Clinical Review & Education

JAMA Psychiatry | Review

Prevention and Treatment of Opioid Misuse and Addiction

A Review
Nora D. Volkow, MD; Emily B. Jones, PhD; Emily B. Einstein, PhD; Eric M. Wargo, PhD

Supplemental content
IMPORTANCE More than 42 000 Americans died of opioid overdoses in 2016, and the
fatalities continue to increase. This review analyzes the factors that triggered the opioid crisis
and its further evolution, along with the interventions to manage and prevent opioid use
disorder (OUD), which are fundamental for curtailing the opioid crisis.

OBSERVATIONS Opioid drugs are among the most powerful analgesics but also among the
most addictive. The current opioid crisis, initially triggered by overprescription of opioid
analgesics, which facilitated their diversion and misuse, has now expanded to heroin and illicit
synthetic opioids (fentanyl and its analogues), the potency of which further increases their
addictiveness and lethality. Although there are effective medications to treat OUD
(methadone hydrochloride, buprenorphine, and naltrexone hydrochloride), these
medications are underused, and the risk of relapse is still high. Strategies to expand
medication use and treatment retention include greater involvement of health care
professionals (including psychiatrists) and approaches to address comorbidities. In particular,
the high prevalence of depression and suicidality among patients with OUD, if untreated,
contributes to relapse and increases the risk of overdose fatalities. Prevention interventions
include screening and early detection of psychiatric disorders, which increase the risk of
substance use disorders, including OUD.

CONCLUSIONS AND RELEVANCE Although overprescription of opioid medications triggered

the opioid crisis, improving opioid prescription practices for pain management, although
important for addressing the opioid crisis, is no longer sufficient. In parallel, strategies to
expand access to medication for OUD and improve treatment retention, including a more
active involvement of psychiatrists who are optimally trained to address psychiatric
comorbidities, are fundamental to preventing fatalities and achieving recovery. Research into
new treatments for OUD, models of care for OUD management that include health care, and Author Affiliations: National
interventions to prevent OUD may further help resolve the opioid crisis and prevent it from Institute on Drug Abuse, Rockville,
Maryland.
happening again.
Corresponding Author: Nora D.
Volkow, MD, National Institute on
JAMA Psychiatry. 2019;76(2):208-216. doi:10.1001/jamapsychiatry.2018.3126 Drug Abuse, 6001 Executive Blvd,
Published online December 5, 2018. Room 5274, Rockville, MD 20852
([email protected]).

M
ore than 2 million Americans have an opioid use disor-
der (OUD), and in 2016, more than 42 000 Americans Opioid Pharmacology
died of opioid overdoses.1,2 Although in the first years
of the opioid crisis, most overdose-associated deaths were caused Opioid drugs—prescription analgesics and illicit drugs—exert their
by misuse of prescription analgesics, heroin and synthetic opioids pharmacologic effects by engaging the endogenous opioid sys-
(fentanyl and its analogues) currently account for most of the fa- tem, where they act as agonists at the μ-opioid receptor (MOR).
talities, a scenario that reflects the changing nature of the opioid cri- The agonist action at the MOR is responsible for the rewarding
sis (Figure 1). We reviewed the pharmacology of opioids because it effects of opioids and analgesia. In the brain, these receptors are
is relevant to their rewarding and analgesic effects that lead to their highly concentrated in regions that are part of the pain and
misuse, the epidemiology of the crisis and its transformations in the reward networks. They are also located in regions that regulate
past 2 decades, and the interventions to treat and prevent OUD that emotions, which is why long-term opioid exposure is frequently
must be implemented to overcome the current crisis and prevent it associated with depression and anxiety.4 In addition, MORs are
from happening again. located in brainstem regions that regulate breathing; there,

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 Prevention and Treatment of Opioid Misuse and Addiction Review Clinical Review & Education

