101,300 drug overdose deaths
occurred in the United States, representing a more than 28% increase from the year prior
(Fig. 1).2 While overdose is a critical driver of mortality, overdose deaths actually represent
a small fraction of the morbidity and mortality associated with OUD.3 In addition to rising
mortality, emergency department visits, hospitalizations for opioid-related causes, and
infectious complications are increasing.4-8

Although the consequences of untreated OUD are significant and can be fatal, OUD is emi-
nently treatable and can be managed effectively across a range of general medical settings,
including primary care, emergency departments, and hospitals. The evidence base for
effective treatments and interventions for OUD has grown significantly in recent decades,
with an impressive body of literature demonstrating the benefit of medication treatment
for OUD (MOUD).9-11 Identifying and treating OUD effectively is relevant for any clinician
practicing amid the worsening overdose crisis, which is the worst epidemic, aside from
Covid-19, that we have seen in more than a century. Unlike the response to Covid-19, in
which historic resources have been marshalled, regulatory hurdles and policy barriers have
The author affiliations are listed
been surmounted, and the health care workforce has rapidly acquired new knowledge and at the end of the article.
provided care for an emerging disease in unprecedented times, most physicians and health Dr. Wakeman can be contacted at
professionals have received little training in and have generally opted out of treating swakeman@[Link] or at
Massachusetts General Hospital,
patients with OUD. To adequately respond to this crisis, we must be willing to address the 55 Fruit St., Founders 860,
historical stigma that exists toward people who use illicit drugs and people with OUD that Boston, MA 02114.

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 120,000

101,300
100,000
84,000
80,000
70,200 69,600 68,700
58,200
60,000
50,300

40,000

20,000

0
Jan-15 Jan-16 Jan-17 Jan-18 Jan-19 Jan-20 Jan-21

Figure 1. U.S. Overdose Deaths for the Preceding 12-Month Period, 2015 to 2021.

leads to common experiences of dehumanization and dis- illicitly manufactured fentanyl as the supply of prescrip-
crimination in health care settings, resulting in delayed tion opioids decreased.15 This transition from nonmedical
care and lack of trust in clinicians.12 Through dismantling prescription opioid use to heroin was demonstrated in
stigma and gaining the skills needed to treat OUD, clini- national data showing that as prescription opioid use
cians can begin to see every patient encounter as an oppor- decreased, concurrent heroin use increased, with individu-
tunity to make a diagnosis, build engagement, reduce the als describing decreased accessibility and rising cost of
consequences of untreated OUD, and rapidly initiate effec- prescription opioids as the primary reason for transition to
tive treatment. This review covers the epidemiology of heroin.16 Opioid initiation data from a national sample of
OUD and its common complications, screening and diag- 8382 individuals accessing addiction treatment showed
nosis, treatment, and harm reduction interventions to the rising use of heroin as an initiating opioid, increasing
reduce the negative consequences of ongoing opioid use. from just under 9% in 2005 to just under 32% in 2015.16
Similar to the transition from prescription opioids to
heroin, the transition from the use of heroin to illicitly
manufactured fentanyl is thought to have been driven by
Epidemiology — OUD and supply-side factors.13
Opioid-Related Morbidity
and Mortality The dynamics of use and death in response to changes in
the opioid supply indicate the need for demand-driven sol-
The recent crisis of opioid-related deaths has unfolded in
utions. While reductions in prescription opioid exposure
three distinct waves.13 The first wave began in association may be important in reducing the incidence of OUD, treat-
with increased prescribing of opioid pain relievers seen in ment and harm reduction efforts are needed to signifi-
the late 1990s. Opioid prescribing peaked in 2012 and has cantly impact current mortality trends.17 Indeed, efforts to
declined each year since.14 Yet rather than seeing a paral- reduce supply without simultaneously ramping up treatment
lel decrease in deaths, there was a subsequent increase in and harm reduction may paradoxically increase fatality as
the rate of opioid-related deaths as the second wave of the people transition from consistent, pharmaceutical-grade
opioid crisis, caused by deaths due to heroin, and then the opioids to unpredictable, illicitly manufactured opioids. For
third wave of deaths attributable to illicitly manufactured example, an analysis of prescription drug monitoring pro-
fentanyl occurred. The second and third waves of the cri- grams, designed to curtail potentially risky opioid prescrib-
sis are likely a result of shifting opioid usage patterns from ing, found that these programs have been associated with a
nonmedical prescription opioid use to heroin and then 22% increase in heroin-related deaths.18

