for the grAde ONLY
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
M ore than 2 million Americans have an opioid use disor-der (OUD), and in 2016, more than 42 000 Americansdied of opioid overdoses.1,2 Although in the first years of the opioid crisis, most overdose-associated deaths were caused by misuse of prescription analgesics, heroin and synthetic opioids (fentanyl and its analogues) currently account for most of the fa- talities, a scenario that reflects the changing nature of the opioid cri- sis (Figure 1). We reviewed the pharmacology of opioids because it is relevant to their rewarding and analgesic effects that lead to their misuse, the epidemiology of the crisis and its transformations in the past 2 decades, and the interventions to treat and prevent OUD that must be implemented to overcome the current crisis and prevent it from happening again.
Opioid Pharmacology
Opioid drugs—prescription analgesics and illicit drugs—exert their pharmacologic effects by engaging the endogenous opioid sys- tem, where they act as agonists at the μ-opioid receptor (MOR). The agonist action at the MOR is responsible for the rewarding effects of opioids and analgesia. In the brain, these receptors are highly concentrated in regions that are part of the pain and reward networks. They are also located in regions that regulate emotions, which is why long-term opioid exposure is frequently associated with depression and anxiety.4 In addition, MORs are located in brainstem regions that regulate breathing; there,
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 interventions to prevent OUD may further help resolve the opioid crisis and prevent it from happening again.
JAMA Psychiatry. 2019;76(2):208-216. doi:10.1001/jamapsychiatry.2018.3126 Published online December 5, 2018.
Supplemental content
Author Affiliations: National Institute on Drug Abuse, Rockville, Maryland.
Corresponding Author: Nora D. Volkow, MD, National Institute on Drug Abuse, 6001 Executive Blvd, Room 5274, Rockville, MD 20852 (nvolkow@nida.nih.gov).
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agonists inhibit neuronal firing, which results in respiratory d e p r e s s i o n , w h i c h i s t h e m a i n c a u s e o f d e a t h f r o m o p i o i d overdoses.5 The various types of opioid analgesics (morphine, hydrocodone, and oxycodone hydrochloride), illicit opioids (heroin and fentanyl and its analogues), and medications to treat OUD (methadone hydrochloride, buprenorphine, and naltrexone hydrochloride) or to reverse overdose (naloxone hydrochloride) differ in terms of their affinities to MOR, their functional effects at the MOR (agonists, partial agonists, or antagonists), and their selectivity for MOR compared with that for κ- or Δ-opioid recep- tors (eTable in the Supplement).
Physical Dependence on Opioids Physical dependence on opioids is distinct from addiction, and al- though they reflect different neuroadaptation processes, they are frequently confused because the term dependence is frequently used to connote addiction. This confusion leads to misunderstand- ing by patients and physicians on the appropriate use of these medi- cations. It has also led to misestimation of the risk of addiction when opioids are used for the treatment of pain.
Physical dependence manifests with the emergence of with- drawal symptoms when use of opioids is abruptly discontinued (or even sometimes when tapered) after long-term administration. Symptoms include insomnia, cramps, diarrhea, nausea, vomiting, and body aches, as well as dysphoria, anxiety, and irritability. The sever- ity of these symptoms varies, depending on chronicity, the opioid drug in question (symptoms are stronger for more potent and shorter-acting drugs), and individual variability.
All patients treated with opioids or misusing them will develop physical dependence, and withdrawal symptoms usually resolve promptly within a few days but can sometimes last weeks after use is discontinued. Dependence can lead to opioid seeking as individu- als attempt to avoid withdrawal symptoms, contributing to addic- tion by perpetuating repeated exposures.