agonists inhibit neuronal firing, which results in respiratory

depression, which is the main cause of death from opioid Opioid Addiction
overdoses.5 The various types of opioid analgesics (morphine,
hydrocodone, and oxycodone hydrochloride), illicit opioids Addiction is distinct from physical dependence and occurs in a smaller
(heroin and fentanyl and its analogues), and medications to treat subset of opioid users, developing much more gradually. The changes
OUD (methadone hydrochloride, buprenorphine, and naltrexone are longer lasting and often require long-term treatment to achieve
hydrochloride) or to reverse overdose (naloxone hydrochloride) recovery. Until recently, it was mistakenly believed that pain pro-
differ in terms of their affinities to MOR, their functional effects at tected against addiction to opioid medications. A study8 assessing
the MOR (agonists, partial agonists, or antagonists), and their Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
selectivity for MOR compared with that for κ- or Δ-opioid recep- (DSM-5) criteria for OUD in a cohort of patients receiving opioids for
tors (eTable in the Supplement). chronic pain found that 28.1% had mild OUD, 9.7% had moderate
OUD, and 3.5% had severe OUD. Multiple factors have been asso-
ciated with vulnerability to opioid addiction (term used here to
refer to moderate or severe OUD), including genetics, age at initia-
Physical Dependence on Opioids
tion, adverse social environments, and psychiatric comorbidities (eg,
Physical dependence on opioids is distinct from addiction, and al- anxiety, depression).
though they reflect different neuroadaptation processes, they are Addiction to opioids (or other drugs) involves molecular pro-
frequently confused because the term dependence is frequently cesses associated with learning, which help consolidate automatic
used to connote addiction. This confusion leads to misunderstand- behaviors in response to the drug and the stimuli associated with
ing by patients and physicians on the appropriate use of these medi- the drug; this is referred to as conditioning. People can become con-
cations. It has also led to misestimation of the risk of addiction when ditioned to opioids because of their rewarding effects or because
opioids are used for the treatment of pain. of their relief of pain, withdrawal symptoms, or dysphoria. With re-
Physical dependence manifests with the emergence of with- peated exposures, conditioning is strengthened, energizing the de-
drawal symptoms when use of opioids is abruptly discontinued (or sire and motivation to consume the drug.
even sometimes when tapered) after long-term administration. Repeated drug exposures also disrupt striatocortical circuits that
Symptoms include insomnia, cramps, diarrhea, nausea, vomiting, and are necessary for the proper functioning of the prefrontal cortex,
body aches, as well as dysphoria, anxiety, and irritability. The sever- which is needed for self-regulation. Disruption of these circuits un-
ity of these symptoms varies, depending on chronicity, the opioid derlies the impulsiveness and compulsivity characteristic of addic-
drug in question (symptoms are stronger for more potent and tion. In addition, disruption of circuits in the extended amygdala that
shorter-acting drugs), and individual variability. regulate emotions and stress renders the person with addiction vul-
All patients treated with opioids or misusing them will develop nerable to dysphoria or depression, anxiety, and irritability.9 These
physical dependence, and withdrawal symptoms usually resolve neurocircuitry changes are mutually reinforcing (Figure 2), contrib-
promptly within a few days but can sometimes last weeks after use uting to addiction’s relapsing nature. Changes to the dopaminergic
is discontinued. Dependence can lead to opioid seeking as individu- circuits of the basal ganglia, the extended amygdala, and the pre-
als attempt to avoid withdrawal symptoms, contributing to addic- frontal cortex correspond to the sequential stages of binge or in-
tion by perpetuating repeated exposures. toxication, withdrawal, and craving that are characteristic of all sub-
stance use disorders. In people addicted to opioids, these changes
also persist long after drug use discontinuation, which is why the

Opioid Misuse
Figure 1. Three Waves of the Increase in Deaths Due to Opioid Overdose
Opioids are misused for their analgesic effects and rewarding prop-
erties; people with physical dependence or addiction to opioids 7.0
may also misuse opioids to avoid withdrawal symptoms. The use of
6.0
opioids for their rewarding effects reflects their ability to increase
Deaths per 100 000 Population

the activity of dopamine neurons in the ventral tegmental area and 5.0
to increase dopamine release in the nucleus accumbens.6 In the
context of prescription opioids, misuse refers to use other than as 4.0
Natural and semisynthetic opioids
prescribed. When misused for their rewarding effects, prescription 3.0
opioids are frequently snorted or injected, which leads to faster Heroin
uptake in the brain, enhancing their rewarding effects; when mis- 2.0

used via oral administration, opioids tend to be taken at higher 1.0

doses and/or in combination with other drugs (eg, alcohol). Synthetic opioids
Although opioid misuse does not necessarily result in addiction, 0
1999 2001 2003 2005 2007 2009 2011 2013 2015
opioids are highly addictive, and the risks increase with repeated Year
use, higher doses, and when injected. According to the National
Comorbidity Survey, the proportion of users becoming addicted to Wave 1 was from 1990 to 2004, wave 2 from 2005 to 2010, and wave 3 from
heroin after using opioids (23%) was higher than for alcohol (15%) 2011 to 2016. Data are from the National Vital Statistics System Mortality File.
Adapted from the Centers for Disease Control and Prevention.3
and cocaine (17%).7

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 Clinical Review & Education Review Prevention and Treatment of Opioid Misuse and Addiction