NEJM EVIDENCE 2
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Developing effective interventions to improve access to decreased among White men over the same time period.30
treatment and harm reduction requires an accurate Lack of attention to the crisis of overdose deaths in Black
understanding of the prevalence of OUD. According to and Latinx communities is consistent with the historical
the National Survey on Drug Use and Health, there were approach in the United States of framing drug use among
2.7 million Americans with an OUD in 2020, accounting minoritized populations as a criminal or legal issue rather
for 1% of the population 12 years of age and older.19 This than as a public health issue.26
likely underestimates the true prevalence of OUD,
because the survey noted above relies on household sur-
vey data, which misses key marginalized populations
such as those who are unhoused or imprisoned. Using a Screening and Diagnosis
different method to assess prevalence, researchers esti- Screening for OUD among general medical patients has uti-
mated that in Massachuestts 4.6% of people 11 years of lized validated drug use screening tools that are not specific
age or older had an OUD in 2015.20 for opioids. A single-item screening question for drug use
asks, “How many times in the past year have you used an
In addition to changes in trends in opioid use, the use of illegal drug or used a prescription drug for a non-medical
other nonopioid substances has been shifting among peo- reason?” with a score of 1 or higher considered positive,
ple with OUD, with notable increases in the co-use of prompting further assessment with a longer screening tool
stimulants. In a study examining a national sample of peo- such as the Drug Abuse Screening Test (DAST) or the Alco-
ple with OUD entering treatment, more than 90% hol, Smoking, and Substance Involvement Screening Test.32
reported other nonopioid drug use in the past month in When using a nonspecific screener such as the DAST, it is
2018, and between 2011 and 2018, there was an 85% important to follow up with further questions about what
increase in methamphetamine use in this population.21 types of drugs are being used. The newer Tobacco, Alcohol,
Similarly, an evaluation of National Survey on Drug Use Prescription Medication, and Other Substance Use (TAPS)
and Health data found that among people who reported tool specifically screens for opioid use.33 The TAPS tool asks
past month use of heroin, methamphetamine use more about the frequency in the past 12 months of tobacco use,
than tripled, from 9% in 2015 to just over 30% in 2017.22 alcohol use, drug use, and nonmedical use of prescription
medications, and then cascades to further questions for
The frequency of intersections with the health care system patients who screen above certain thresholds. This screening
for persons with OUD has also been increasing over time. test has a high specificity, but low sensitivity, in detecting
From 2004 to 2015, the national rate of opioid-related hospi- OUD.33 The Rapid Opioid Dependence Screen (RODS) is an
talizations increased by 64% and opioid-related emergency alternative, eight-item screening instrument that was devel-
department visits increased by 99%.4 Despite encounters oped as a brief, targeted measure and was found to have
with the medical system, most people with OUD never high sensitivity (97%) and reasonable specificity (76%).34
receive treatment for their OUD. From 2005 to 2013, only
20% of persons affected ever received treatment for The diagnosis of OUD is made using the case definition in
OUD.23,24 As with other health care conditions, racism has the fifth edition of the Diagnostic and Statistical Manual of
resulted in disparities in access to OUD treatment, for Black Mental Disorders.35 The hallmark of OUD is continued and
and Latinx individuals in particular.25-28 Racial disparities compulsive use of opioids despite harmful consequences.
have also emerged in overdose mortality. Although the pub- OUD is diagnosed if at least 2 of 11 listed symptoms are
lic narrative has focused predominantly on the impact of experienced in the past 12 months, resulting in clinically
overdose mortality among White Americans, deaths are ris- significant impairment or distress. The severity of OUD is
ing more steeply among Black Americans; in parts of the based on the number of symptoms met, with a mild OUD
country, opioid-related overdose death rates are highest diagnosed if 2 to 3 symptoms are met, a moderate OUD if
among Black and Latinx residents.26,29–31 A study examining 4 to 5 are met, and a severe OUD if 6 to 11 are met.36 The
opioid overdose death rates across four states found a 40% 11 symptoms are related to the following: tolerance, with-
increase in the opioid overdose death rate for Black individu- drawal, using more than intended, problems controlling
als relative to White individuals.29 In Massachusetts, opioid- consumption, increased time spent involved with opioids,
related overdose death rates increased from 32.6 to 57.1 per craving, physically hazardous use, using despite health
100,000 between 2019 and 2020 for Black men and from problems caused or exacerbated, failure to meet role
57.2 to 59.8 per 100,000 among Latino men, while rates obligations, continued use despite social problems, and