Opioid Misuse Opioids are misused for their analgesic effects and rewarding prop- erties; people with physical dependence or addiction to opioids may also misuse opioids to avoid withdrawal symptoms. The use of opioids for their rewarding effects reflects their ability to increase the activity of dopamine neurons in the ventral tegmental area and to increase dopamine release in the nucleus accumbens.6 In the context of prescription opioids, misuse refers to use other than as prescribed. When misused for their rewarding effects, prescription opioids are frequently snorted or injected, which leads to faster uptake in the brain, enhancing their rewarding effects; when mis- used via oral administration, opioids tend to be taken at higher doses and/or in combination with other drugs (eg, alcohol). Although opioid misuse does not necessarily result in addiction, opioids are highly addictive, and the risks increase with repeated use, higher doses, and when injected. According to the National Comorbidity Survey, the proportion of users becoming addicted to heroin after using opioids (23%) was higher than for alcohol (15%) and cocaine (17%).7
Opioid Addiction
Addiction is distinct from physical dependence and occurs in a smaller subset of opioid users, developing much more gradually. The changes are longer lasting and often require long-term treatment to achieve recovery. Until recently, it was mistakenly believed that pain pro- tected against addiction to opioid medications. A study8 assessing Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD in a cohort of patients receiving opioids for 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- tion, adverse social environments, and psychiatric comorbidities (eg, anxiety, depression).
Addiction to opioids (or other drugs) involves molecular pro- cesses associated with learning, which help consolidate automatic behaviors in response to the drug and the stimuli associated with the drug; this is referred to as conditioning. People can become con- ditioned to opioids because of their rewarding effects or because of their relief of pain, withdrawal symptoms, or dysphoria. With re- peated exposures, conditioning is strengthened, energizing the de- sire and motivation to consume the drug.
Repeated drug exposures also disrupt striatocortical circuits that are necessary for the proper functioning of the prefrontal cortex, which is needed for self-regulation. Disruption of these circuits un- derlies the impulsiveness and compulsivity characteristic of addic- tion. In addition, disruption of circuits in the extended amygdala that regulate emotions and stress renders the person with addiction vul- nerable to dysphoria or depression, anxiety, and irritability.9 These neurocircuitry changes are mutually reinforcing (Figure 2), contrib- uting to addiction’s relapsing nature. Changes to the dopaminergic circuits of the basal ganglia, the extended amygdala, and the pre- frontal cortex correspond to the sequential stages of binge or in- 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
Figure 1. Three Waves of the Increase in Deaths Due to Opioid Overdose
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
D ea
th s
pe r
10 0
00 0
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1999 2001 2003 2005 2007 2009 2011 2013 2015
Wave 1 was from 1990 to 2004, wave 2 from 2005 to 2010, and wave 3 from 2011 to 2016. Data are from the National Vital Statistics System Mortality File. Adapted from the Centers for Disease Control and Prevention.3
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treatment of opioid addiction requires continuous care to achieve recovery.
Opioid Analgesia Opioids are effective for treating severe acute pain, but their effec- tiveness in treating chronic pain is less clear.11 Tolerance rapidly de- velops to their analgesic effects; thus, patients require increasingly higher doses, thereby increasing the risk of addiction, respiratory de- pression, and fatal overdose. Furthermore, opioids can result in hy- peralgesia, exacerbating instead of alleviating pain.12 The opioid cri- sis has led to various measures that encourage greater caution in opioid prescribing, including new Centers for Disease Control and Pre- vention guidelines for management of chronic pain.13 Prescription 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.
Shifting Patterns of Opioid Misuse The opioid crisis was sparked initially by the overreliance on opi- oids to treat pain. The overprescription of opioid analgesics facili- tated their diversion and misuse, while also exposing patients with chronic pain to the risk of addiction and overdose without neces- sarily improving their pain conditions.
Beginning in the early 2000s, some of those addicted to pre- scription opioids (particularly young adults) began transitioning to heroin because the latter was cheaper and easier to obtain. Three quarters of treatment-seeking heroin users who had begun their drug use in the 2000s began with prescription opioids.14 Increased avail-
ability of inexpensive, high-purity heroin has made it easier for new 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 33.3%.15
The shift toward heroin use contributed to the escalation of opioid-associated fatalities, now further exacerbated by adultera- tion of heroin with fentanyl or fentanyl analogues. As of 2016, fen- tanyl and other synthetic opioids accounted for more overdose deaths than prescription opioids or heroin (Figure 1). The high po- tency of fentanyl (50 times more potent than heroin) increases the risk of overdosing; this risk is further exacerbated by its combina- tion with other drugs and the impossibility of controlling the dose administered.