Figure 2. Three Stages of the Addiction Cycle and Associated Neural Circuits

Incentive salience

Binge or
intoxication

Basal
ganglia

DS People with substance use disorders

Prefrontal cycle through 3 stages in rates that
cortex vary with the drug and the severity of
NAc
their disorder: binge or intoxication,
VTA negative affect or withdrawal, and
BNST
PFC preoccupation or anticipation
CeA (craving); these stages are associated
Extended with activity in the basal ganglia
amygdala (nucleus accumbens [NAc] and dorsal
striatum [DS]), extended amygdala,
Preo ticipa

e a l or
Dopamine and prefrontal cortex (PFC),

t
an

ffec
ccu tio

a
ga aw
Opioid peptides respectively. BNST indicates bed
pat n

ne ithdr
Corticotropin-releasing nucleus of the stria terminalis;

tiv
ion

factor

W
CeA, central nucleus of the amygdala;
or

Dynorphin
Executive function Glutamate Reward deficit and and VTA, ventral tegmental area.
deficits stress surfeit Adapted from Koob GF and Volkow
ND. Neurobiology of addiction: a
neurocircuitry analysis. Lancet
Psychiatry. 2016;38:760-773.10

treatment of opioid addiction requires continuous care to achieve ability of inexpensive, high-purity heroin has made it easier for new
recovery. opioid users to initiate drug use with heroin, possibly in part be-
cause high-quality heroin can be administered through other routes
than injection. Between 2005 and 2015, the percentage of new opi-
oid users initiating drug use with heroin increased from 8.7% to
Opioid Analgesia
33.3%.15
Opioids are effective for treating severe acute pain, but their effec- The shift toward heroin use contributed to the escalation of
tiveness in treating chronic pain is less clear.11 Tolerance rapidly de- opioid-associated fatalities, now further exacerbated by adultera-
velops to their analgesic effects; thus, patients require increasingly tion of heroin with fentanyl or fentanyl analogues. As of 2016, fen-
higher doses, thereby increasing the risk of addiction, respiratory de- tanyl and other synthetic opioids accounted for more overdose
pression, and fatal overdose. Furthermore, opioids can result in hy- deaths than prescription opioids or heroin (Figure 1). The high po-
peralgesia, exacerbating instead of alleviating pain.12 The opioid cri- tency of fentanyl (50 times more potent than heroin) increases the
sishasledtovariousmeasuresthatencouragegreatercautioninopioid risk of overdosing; this risk is further exacerbated by its combina-
prescribing, including new Centers for Disease Control and Pre- tion with other drugs and the impossibility of controlling the dose
vention guidelines for management of chronic pain.13 Prescription administered.
drug monitoring programs are intended to reduce “doctor shop-
ping” (receiving prescriptions for controlled substances from several
physicians) by patients and harmful prescribing by physicians.
Epidemiology of Opioid Misuse and OUD
In 2016, almost 11 million American adults (age ⱖ18 years) misused
opioids in the past year, with males (6.4 million [4.9%]) misusing opi-
Shifting Patterns of Opioid Misuse
oids more frequently than females (5.4 million [3.9%]).1 Misuse of
The opioid crisis was sparked initially by the overreliance on opi- opioids by adolescents remains low, whereas the highest rates of mis-
oids to treat pain. The overprescription of opioid analgesics facili- use are among young adults aged 18 to 25 years. In 2016, a total of
tated their diversion and misuse, while also exposing patients with 392 000 individuals aged 18 to 25 years (1.1%) had OUD compared
chronic pain to the risk of addiction and overdose without neces- with 153 00 (0.6%) of adolescents and 1 599 000 (0.8%) of adults
sarily improving their pain conditions. 26 years and older.1
Beginning in the early 2000s, some of those addicted to pre- The rates of fatalities due to OUD and overdose and the types
scription opioids (particularly young adults) began transitioning to of opioids triggering overdoses vary markedly by state. In 2016, there
heroin because the latter was cheaper and easier to obtain. Three were 43.4 opioid overdose fatalities per 100 000 persons in West
quarters of treatment-seeking heroin users who had begun their drug Virginia compared with 29.7 in Massachusetts and 5.9 in Arkansas.16
use in the 2000s began with prescription opioids.14 Increased avail- The geographic diversity correlates to a certain extent with socio-