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 Medication (MOUD) Psychosocial interventions

• Cornerstone of treatment, effective with or without • Less effective than medication

adjunctive psychosocial treatment
• Should be offered with medication but not required
• Methadone and buprenorphine first-line, associated
with improved remission, reduced mortality
M
Methad
done

• Extended-release naltrexone second-line, noninferior

to buprenorphine among people able to complete
opioid withdrawal and initiate medication

Recovery supports Harm reduction

• Not formal treatment, can be adjunctive, helpful • Philosophy and set of interventions that respect
support dignity and autonomy of person and aim to reduce
negative consequences of use, irrespective of whether
• Voluntary attendance associated with positive someone is able or wants to make changes to opioid
outcomes; no benefit to required participation; use
anti-MOUD stigma in some settings can be barrier
• Evidence supports range of interventions including
• Mutual help (12-step, SMART Recovery, Refuge syringe service programs, naloxone, overdose
Recovery, etc.), recovery coaching, and communi- prevention sites, and prescription heroin programs
ty-based, peer-led, recovery support centers

Figure 2. Treatments and Interventions for Opioid Use Disorder.

MOUD denotes medication treatment for OUD.

activities reduced or given up. Importantly, OUD cannot

be diagnosed if only tolerance and withdrawal are met in
someone using prescribed opioids, because physiological
Pharmacotherapy
dependence is a predictable occurrence for anyone chroni- There are three Food and Drug Administration (FDA)–ap-
cally taking opioids and is not synonymous with OUD.37 proved medications to treat OUD in the United States; the
full opioid agonist methadone, the partial opioid agonist
buprenorphine, and the opioid antagonist naltrexone
(Table 1).10 There is robust evidence that MOUD improves
mortality, treatment retention, and remission; however,
Treatment most people with OUD do not receive these treat-
OUD is a highly treatable illness with an extensive body of ments.9-12,38,42,44–48 Access gaps remain. In 2017, 56% of
evidence supporting effective interventions, particularly rural counties did not have a single buprenorphine pre-
the use of MOUD (Fig. 2).9-12 If we use an approach simi- scriber, leaving nearly one third of rural Americans living
lar to those that we use for other chronic health condi- in a county with no access to buprenorphine.49 Even spe-
tions, such as diabetes or human immunodeficiency virus cialty treatment facilities offer only limited access to these
(HIV), the goal of treatment is to diminish the symptoms treatments. In 2016, 6% of addiction treatment facilities
of active illness to prevent acute and chronic consequen- offered all three FDA-approved MOUDs.50 Access to
ces. MOUDs are first-line treatments for OUD, as insulin MOUD has been limited by restrictive federal and state
or antiretrovirals are for type 1 diabetes or HIV, respec- regulations such as the requirements for methadone to be
tively. The recent transition in the nomenclature from dispensed only out of opioid treatment programs and
“medication-assisted treatment” to terminology that rec- for a separate X-waiver from the Drug Enforcement Ad-
ognizes the importance of medication, such as MOUD, ministration to prescribe buprenorphine, which only rein-
has been an intentional shift to emphasize that medica- force the deeply entrenched stigma about the use of
tions are integral to the care of this illness. MOUD.51,52 For methadone specifically, limiting access to

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 Table 1. Pharmacotherapy for Opioid Use Disorder.*