Epidemiology of Opioid Misuse and OUD In 2016, almost 11 million American adults (age �18 years) misused opioids in the past year, with males (6.4 million [4.9%]) misusing opi- oids more frequently than females (5.4 million [3.9%]).1 Misuse of opioids by adolescents remains low, whereas the highest rates of mis- use are among young adults aged 18 to 25 years. In 2016, a total of 392 000 individuals aged 18 to 25 years (1.1%) had OUD compared with 153 00 (0.6%) of adolescents and 1 599 000 (0.8%) of adults 26 years and older.1
The rates of fatalities due to OUD and overdose and the types of opioids triggering overdoses vary markedly by state. In 2016, there were 43.4 opioid overdose fatalities per 100 000 persons in West Virginia compared with 29.7 in Massachusetts and 5.9 in Arkansas.16
The geographic diversity correlates to a certain extent with socio-
Figure 2. Three Stages of the Addiction Cycle and Associated Neural Circuits
intoxication Binge or
W ith
dr aw
al o
r
ne ga
tiv e
af fe
ct
Glutamate
Dopamine Opioid peptides Corticotropin-releasing factor Dynorphin
Incentive salience
Executive function deficits
Reward deficit and stress surfeit
Preoccupation or
anticipation
intoxication Binge or
Opioid peptides Dopamine
PFC CeA
BNST
DS
VTAVTA
NAcNAc
Extended amygdala Extended amygdala
Prefrontal cortex
Prefrontal cortex
Basal ganglia Basal
ganglia
People with substance use disorders cycle through 3 stages in rates that vary with the drug and the severity of their disorder: binge or intoxication, negative affect or withdrawal, and preoccupation or anticipation (craving); these stages are associated with activity in the basal ganglia (nucleus accumbens [NAc] and dorsal striatum [DS]), extended amygdala, and prefrontal cortex (PFC), respectively. BNST indicates bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; and VTA, ventral tegmental area. Adapted from Koob GF and Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry. 2016;38:760-773.10
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economic factors, such as poverty. Among those under the pov- erty level, 5.9% were reported to have OUD compared with 4.8% of those between 100% and 199% of the poverty level and 3.9% of those at twice or more than the poverty level.1 There is also variabil- ity among races/ethnicities, with opioid misuse being most preva- lent among non-Hispanic white individuals (4.6% vs 4.0% among African American individuals and 1.8% among Asian individuals).1
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- 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 per 1000 hospital births).17 As in other populations, opioid expo- sure in pregnant women reflects prescription of opioids for pain man- agement, medication-assisted treatment for OUD, and opioid mis- use. On the basis of data through 2007, a total of 23% of pregnant women enrolled in Medicaid filled an opioid prescription during pregnancy.18 Although severity of neonatal abstinence syndrome has been shown to be substantially milder when women are treated with methadone or buprenorphine, their newborns still require care for neonatal abstinence syndrome.19
Comorbidity of OUD Pain is frequently comorbid with OUD, reflecting that opioid expo- sure was initially intended to alleviate pain and that hyperalgesia is as- sociated with repeated exposure to prescription and illicit opioids.20
Chronic pain might increase the risk of an OUD in part by dysregulat- ing the brain’s stress circuitry and by increasing risk of tolerance to the analgesic effects of opioids. Increased conditioning to high doses of morphine was reported in an animal model of chronic pain.21
In addition, OUD is highly comorbid with other mental ill- nesses, especially mood disorders, likely because individuals with mental illness, particularly a mood disorder, are more apt to be pre- scribed an opioid analgesic. A recent article22 reported that approxi- mately 50% of opioid prescriptions are written for individuals with a mental illness, even though they represent only 16% of the popu- lation. This finding reflected the higher prevalence of chronic pain among those with a mood disorder. Even after controlling for se- verity and type of pain condition, those with a mood disorder were more likely to receive a prescription and to receive a higher opioid dose than those without a mood disorder. Patients with mood dis- orders might also be at greater risk of misusing opioids because of their antidepressant properties.23,24
Some of the opioid overdose fatalities could also reflect inten- tional suicide because suicide risk is higher in patients with OUD, chronic pain, or a mood disorder.25 Moreover, among patients with chronic pain and suicidal ideation, 75% reported that they planned to do so through overdose, and risk of successful suicide was doubled in patients with chronic pain compared with control individuals with- out pain.26 A previous report27 tried to estimate the risk of suicide among veterans with OUD. In female veterans with OUD, suicide risk was more than 8 times greater than for those without OUD; in male veterans, the risk was more than twice that for those without OUD. Estimating the exact proportion of suicides among fatalities classi- fied as being due to overdose is difficult, but this incidence might be between 20% and 30%.28