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 Prevention and Treatment of Opioid Misuse and Addiction Review Clinical Review & Education

economic factors, such as poverty. Among those under the pov- Frequently, OUDs are comorbid with infectious diseases be-
erty level, 5.9% were reported to have OUD compared with 4.8% cause injecting drugs increases the risk of blood-transmitted infec-
of those between 100% and 199% of the poverty level and 3.9% of tions, including HIV infection, hepatitis C virus infection, and endo-
those at twice or more than the poverty level.1 There is also variabil- carditis. In 2015, injection drug use accounted for 9.1% of the 39 513
ity among races/ethnicities, with opioid misuse being most preva- new diagnoses of HIV infection in the United States,29 and the
lent among non-Hispanic white individuals (4.6% vs 4.0% among incidence of hepatitis C virus infection increased 2.9-fold from 2010
African American individuals and 1.8% among Asian individuals).1 to 2015.30
These prevalence rates are changing, however, as prescription
opioids are being replaced by heroin and synthetic opioids.
The increase in the exposure to opioids among females has trans-
Prevention
lated into a 4-fold increase in the number of neonates born with neo-
natal abstinence syndrome between 1999 and 2013 (from 1.5 to 6.0 The misuse of and addiction to prescription analgesics, heroin, and
per 1000 hospital births).17 As in other populations, opioid expo- synthetics (fentanyl and analogues) require universal and targeted
sure in pregnant women reflects prescription of opioids for pain man- prevention strategies. An important intervention to decrease pre-
agement, medication-assisted treatment for OUD, and opioid mis- scription opioid misuse is reducing inappropriate prescribing. New
use. On the basis of data through 2007, a total of 23% of pregnant federal guidelines and improved physician education in opioid pre-
women enrolled in Medicaid filled an opioid prescription during scribing and pain management are already having an influence on
pregnancy.18 Although severity of neonatal abstinence syndrome has reducing overprescribing, although prescription rates in the United
been shown to be substantially milder when women are treated with States are still high, with prescriptions of 178 billion morphine mil-
methadone or buprenorphine, their newborns still require care for ligram equivalents in 2017.31 Prescription drug monitoring pro-
neonatal abstinence syndrome.19 grams have been implemented in all states, although their effec-
tiveness has been mixed depending on their ease of operability and
how they are regulated.
Other strategies include developing new, safer pain medica-
Comorbidity of OUD
tions and abuse-deterrent formulations (ADFs) of existing opioid
Pain is frequently comorbid with OUD, reflecting that opioid expo- medications. The ADFs contain properties intended to make inten-
sure was initially intended to alleviate pain and that hyperalgesia is as- tional misuse more difficult or less rewarding, and evidence sug-
sociated with repeated exposure to prescription and illicit opioids.20 gests that they can decrease misuse of that specific formulation.
Chronic pain might increase the risk of an OUD in part by dysregulat- However, even though ADFs have been clinically available for
ing the brain’s stress circuitry and by increasing risk of tolerance to the several years, they represent a small percentage of the total opioid
analgesic effects of opioids. Increased conditioning to high doses of prescriptions. The restricted penetration of ADF opioids is likely to
morphine was reported in an animal model of chronic pain.21 reflect their higher costs, which limit their reimbursement.32 In some
In addition, OUD is highly comorbid with other mental ill- instances, as was the case for the original oxycodone hydrochlo-
nesses, especially mood disorders, likely because individuals with ride formulation, ADFs may encourage a shift to misuse of other opi-
mental illness, particularly a mood disorder, are more apt to be pre- oids or to unexpected routes of administration.33,34 A Risk Evalua-
scribed an opioid analgesic. A recent article22 reported that approxi- tion and Mitigation Strategy can be required by the US Food and Drug
mately 50% of opioid prescriptions are written for individuals with Administration for medications with serious safety concerns. The Risk
a mental illness, even though they represent only 16% of the popu- Evaluation and Mitigation Strategy for opioid medications includes
lation. This finding reflected the higher prevalence of chronic pain training in acute and chronic pain management, including pharma-
among those with a mood disorder. Even after controlling for se- cologic and nonpharmacologic treatments.35
verity and type of pain condition, those with a mood disorder were Strategies that would have an influence on all forms of opioid
more likely to receive a prescription and to receive a higher opioid misuse involve implementing evidence-based prevention interven-
dose than those without a mood disorder. Patients with mood dis- tions for substance use disorders in family, school, and/or commu-
orders might also be at greater risk of misusing opioids because of nity settings. Universal prevention interventions initiated in child-
their antidepressant properties.23,24 hood and adolescence decrease later drug use, including prescription
Some of the opioid overdose fatalities could also reflect inten- opioid misuse.36-38 These interventions share common elements in-
tional suicide because suicide risk is higher in patients with OUD, tended to strengthen protective factors in individuals and their fami-
chronic pain, or a mood disorder.25 Moreover, among patients with lies, schools, and communities while decreasing factors associated
chronic pain and suicidal ideation, 75% reported that they planned with risk (Box 1). For children or adolescents who are at high risk
to do so through overdose, and risk of successful suicide was doubled because of adverse social environments or psychiatric disorders, tai-
in patients with chronic pain compared with control individuals with- lored interventions can prevent future drug misuse.40
out pain.26 A previous report27 tried to estimate the risk of suicide Socioeconomic factors continue to influence the opioid crisis. Re-
among veterans with OUD. In female veterans with OUD, suicide risk stricted job opportunities, erosion of communities, and loss of pur-
was more than 8 times greater than for those without OUD; in male pose have been linked to the psychological pain and stress fueling the
veterans, the risk was more than twice that for those without OUD. demand for opioids.41 Initially, opioid misuse was mostly concen-
Estimating the exact proportion of suicides among fatalities classi- trated in rural areas and among poor white Americans, but as misuse
fied as being due to overdose is difficult, but this incidence might of heroin and synthetics has expanded, it is now affecting urban areas
be between 20% and 30%.28 and minority groups. Thus, strategies that provide access to educa-