Medication
(Mechanism of Action) Relative Efficacy Licensing Requirement Typical Dosing
Methadone (l-opioid Reduced all-cause and In the United States, dispensed Usual maintenance dose is 80 to
agonist) overdose-specific mortality10,38 only out of opioid treatment 120 mg daily; however, there is
programs significant individual variation,
and dosing should be based on
careful assessment of the
patient’s response
Reduced suicide, cancer, and In a hospital setting, methadone
drug-related, alcohol-related, and can be administered for
cardiovascular-related mortality39 maintenance or for withdrawal
management while the patient is
admitted for treatment of another
medical/surgical condition
Improved retention in addiction
treatment and reduced illicit opioid
use10
Improved social functioning,
decreased injection drug use, reduced
risk of HIV and HCV, and better
quality of life10
In pregnant people, improved
retention in OUD treatment,
increased adherence to prenatal care,
reduced illicit drug use, reduced
infection exposure (e.g., HIV, HCV, or
HBV), improved maternal nutrition,
and improved infant birth weight40
Buprenorphine Reduced all-cause and Can be prescribed for up to 30 8 to 24 mg sublingually daily;
(l-opioid partial overdose-specific mortality10,38 patients at any one time by any extended release dosing 100 to
agonist) physician, PA, NP, clinical nurse 300 mg subcutaneously monthly
specialist, certified registered
nurse anesthetist, or certified
nurse midwife who submits a
notice of intent under recent
practice guidelines
Reduced suicide, cancer, and Qualified practitioners who
drug-related, alcohol-related, and complete additional training (8 hr
cardiovascular-related mortality39 for physicians, 24 hr for PAs/
NPs) can treat up to 100 patients
in the first year and ultimately up
to 275 patients
Improved retention in addiction In a hospital setting,
treatment and reduced illicit opioid buprenorphine can be
use10 administered for maintenance or
for withdrawal management while
the patient is admitted for
treatment of another medical/
surgical condition41
Improved social functioning,
decreased injection drug use, reduced
risk of HIV and HCV, and better
quality of life10
In pregnant people, improved
retention in OUD treatment,
increased adherence to prenatal care,
reduced illicit drug use, reduced
infection exposure (e.g., HIV, HCV, or
HBV), improved maternal nutrition,
and improved infant birth weight40
At high doses (16 mg),
buprenorphine is as effective as
methadone at reducing opioid use
(continued)

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 Table 1. Pharmacotherapy for Opioid Use Disorder.* (cont.)

Medication
(Mechanism of Action) Relative Efficacy Licensing Requirement Typical Dosing
and retaining individuals in
treatment42
In pregnant people, improved
neonatal outcomes and less neonatal
opioid withdrawal syndrome
compared with methadone40
Extended-release Associated with reduced opioid use Any practitioner with prescriptive 380 mg intramuscularly monthly
naltrexone (l-opioid compared with placebo or authority can prescribe
antagonist) nonpharmacologic treatment10
Less effective at reducing recurrence
of opioid use compared with
buprenorphine43
Increased risk of overdose as patients
approach the end of the 28-d period
of the extended-release formulation10
* HBV denotes hepatitis B virus, HCV hepatitis C virus, HIV human immunodeficiency virus, NP nurse practitioner, OUD opioid use disorder, PA
physician assistant.

opioid treatment programs that require daily attendance strengths of injectable buprenorphine with placebo plus
can be an insurmountable barrier for people in rural areas, individualized addiction counseling further emphasizes the
for those lacking transportation, for people with serious limited success of counseling alone; among those randomly
medical illness, or for others for whom daily visit atten- assigned to the placebo plus counseling group, the mean
dance is challenging.53 abstinence rate was 5%.63