Frequently, OUDs are comorbid with infectious diseases be- cause injecting drugs increases the risk of blood-transmitted infec- tions, including HIV infection, hepatitis C virus infection, and endo- carditis. In 2015, injection drug use accounted for 9.1% of the 39 513 new diagnoses of HIV infection in the United States,29 and the incidence of hepatitis C virus infection increased 2.9-fold from 2010 to 2015.30
Prevention The misuse of and addiction to prescription analgesics, heroin, and synthetics (fentanyl and analogues) require universal and targeted prevention strategies. An important intervention to decrease pre- scription opioid misuse is reducing inappropriate prescribing. New federal guidelines and improved physician education in opioid pre- scribing and pain management are already having an influence on reducing overprescribing, although prescription rates in the United States are still high, with prescriptions of 178 billion morphine mil- ligram equivalents in 2017.31 Prescription drug monitoring pro- 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- tions and abuse-deterrent formulations (ADFs) of existing opioid medications. The ADFs contain properties intended to make inten- tional misuse more difficult or less rewarding, and evidence sug- gests that they can decrease misuse of that specific formulation. However, even though ADFs have been clinically available for several years, they represent a small percentage of the total opioid prescriptions. The restricted penetration of ADF opioids is likely to reflect their higher costs, which limit their reimbursement.32 In some instances, as was the case for the original oxycodone hydrochlo- ride formulation, ADFs may encourage a shift to misuse of other opi- oids or to unexpected routes of administration.33,34 A Risk Evalua- tion and Mitigation Strategy can be required by the US Food and Drug Administration for medications with serious safety concerns. The Risk Evaluation and Mitigation Strategy for opioid medications includes training in acute and chronic pain management, including pharma- cologic and nonpharmacologic treatments.35
Strategies that would have an influence on all forms of opioid misuse involve implementing evidence-based prevention interven- tions for substance use disorders in family, school, and/or commu- nity settings. Universal prevention interventions initiated in child- hood and adolescence decrease later drug use, including prescription opioid misuse.36-38 These interventions share common elements in- tended to strengthen protective factors in individuals and their fami- lies, schools, and communities while decreasing factors associated with risk (Box 1). For children or adolescents who are at high risk because of adverse social environments or psychiatric disorders, tai- lored interventions can prevent future drug misuse.40
Socioeconomic factors continue to influence the opioid crisis. Re- stricted job opportunities, erosion of communities, and loss of pur- pose have been linked to the psychological pain and stress fueling the demand for opioids.41 Initially, opioid misuse was mostly concen- trated in rural areas and among poor white Americans, but as misuse of heroin and synthetics has expanded, it is now affecting urban areas and minority groups. Thus, strategies that provide access to educa-
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tion to all citizens and sustainable work opportunities are long-term interventions for preventing OUD and associated problems.
Treatment The strong evidence for the effectiveness of medications for OUD (frequently also referred to as medication-assisted treatment) has made medications for OUD the criterion standard of treatment for
OUD. Currently, 3 medications are approved by the US Food and Drug Administration to treat OUD: methadone (a full agonist at the MOR), buprenorphine (a partial agonist at the MOR), and extended-release naltrexone (an antagonist at the MOR). Details on doses, dispensing, and clinical effects for medications for OUD are provided in Box 2. Medications for OUD are ordinarily given in conjunction with behavioral treatment, and studies49,50 have generally shown strong benefits of medications for OUD compared with behavioral treatments alone. Medications for OUD increase social functioning while reducing illicit opioid use, risk of overdose, transmission of infectious disease, criminality, and treatment retention. Unfortu- nately, stigma toward methadone and buprenorphine because of their agonist actions at the MOR has limited their use because of the belief by many that their use substitutes one addictive drug for another.
Treatment with agonists and partial agonists is pharmacody- namically distinct from sustaining an addiction to a prescription or illicit opioid.51 The slow rate of entry of methadone and buprenor- phine into the brain (Box 2) limits their rewarding effects. This limitation is because drug reward is accentuated when drugs enter the brain rapidly and have fast-binding properties, which explains why methadone and buprenorphine, although providing relief from craving and withdrawal, do not produce the intense euphoria achieved with heroin or other opioids when they are injected or taken at high doses. In addition, their slow dissociation and clearance from MOR prevent emergence of craving and with- drawal symptoms during treatment. The physiologic stability pro- vided by medications for OUD facilitates the reentry and integra- tion of patients to their communities.