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 Clinical Review & Education Review Prevention and Treatment of Opioid Misuse and Addiction

OUD. Currently, 3 medications are approved by the US Food and Drug

Box 1. Risk and Protective Factors for Adolescent and Young Administration to treat OUD: methadone (a full agonist at the MOR),
Adult Substance Use buprenorphine (a partial agonist at the MOR), and extended-release
naltrexone (an antagonist at the MOR). Details on doses, dispensing,
Risk Factors and clinical effects for medications for OUD are provided in Box 2.
Individual
Medications for OUD are ordinarily given in conjunction with
Genetic factors
behavioral treatment, and studies 49,50 have generally shown
Starting substance use early
strong benefits of medications for OUD compared with behavioral
Perceiving little risk in substance use treatments alone. Medications for OUD increase social functioning
Peers who use substances while reducing illicit opioid use, risk of overdose, transmission of
Emotional distress or aggressiveness that starts early and is per- infectious disease, criminality, and treatment retention. Unfortu-
sistent nately, stigma toward methadone and buprenorphine because of
Psychiatric disorder their agonist actions at the MOR has limited their use because of
Family the belief by many that their use substitutes one addictive drug for
Substance misuse in the family another.
Family conflict, abuse, or neglect Treatment with agonists and partial agonists is pharmacody-
Parents who favorably view or approve of substance use namically distinct from sustaining an addiction to a prescription or
illicit opioid.51 The slow rate of entry of methadone and buprenor-
School
Poor academic performance phine into the brain (Box 2) limits their rewarding effects. This
Student does not view school as rewarding or meaningful and
limitation is because drug reward is accentuated when drugs
lacks commitment to school enter the brain rapidly and have fast-binding properties, which
Perception that use of drugs among classmates is high
explains why methadone and buprenorphine, although providing
relief from craving and withdrawal, do not produce the intense
Poor control over school drug consumption
euphoria achieved with heroin or other opioids when they are
Community
injected or taken at high doses. In addition, their slow dissociation
Lower socioeconomic status
and clearance from MOR prevent emergence of craving and with-
Availability and cost of drugs and alcohol
drawal symptoms during treatment. The physiologic stability pro-
Community norms favorable toward alcohol and drugs vided by medications for OUD facilitates the reentry and integra-
Protective Factors tion of patients to their communities.
Individual Because of their agonist properties, methadone and
Resiliency buprenorphine are only available from opioid treatment pro-
Self-efficacy grams (methadone) or from prescribers with a special Drug Abuse
Spirituality Treatment Act 2000 waiver (buprenorphine). Extended-release
Interpersonal skills, including social, emotional, and cognitive naltrexone, because it is an antagonist, can be prescribed by any
skills physician and presents no abuse liability; because the use of
Treatment of psychiatric disorder extended-release naltrexone for OUD is relatively new and adher-
ence to the immediate-release naltrexone has historically been a
Family, school, and community
Attachment to family, school, and community problem, fewer studies47,48 have reported naltrexone’s effective-
ness, but evidence is mounting that it may be as effective as
Meaningful involvement with family, school, or community
buprenorphine for some patients.
Positive behavior is recognized
Despite their efficacy, medications for OUD are underused. In
Norms in the family, school, and community that drug misuse is
2015, between 31% and 37% of patients with OUD in specialty
not acceptable
facilities received medications for OUD.52 A recent study53 in
Being in a committed relationship or marriage with a partner
Massachusetts reported that only 30% of those who survived an
who does not misuse drugs
opioid overdose received medications for OUD in the year after
Opportunity for fulfilling extracurricular activities
their overdose. In addition, when they are prescribed, buprenor-
Adapted and modified from US Department of Health.39 phine and methadone are frequently given at too low a dose
and/or for too short a duration. For example, one study 54
reported that nearly half of patients treated with buprenorphine
tion to all citizens and sustainable work opportunities are long-term in opioid treatment facilities receive 90 or fewer days or continu-
interventions for preventing OUD and associated problems. ous treatment.
Expanding access to medications for OUD in primary care and
specialty settings (psychiatrists, pain clinics, emergency depart-
ments, and infectious diseases clinics) will require educating prac-
Treatment
titioners throughout health care to screen and treat OUD, clearing
The strong evidence for the effectiveness of medications for OUD misconceptions about medications for OUD and how to use them,
(frequently also referred to as medication-assisted treatment) has and removing infrastructural barriers to their use, including loosen-
made medications for OUD the criterion standard of treatment for ing restrictions on who can prescribe them.55-57