Clinical trials and observational studies have demonstrated In choosing among the three types of MOUDs, buprenor-
superior outcomes of treatment involving MOUD compared phine, when dosed adequately, appears to be as effective
with medically supervised withdrawal (“detoxification”) or as methadone.42 Oral naltrexone is generally ineffective
psychosocial-only treatments.38,42,44–48 A small randomized as a result of poor treatment adherence; however, studies
controlled trial of buprenorphine maintenance treatment of long-acting formulations of naltrexone have shown
compared with medically supervised withdrawal plus a year extended-release naltrexone to have better outcomes
of intensive counseling found that in the control arm, no compared with no medication.64 There are no head-to-
one was retained in treatment and 20% had died by the head trials comparing methadone with extended-release
end of the 1-year study period.54 In contrast, among those naltrexone. In a multisite randomized controlled trial of
randomly assigned to buprenorphine maintenance, 75% individuals voluntarily seeking medically supervised with-
were retained in treatment, 75% were abstinent by toxicol- drawal management, extended-release naltrexone was com-
ogy, and no one died.54 Consistent with these findings, pared with buprenorphine and was found to be less effective
studies of short-term medically supervised withdrawal not in the main intention-to-treat analysis.43 However, a per pro-
followed by maintenance treatment with MOUD have tocol analysis of only those participants who successfully
shown high opioid use recurrence rates and low retention started the medication showed extended-release naltrexone
in treatment.55-60 A study of individuals with OUD access- to be noninferior.43 A subsequent cost-effectiveness analysis
ing medically supervised withdrawal programs found that demonstrated buprenorphine to be preferable to extended-
the adjusted odds of successfully completing treatment release naltrexone as first-line therapy.65
declined with each successive attempt.61 Longer-term with-
drawal strategies have also shown inferior outcomes com- One outcome that is worth highlighting is the impact
pared with maintenance with MOUD. A study comparing of MOUD on mortality. Observational studies, meta-
a 180-day psychosocially enriched methadone taper with analyses, and at least one small randomized controlled trial
methadone maintenance found a significantly longer have demonstrated a substantial reduction in both over-
treatment retention and lower heroin use rates in the dose and all-cause mortality among individuals treated
maintenance group compared with the taper group.62 with methadone or buprenorphine.10 In contrast, there
A randomized controlled trial comparing two different may be a trend toward increased mortality in some studies

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of naltrexone, which could be attributable to poor adher- from medication management with supportive counseling
ence but may also indicate the possibility of opioid toxicity provided by the prescriber to adjunctive counseling, recov-
even in the context of a therapeutic naltrexone dose.47,66 ery coaching, or mental health services; however, MOUD
should never be withheld because of a lack of access to or
Despite the evidence supporting MOUD, high utilization interest in adjunctive psychosocial services.10
of medically supervised withdrawal management and out-
patient counseling alone continues. Stigma against MOUD Although psychosocial treatments alone are associated
and lack of access to MOUD likely both contribute to this with worse outcomes than MOUD, understanding the
pattern of care; however, some patients also prefer non- range of approaches is important for patients who decline
medication treatment.67,68 In addition, regional access to MOUD even after careful education. Community Rein-
different types of MOUD, insurance barriers, and racial forcement Approach and Family Training (CRAFT) and
disparities in access to treatment may limit availability. contingency management are two interventions that may
Racial disparities in MOUD treatment are particularly improve treatment retention among patients not treated
notable, with decreased buprenorphine treatment of with MOUD.79,80
Black individuals with OUD compared with White
individuals.69-71

Mutual Help and Peer

Psychosocial Treatment Recovery Support
Mutual help groups, such as Narcotics Anonymous or
Well-designed randomized controlled trials examining the
SMART Recovery (Self-Management and Recovery Train-
benefit of psychosocial treatments added to methadone or
ing), are free, community-based recovery supports. Volun-
buprenorphine have found that patients randomly as-
tary mutual help attendance may offer additional,
signed to opioid agonist therapy without additional psy-
nontreatment support for patients treated with MOUD
chosocial treatment have similar opioid use outcomes.72 A
who find peer support helpful. In a 42-month follow-up
randomized controlled trial of buprenorphine treatment
assessment of individuals treated with buprenorphine, the
for prescription OUD evaluated medical management
strongest predictor of opioid abstinence was still being
alone or combined with individual counseling and found
treated with buprenorphine; however, mutual help meet-
no difference in the primary outcome of opioid abstinence
between the groups.56 A primary care–based study found ing attendance was also associated with a greater likeli-
no difference between medical management with bupre- hood of opioid abstinence.81 A mixed-methods analysis of
norphine alone compared with the addition of cognitive individuals treated with buprenorphine found that volun-
behavioral therapy.73 A randomized controlled trial of tary mutual help attendance was associated with a higher
adjunctive cognitive behavioral therapy, contingency man- rate of treatment retention and abstinence; however,
agement, both, or medical management alone with bupre- being required to attend meetings did not lead to better
norphine found no differences in opioid use outcomes.74 It outcomes, and participants identified stigma against
is possible that medical management as offered in clinical MOUD within peer support groups as a barrier.82 Recovery
trial settings is more comprehensive than that which hap- coaching is another form of peer support delivered by
pens in real-world settings; however, interim medication non–clinical care team members who are themselves in
treatment studies that look at the impact of medication recovery. An observational study of people with OUD initi-
alone without any provider support have also shown posi- ating buprenorphine found that current engagement with
tive outcomes.75-77 One subgroup who may benefit from a recovery coach was associated with an increased odds of
personalized and flexible psychosocial interventions is indi- treatment retention and opioid ab-stinence.83
viduals who continue to use opioids despite treatment with
opioid agonist therapy. A study in this population found a
greater improvement in opioid and cocaine abstinence
among the group who received a flexible toolkit of psycho- Harm Reduction
logical change methods in addition to methadone.78 On the Harm reduction, a patient-centered approach that focuses
basis of these findings, patients treated with MOUD should on minimizing the negative consequences of drug use,
be offered individualized psychosocial support ranging supporting the dignity and autonomy of people who use