B e c a u s e o f t h e i r a g o n i s t p r o p e r t i e s , m e t h a d o n e a n d buprenorphine are only available from opioid treatment pro- grams (methadone) or from prescribers with a special Drug Abuse Treatment Act 2000 waiver (buprenorphine). Extended-release naltrexone, because it is an antagonist, can be prescribed by any physician and presents no abuse liability; because the use of extended-release naltrexone for OUD is relatively new and adher- ence to the immediate-release naltrexone has historically been a problem, fewer studies47,48 have reported naltrexone’s effective- ness, but evidence is mounting that it may be as effective as buprenorphine for some patients.
Despite their efficacy, medications for OUD are underused. In 2015, between 31% and 37% of patients with OUD in specialty facilities received medications for OUD.52 A recent study53 in Massachusetts reported that only 30% of those who survived an opioid overdose received medications for OUD in the year after their overdose. In addition, when they are prescribed, buprenor- phine and methadone are frequently given at too low a dose and/or for too shor t a duration. For example, one study 5 4
reported that nearly half of patients treated with buprenorphine in opioid treatment facilities receive 90 or fewer days or continu- 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- titioners throughout health care to screen and treat OUD, clearing misconceptions about medications for OUD and how to use them, and removing infrastructural barriers to their use, including loosen- ing restrictions on who can prescribe them.55-57
Box 1. Risk and Protective Factors for Adolescent and Young Adult Substance Use
Risk Factors Individual
Genetic factors
Starting substance use early
Perceiving little risk in substance use
Peers who use substances
Emotional distress or aggressiveness that starts early and is per- sistent
Psychiatric disorder
Family Substance misuse in the family
Family conflict, abuse, or neglect
Parents who favorably view or approve of substance use
School Poor academic performance
Student does not view school as rewarding or meaningful and lacks commitment to school
Perception that use of drugs among classmates is high
Poor control over school drug consumption
Community Lower socioeconomic status
Availability and cost of drugs and alcohol
Community norms favorable toward alcohol and drugs
Protective Factors Individual
Resiliency
Self-efficacy
Spirituality
Interpersonal skills, including social, emotional, and cognitive skills
Treatment of psychiatric disorder
Family, school, and community Attachment to family, school, and community
Meaningful involvement with family, school, or community
Positive behavior is recognized
Norms in the family, school, and community that drug misuse is not acceptable
Being in a committed relationship or marriage with a partner who does not misuse drugs
Opportunity for fulfilling extracurricular activities
Adapted and modified from US Department of Health.39
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Box 2. Medications for Opioid Use Disorder
Methadone Full MOR agonist, typically daily oral doses of 80-160 mg methadone hydrochloride, used for more than 4 decades
Dispensing mostly limited to licensed opioid treatment programs or methadone clinics
Reduces cravings and withdrawal symptoms
Does not produce euphoria in opioid-dependent individuals because MOR binding is slower and longer lasting than that of heroin or fen- tanyl and oral delivery slows its entry into the brain
Normalizes the physiology of the stress-responsive hypothalamic- pituitary-adrenal axis42
Produces physical dependence and, if use is abruptly discontinued, results in acute withdrawal; thus, discontinuation of the drug re- quires slow tapering to avoid withdrawal
Strong evidence that it reduces illicit opioid use and risk of overdose and improves other outcomes (a Cochrane review43 in 2009 found 33% fewer opioid-positive drug test results for patients taking methadone, who were also 4.4 times more likely to stay in treatment than those not taking medication)
Buprenorphine Partial MOR agonist
κ-Opioid receptor antagonist
Nociceptin receptor agonist44
IR formulation Generally taken 3-4 times/wk at daily doses typically between 16 and 24 mg45
Most frequently prescribed as a sublingual film that contains nal- oxone, which induces withdrawal when drug is injected
ER formulations A subdermal implant that delivers the equivalent of 8 mg of bu- prenorphine was approved in 2016, but use was limited by the restricted doses it delivers
A once-monthly depot injection was approved in 2017, and addi- tional once-monthly and once-weekly formulations are currently being reviewed for FDA approval
Approved to treat OUD in 2002
Dispensing by physicians or nurses who have a Drug Abuse Treat- ment Act 2000 waiver
Reduces cravings and withdrawal symptoms