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 Prevention and Treatment of Opioid Misuse and Addiction Review Clinical Review & Education

Box 2. Medications for Opioid Use Disorder

Methadone Naltrexone
Full MOR agonist, typically daily oral doses of 80-160 mg methadone Antagonist at MOR
hydrochloride, used for more than 4 decades Antagonist at κ-opioid receptor
Dispensing mostly limited to licensed opioid treatment programs or IR formulation: 50 mg once daily
methadone clinics
ER formulation: 380 mg delivered intramuscularly every 4 wk
Reduces cravings and withdrawal symptoms
IR formulation approved for OUD in 1984 but had poor adherence
Does not produce euphoria in opioid-dependent individuals because
ER formulation approved for OUD in 2010, which has facilitated ad-
MOR binding is slower and longer lasting than that of heroin or fen-
herence
tanyl and oral delivery slows its entry into the brain
Does not require a license or waiver to prescribe
Normalizes the physiology of the stress-responsive hypothalamic-
pituitary-adrenal axis42 Interferes with the binding of opioid drugs, thus inhibiting their ef-
fects, including reward and analgesia
Produces physical dependence and, if use is abruptly discontinued,
results in acute withdrawal; thus, discontinuation of the drug re- Patients need to undergo detoxification before initiating naltrexone
quires slow tapering to avoid withdrawal treatment to avert withdrawal, which can be challenging, and not all
patients succeed
Strong evidence that it reduces illicit opioid use and risk of overdose
and improves other outcomes (a Cochrane review43 in 2009 found The evidence is still limited, but studies thus far suggest that the ER
33% fewer opioid-positive drug test results for patients taking formulation reduces opioid use, and preliminary data suggest it
methadone, who were also 4.4 times more likely to stay in treatment might prevent overdoses (2 comparative-effectiveness studies47,48
than those not taking medication) in 2017 found that, after patients were inducted on treatment with
ER naltrexone, it was equally effective as buprenorphine at promot-
Buprenorphine ing abstinence and retaining patients in treatment)
Partial MOR agonist
Lofexidine
κ-Opioid receptor antagonist
α-Adrenergic receptor agonist, three 0.18-mg tablets taken orally, 4
44
Nociceptin receptor agonist times daily at 5- to 6-h intervals
IR formulation Approved in 2018 as the first FDA medication to treat opioid with-
Generally taken 3-4 times/wk at daily doses typically between 16 drawal, although it has been used to treat opioid withdrawal in the
and 24 mg45 United Kingdom since the 1990s
Most frequently prescribed as a sublingual film that contains nal- Dispensing is by physicians
oxone, which induces withdrawal when drug is injected
Research is needed to determine whether it might be helpful in fa-
ER formulations cilitating induction into naltrexone or buprenorphine for patients
A subdermal implant that delivers the equivalent of 8 mg of bu- with high levels of tolerance and whether it can improve adherence
prenorphine was approved in 2016, but use was limited by the in patients treated with medications for OUD
restricted doses it delivers
Naloxone
A once-monthly depot injection was approved in 2017, and addi-
Antagonist at MOR
tional once-monthly and once-weekly formulations are currently
being reviewed for FDA approval Autoinjection: 2 mg of 0.4 mL of naloxone hydrochloride solution in
a prefilled autoinjector for intramuscular or subcutaneous injection
Approved to treat OUD in 2002
Nasal spray: 4 mg of naloxone hydrochloride in 0.1 mL for intranasal
Dispensing by physicians or nurses who have a Drug Abuse Treat-
administration
ment Act 2000 waiver
Injection: 0.4 mg/mL, available in 2 pack sizes, containing 0.8 mg of
Reduces cravings and withdrawal symptoms
naloxone in 2 mL or 2.0 mg of naloxone hydrochloride in 5 mL
Does not produce euphoria in opioid-dependent patients because
FDA first approved naloxone for overdoses in 1971
its binding to MOR is slow (slower than for methadone) and (as a
partial agonist) it has less efficacy to stimulate reward The autoinjector was approved in 2014
Because buprenorphine is a partial agonist, its use in patients with The intranasal spray was approved in 2015
OUD with high levels of tolerance might result in acute withdrawal, Increasing access to naloxone is a major component to reverse the
in which case treatment with methadone, with its full agonist ef- overdose epidemic (in Massachusetts communities where overdose
fects, might be more beneficial education and naloxone distribution were implemented, death due
ER formulations of buprenorphine will facilitate adherence and OUD to overdose was reduced 27%-46%)
management, including for patients living in rural areas With the increase in overdoses from fentanyl and other synthetic opi-
Strong evidence that it reduces illicit opioid use and overdoses and oids, multiple naloxone doses are necessary for reversal (reversals
improves other outcomes (a Swedish study found a 100% failure might fail when opioids are combined with other respiratory-depress-
rate within 3 mo when treatment with buprenorphine was tapered ing drugs, eg, alcohol, benzodiazepines; thus, there is a need for lon-
after 6 d vs 25% when buprenorphine treatment was maintained ger-lasting naloxone formulations or other overdose-reversal tools)
and a 20% mortality rate among those who left treatment)46
Abbreviations: ER, extended release; FDA, US Food and Drug Administration;
IR, immediate release; MOR, μ-opioid receptor; OUD, opioid use disorder.