NEJM EVIDENCE 7
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drugs, and promoting health, has a range of important 4. Weiss AJ, Elixhauser A, Barrett ML, Steiner CA, Bailey MK, O’Mal-

applications for OUD treatment. Effective harm reduction ley L. Opioid-related inpatient stays and emergency department
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5. Wurcel AG, Anderson JE, Chui KK, et al. Increasing infectious
practices; prescription heroin treatment decreases illicit
endocarditis admissions among young people who inject drugs.
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ment retention; overdose prevention sites engage margin-
6. Zibbell JE, Iqbal K, Patel RC, et al.; Centers for Disease Control
alized patients, promote safer use, increase primary care
and Prevention (CDC). Increases in hepatitis C virus infection
access, and reduce overdose mortality; naloxone distribu- related to injection drug use among persons aged 30 years - Ken-
tion programs reduce mortality; and low-threshold MOUD tucky, Tennessee, Virginia, and West Virginia, 2006-2012. MMWR
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reached by traditional addiction treatment.84-88 7. Peters PJ, Pontones P, Hoover KW, et al.; Indiana HIV Outbreak
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morphone in Indiana, 2014-2015. N Engl J Med 2016;375:229-239.

8. See I, Gokhale RH, Geller A, et al. National public health burden esti-
Conclusions mates of endocarditis and skin and soft-tissue infections related to
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and managed in health care settings. MOUD is the corner- 9. Bart G. Maintenance medication for opiate addiction: the founda-
stone of treatment; however, broader access and targeted tion of recovery. J Addict Dis 2012;31:207-225.
interventions to eliminate racial disparities are needed. 10. National Academies of Sciences, Engineering, and Medicine. Medi-
Harm reduction interventions are complementary and cations for opioid use disorder save lives. Washington, DC:
necessary services to engage marginalized individuals National Academies Press, 2019. DOI: 10.17226/25310.
with OUD and reduce the risk of negative consequences 11. Biancarelli DL, Biello KB, Childs E, et al. Strategies used by people
at the individual and community levels. who inject drugs to avoid stigma in healthcare settings. Drug Alco-
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Disclosures 12. Crotty K, Freedman KI, Kampman KM. Executive Summary of the
Focused Update of the ASAM National Practice Guideline for the
Disclosure forms provided by the author are available with the full text of
Treatment of Opioid Use Disorder. J Addict Med 2020;14:99-112.
this article at [Link].
13. Ciccarone D. The triple wave epidemic: Supply and demand drivers
Author Affiliations of the US opioid overdose crisis. Int J Drug Policy 2019;71:183-188.
1
Division of General Internal Medicine, Department of Medicine, Massa-
14. Schieber LZ, Guy GP Jr, Seth P, et al. Trends and patterns of geo-
chusetts General Hospital, Boston
2 graphic variation in opioid prescribing practices by state, United
Department of Medicine, Harvard Medical School, Boston
3
States, 2006-2017. JAMA Netw Open 2019;2:e190665.
Department of Quality, Patient Experience, and Equity, Mass General
Brigham, Boston 15. Cicero TJ, Ellis MS, Harney J. Shifting patterns of prescription opi-
oid and heroin abuse in the United States. N Engl J Med 2015;373:
1789-1790.
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