Does not produce euphoria in opioid-dependent patients because its binding to MOR is slow (slower than for methadone) and (as a partial agonist) it has less efficacy to stimulate reward
Because buprenorphine is a partial agonist, its use in patients with OUD with high levels of tolerance might result in acute withdrawal, in which case treatment with methadone, with its full agonist ef- fects, might be more beneficial
ER formulations of buprenorphine will facilitate adherence and OUD management, including for patients living in rural areas
Strong evidence that it reduces illicit opioid use and overdoses and improves other outcomes (a Swedish study found a 100% failure rate within 3 mo when treatment with buprenorphine was tapered after 6 d vs 25% when buprenorphine treatment was maintained and a 20% mortality rate among those who left treatment)46
Naltrexone Antagonist at MOR
Antagonist at κ-opioid receptor
IR formulation: 50 mg once daily
ER formulation: 380 mg delivered intramuscularly every 4 wk
IR formulation approved for OUD in 1984 but had poor adherence
ER formulation approved for OUD in 2010, which has facilitated ad- herence
Does not require a license or waiver to prescribe
Interferes with the binding of opioid drugs, thus inhibiting their ef- fects, including reward and analgesia
Patients need to undergo detoxification before initiating naltrexone treatment to avert withdrawal, which can be challenging, and not all patients succeed
The evidence is still limited, but studies thus far suggest that the ER formulation reduces opioid use, and preliminary data suggest it might prevent overdoses (2 comparative-effectiveness studies47,48
in 2017 found that, after patients were inducted on treatment with ER naltrexone, it was equally effective as buprenorphine at promot- ing abstinence and retaining patients in treatment)
Lofexidine α-Adrenergic receptor agonist, three 0.18-mg tablets taken orally, 4 times daily at 5- to 6-h intervals
Approved in 2018 as the first FDA medication to treat opioid with- drawal, although it has been used to treat opioid withdrawal in the United Kingdom since the 1990s
Dispensing is by physicians
Research is needed to determine whether it might be helpful in fa- cilitating induction into naltrexone or buprenorphine for patients with high levels of tolerance and whether it can improve adherence in patients treated with medications for OUD
Naloxone Antagonist at MOR
Autoinjection: 2 mg of 0.4 mL of naloxone hydrochloride solution in a prefilled autoinjector for intramuscular or subcutaneous injection
Nasal spray: 4 mg of naloxone hydrochloride in 0.1 mL for intranasal administration
Injection: 0.4 mg/mL, available in 2 pack sizes, containing 0.8 mg of naloxone in 2 mL or 2.0 mg of naloxone hydrochloride in 5 mL
FDA first approved naloxone for overdoses in 1971
The autoinjector was approved in 2014
The intranasal spray was approved in 2015
Increasing access to naloxone is a major component to reverse the overdose epidemic (in Massachusetts communities where overdose education and naloxone distribution were implemented, death due to overdose was reduced 27%-46%)
With the increase in overdoses from fentanyl and other synthetic opi- oids, multiple naloxone doses are necessary for reversal (reversals might fail when opioids are combined with other respiratory-depress- ing drugs, eg, alcohol, benzodiazepines; thus, there is a need for lon- ger-lasting naloxone formulations or other overdose-reversal tools)
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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Access to medications for OUD can also be expanded by en- gaging criminal justice settings. Approximately 60% of inmates in state and federal prisons have a substance use disorder,58 often an OUD. Because OUD is mostly untreated during incarceration, in- mates face a high risk of overdose after release (mortality is 12 times higher than for the general population within 2 weeks of release).59
Treating inmates with medications for OUD while they are incarcer- ated or initiating treatment with medications for OUD before in- mates are released can reduce opioid use, increase treatment en- gagement, and reduce overdoses.60-62 Another medication fundamental for reversing opioid overdoses is naloxone, a MOR an- tagonist with fast-binding dynamics that, when used promptly and at adequate doses, quickly reverses an opioid overdose (Box 2). In- creasing access to naloxone is a major strategy for decreasing over- dose fatalities.63
Research Gaps and Conclusion
More research is needed in pain and OUD to further understand the neurobiology of these disorders and to help develop more effec- tive prevention and treatment interventions. The potential thera- peutic role of marijuana or its extracts in pain treatment should also be explored because this substance is increasingly available across the United States and Canada (Box 3).64-67