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 Clinical Review & Education Review Prevention and Treatment of Opioid Misuse and Addiction

Box 3. Research Gaps

Pain Neurobiology OUD Treatment

Factors underlying the transition from acute to chronic pain New treatment options
Risk factors for chronic pain (including sex) Comparative effectiveness of existing treatments
Risk factors for addiction when patients with pain are prescribed an Implementation research to increase medication of OUD use
opioid medication Effectiveness of medications for OUD with specific populations
Comorbidity of pain syndromes, mood disorders, and addiction Appropriate duration of use of medication for OUD
Pain Treatment How to better personalize behavioral treatments to the individual
New compounds that target non–opioid pain-modulating systems in How to determine when a patient is ready to be tapered off medica-
the body, such as the endocannabinoid system tion for OUD
New compounds that target the MOR but in a manner that produces Improved assessment of when inpatient treatment is indicated
fewer adverse effects and less misuse liability (eg, biased agonists,
Biomarkers or other indicators to determine which medication for
bivalent molecules that concomitantly target μ and galanin or noci-
OUD is optimal for a given patient
ceptin receptors)
Treatment strategy for individuals who may be misusing opioids but
Strategies to interfere with signaling of molecules that produce pain,
have yet to develop a moderate to severe OUD
such as sodium and calcium channel blockers that modulate excit-
ability of pain fibers Treatment of adolescents with OUD, including the use of medication
for OUD
Strategies that block the source of the pain (ie, CGRP)
What is the best form of medication for OUD to use for pregnant
Nonpharmacologic interventions, such as transcranial magnetic
women (this should include studies to evaluate the benefits from ER
stimulation, peripheral nerve stimulation, mindfulness, biofeedback,
naltrexone)?
and others
Improved metrics to assess outcomes of therapeutic interventions
OUD Neurobiology
Interactions between pain and rewarding effects of opioids Marijuana and OUD
Relevant to the high comorbidity between pain and OUD A few highly publicized studies64-66 have suggested an association
between the availability of medical marijuana in some states and
Will lead to better ways of preventing OUD in patients with pain
lower-than-expected rates of opioid overdoses or opioid prescrip-
Effects of long-term opioid use on emotion and stress networks tions in those states, which led to the suggestion that marijuana, as
Relevant to the high risk of dysphoria, suicidality, and social with- an alternative pain treatment and/or as an alternative recreational
drawal in OUD substance, may lead to less opioid use
Neurobiological mechanisms by which adverse social environments However, longitudinal research shows that marijuana use increases
influence vulnerability for OUD risk for later opioid use, even in people with pain67
OUD Prevention Research is needed to clarify the association(s), if any, between
Prevention strategies in young adults (who are at highest risk of first marijuana use and opioid use and misuse at the individual and popu-
misusing opioids and then developing an OUD) lation levels
Prevention strategies in patients with pain treated with opioids Abbreviations: CGRP, calcitonin gene–related peptide; MOR, μ-opioid receptor;
Improved metrics to assess the results of prevention interventions OUD, opioid use disorder.

Strategies to integrate a comprehensive set of evidence-based pre-

vention and treatment interventions at the community level
Implementation research to increase adoption of effective preven-
tion interventions

Access to medications for OUD can also be expanded by en-

gaging criminal justice settings. Approximately 60% of inmates in Research Gaps and Conclusion
state and federal prisons have a substance use disorder,58 often an
OUD. Because OUD is mostly untreated during incarceration, in- More research is needed in pain and OUD to further understand the
mates face a high risk of overdose after release (mortality is 12 times neurobiology of these disorders and to help develop more effec-
higher than for the general population within 2 weeks of release).59 tive prevention and treatment interventions. The potential thera-
Treating inmates with medications for OUD while they are incarcer- peutic role of marijuana or its extracts in pain treatment should also
ated or initiating treatment with medications for OUD before in- be explored because this substance is increasingly available across
mates are released can reduce opioid use, increase treatment en- the United States and Canada (Box 3).64-67
gagement, and reduce overdoses. 60-62 Another medication In the meantime, 4 areas are central to reversing the opioid cri-
fundamental for reversing opioid overdoses is naloxone, a MOR an- sis: (1) improving treatments for pain and improved opioid prescrip-
tagonist with fast-binding dynamics that, when used promptly and tion practices, (2) expanding access to medications for OUD, (3) ex-
at adequate doses, quickly reverses an opioid overdose (Box 2). In- panding availability of naloxone and developing models to link
creasing access to naloxone is a major strategy for decreasing over- patients who experience overdose to OUD treatment, and (4) im-
dose fatalities.63 proving prevention focused on the risk factors for opioid misuse and

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 Prevention and Treatment of Opioid Misuse and Addiction Review Clinical Review & Education

OUD. Achieving these goals requires reversing stigma attached to ment. Against this background, remediation strategies to address
medications for OUD, removing infrastructural barriers to their adop- the psychosocial factors that lead people to use opioids and other
tion, and expanding engagement of health care professionals (in- drugs are necessary to prevent the emergence of another similar cri-
cluding psychiatrists) and in criminal justice settings in OUD treat- sis in the future.

ARTICLE INFORMATION 2016;3(8):760-773. doi:10.1016/S2215-0366(16) 24. Ehrich E, Turncliff R, Du Y, et al. Evaluation of

Accepted for Publication: August 21, 2018. 00104-8 opioid modulation in major depressive disorder.
11. Reuben DB, Alvanzo AA, Ashikaga T, et al. Neuropsychopharmacology. 2015;40(6):1448-1455.
Published Online: December 5, 2018. doi:10.1038/npp.2014.330
doi:10.1001/jamapsychiatry.2018.3126 National Institutes of Health Pathways to
Prevention Workshop: the role of opioids in the 25. Campbell G, Bruno R, Darke S, et al. Prevalence
Author Contributions: Dr Volkow had full access to treatment of chronic pain. Ann Intern Med. 2015;162 and correlates of suicidal thoughts and suicide
all the data in the study and takes responsibility for (4):295-300. doi:10.7326/M14-2775 attempts in people prescribed pharmaceutical
the integrity of the data and the accuracy of the opioids for chronic pain. Clin J Pain. 2016;32(4):
data analysis. 12. Roeckel LA, Le Coz GM, Gavériaux-Ruff C,
Simonin F. Opioid-induced hyperalgesia: cellular 292-301. doi:10.1097/AJP.0000000000000283
Concept and design: Volkow, Einstein, Wargo.
Acquisition, analysis, or interpretation of data: and molecular mechanisms. Neuroscience. 2016; 26. Cheatle MD. Depression, chronic pain, and
Volkow, Jones. 338:160-182. doi:10.1016/j.neuroscience.2016.06. suicide by overdose: on the edge. Pain Med. 2011;12
Drafting of the manuscript: Volkow, Wargo. 029 (suppl 2):S43-S48. doi:10.1111/j.1526-4637.2011.01131.
Critical revision of the manuscript for important 13. Dowell D, Haegerich TM, Chou R. CDC Guideline x
intellectual content: All authors. for Prescribing Opioids for Chronic Pain–United 27. Bohnert KM, Ilgen MA, Louzon S, McCarthy JF,
Administrative, technical, or material support: States, 2016. MMWR Recomm Rep. 2016;65(1):1-49. Katz IR. Substance use disorders and the risk of
Wargo doi:10.15585/mmwr.rr6501e1 suicide mortality among men and women in the US
Conflict of Interest Disclosures: None reported. 14. Cicero TJ, Ellis MS, Surratt HL, Kurtz SP. The Veterans Health Administration. Addiction. 2017;112
changing face of heroin use in the United States: (7):1193-1201. doi:10.1111/add.13774
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