In the meantime, 4 areas are central to reversing the opioid cri- sis: (1) improving treatments for pain and improved opioid prescrip- tion practices, (2) expanding access to medications for OUD, (3) ex- panding availability of naloxone and developing models to link patients who experience overdose to OUD treatment, and (4) im- proving prevention focused on the risk factors for opioid misuse and
Box 3. Research Gaps
Pain Neurobiology Factors underlying the transition from acute to chronic pain
Risk factors for chronic pain (including sex)
Risk factors for addiction when patients with pain are prescribed an opioid medication
Comorbidity of pain syndromes, mood disorders, and addiction
Pain Treatment New compounds that target non–opioid pain-modulating systems in the body, such as the endocannabinoid system
New compounds that target the MOR but in a manner that produces fewer adverse effects and less misuse liability (eg, biased agonists, bivalent molecules that concomitantly target μ and galanin or noci- ceptin receptors)
Strategies to interfere with signaling of molecules that produce pain, such as sodium and calcium channel blockers that modulate excit- ability of pain fibers
Strategies that block the source of the pain (ie, CGRP)
Nonpharmacologic interventions, such as transcranial magnetic stimulation, peripheral nerve stimulation, mindfulness, biofeedback, and others
OUD Neurobiology Interactions between pain and rewarding effects of opioids
Relevant to the high comorbidity between pain and OUD
Will lead to better ways of preventing OUD in patients with pain
Effects of long-term opioid use on emotion and stress networks Relevant to the high risk of dysphoria, suicidality, and social with- drawal in OUD
Neurobiological mechanisms by which adverse social environments influence vulnerability for OUD
OUD Prevention Prevention strategies in young adults (who are at highest risk of first misusing opioids and then developing an OUD)
Prevention strategies in patients with pain treated with opioids
Improved metrics to assess the results of prevention interventions
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
OUD Treatment New treatment options
Comparative effectiveness of existing treatments
Implementation research to increase medication of OUD use
Effectiveness of medications for OUD with specific populations
Appropriate duration of use of medication for OUD
How to better personalize behavioral treatments to the individual
How to determine when a patient is ready to be tapered off medica- tion for OUD
Improved assessment of when inpatient treatment is indicated
Biomarkers or other indicators to determine which medication for OUD is optimal for a given patient
Treatment strategy for individuals who may be misusing opioids but have yet to develop a moderate to severe OUD
Treatment of adolescents with OUD, including the use of medication for OUD
What is the best form of medication for OUD to use for pregnant women (this should include studies to evaluate the benefits from ER naltrexone)?
Improved metrics to assess outcomes of therapeutic interventions
Marijuana and OUD A few highly publicized studies64-66 have suggested an association between the availability of medical marijuana in some states and lower-than-expected rates of opioid overdoses or opioid prescrip- tions in those states, which led to the suggestion that marijuana, as an alternative pain treatment and/or as an alternative recreational substance, may lead to less opioid use
However, longitudinal research shows that marijuana use increases risk for later opioid use, even in people with pain67
Research is needed to clarify the association(s), if any, between marijuana use and opioid use and misuse at the individual and popu- lation levels
Abbreviations: CGRP, calcitonin gene–related peptide; MOR, μ-opioid receptor; OUD, opioid use disorder.
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OUD. Achieving these goals requires reversing stigma attached to medications for OUD, removing infrastructural barriers to their adop- tion, and expanding engagement of health care professionals (in- cluding psychiatrists) and in criminal justice settings in OUD treat-
ment. Against this background, remediation strategies to address the psychosocial factors that lead people to use opioids and other drugs are necessary to prevent the emergence of another similar cri- sis in the future.
ARTICLE INFORMATION
Accepted for Publication: August 21, 2018.
Published Online: December 5, 2018. doi:10.1001/jamapsychiatry.2018.3126
Author Contributions: Dr Volkow had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Volkow, Einstein, Wargo. Acquisition, analysis, or interpretation of data: Volkow, Jones. Drafting of the manuscript: Volkow, Wargo. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: Wargo
Conflict of Interest Disclosures: None reported.
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