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DISEASES AND DISORDERS Copyright © 2019

The Authors, some
Current status of opioid addiction treatment rights reserved;
exclusive licensee
and related preclinical research American Association
for the Advancement
of Science. No claim to
M. J. Kreek*, B. Reed, E. R. Butelman original U.S. Government
Works. Distributed
Opioid use disorders (OUDs) are diseases of the brain with behavioral, psychological, neurobiological, and medical under a Creative
manifestations. Vulnerability to OUDs can be affected by factors such as genetic background, environment, stress, Commons Attribution
and prolonged exposure to -opioid agonists for analgesia. Two standard-of-care maintenance medications, NonCommercial
methadone and buprenorphine-naloxone, have a long-term positive influence on health of persons with opioid License 4.0 (CC BY-NC).
addiction. Buprenorphine and another medication, naltrexone, have also been approved for administration as
monthly depot injections. However, neither medication is used as widely as needed, due largely to stigma, insuffi-
cient medical education or training, inadequate resources, and inadequate access to treatment. Ongoing directions
in the field include (i) personalized approaches leveraging genetic factors for prediction of OUD vulnerability and
prognosis, or for targeted pharmacotherapy, and (ii) development of novel analgesic medicines with new neuro-
biological targets with reduced abuse potential, reduced toxicity, and improved effectiveness, especially for
chronic pain states other than cancer pain.

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ADDICTION TO -OPIOID AGONISTS SUCH AS HEROIN, an improved analgesic is oxycodone (Fig. 1C). Oxycodone is syn-
PRESCRIPTION OPIOIDS, AND FENTANYL ANALOGS thesized from opium extracts of thebaine as a starting point (9). As
Opioid use disorders (OUDs), including their most severe form can be seen from Fig. 1, oxycodone is structurally similar to morphine,
(opioid addiction), are a major public health challenge, in both in- sharing a common backbone structure, referred to as a morphinan.
dustrialized and developing countries (1, 2). Acute mortality from Although oxycodone has been in clinical use since shortly following its
OUDs is related primarily to respiratory depression, modulated by initial synthesis and characterization in the 1910s, its use increased
-receptors in brainstem nuclei (3, 4). Opioid-induced mortality is vastly with the development of a patented 12-hour extended-release
also often observed in persons who are exposed to multiple other formulation, introduced in 1996, and enhanced marketing and pre-
substances, including alcohol, cocaine, and benzodiazepines (5). scriptions for pain therapy (10). Other common morphinans that
There are other major sources of morbidity and comorbidity in are medically approved analgesics but are commonly misused include
OUDs, and these include increased prevalence of infectious diseases morphine (Fig. 1A), hydrocodone, and oxymorphone (11).
(e.g., HIV/AIDS and hepatitis C) (6). Synthetic compounds with considerable structural deviation
Smoking and ingestion of dried opium wax isolated from the from the classical morphinans also have -opioid agonist effects.
poppy bulbs of Papaver somniferum have been occurring for millennia, Fentanyl (Fig. 1D), for instance, is a selective -opioid receptor
for the purposes of medical pain relief and of achieving altered states agonist with high in vivo potency. Fentanyl was approved by the
of consciousness (7). Physical dependence following daily chronic Food and Drug Administration (FDA) in 1968 and is available for
use of opium, defined in the context of withdrawal symptoms upon perioperative intravenous or epidural/intrathecal administration, as
abstinence, has been historically documented as early as the 16th well as in various other formulations for take-home use, including
century (6). Two discoveries in the 19th century were crucial for the transdermal patches, buccal film, buccal spray, buccal tablet, nasal
improvement of analgesic therapeutics as well as leading to devas- spray, and lozenges.
tating consequences in terms of opioid addiction and potential for Various fentanyl analogs have also been approved for use in spe-
fatal overdose as a consequence of respiratory depression: the ex- cific situations. Remifentanil was approved by the FDA in 1996 and
traction of morphine (Fig. 1A) as the primary active ingredient of is used in intravenous formulation during anesthesia. Sufentanil,
opium and the development of the hypodermic needle for intravenous approved initially in 1984, is similarly used perioperatively in con-
administration (7). Heroin (Fig. 1B) was later developed as a semi- junction with anesthesia and is also used epidurally for pain relief
synthetic derivative of morphine, involving diacetylation of the during labor and delivery. Very recently, a new sublingual tablet
hydroxyl groups that leads to a 10-fold increase in potency in vivo, formulation of sufentanil was approved by the FDA for the treatment
due to enhanced delivery to the brain (8). Heroin itself has limited of acute pain, in medically supervised health care settings. Alfentanil
affinity for -opioid receptors, but following distribution to the was also approved for use in 1986 for perioperative intravenous
brain undergoes biotransformation, initially yielding primarily 6-acetyl administration in conjunction with anesthetics. Another analog,
morphine and then morphine as active metabolites (Fig. 2A). carfentanil, is used in veterinary medicine for large mammals and
Myriad derivatives of morphine have been synthesized in the also as a positron emission tomography (PET) radiotracer (12). The
quest for improved analgesics, beginning in the 19th century and potency of carfentanil makes it particularly dangerous, with a high
continuing to this day. A prominent example of a drug developed as potential for overdose, when abused by humans.
In recent years, there has been an increasing problem with pro-
duction of fentanyl and its analogs in different countries including
Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York,
NY, USA. Mexico and China (13) and with these products entering the United
*Corresponding author. Email: [email protected] States across borders and by mail (14–17). Fentanyl and its analogs

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Fig. 1. Chemical structures of the most commonly abused opioids. Structures of (A) morphine, (B) heroin, (C) oxycodone, and (D) fentanyl and of the opioidergic
therapeutics methadone (E) and buprenorphine (F). In addition, shown are antagonists naltrexone (G) and nalmefene (H). The structurally similar morphinan derivatives
(A, B, C, F, G, and H) derived from opium, or synthesized from thebaine obtained from opium, contrast sharply with the structures of the synthetic opioids methadone and
fentanyl (E and D, respectively).

have thus become “street” drugs, occasionally sold illicitly alone, and, education until the mid-1990s), accompanied by extensive promo-
more commonly, as additives to heroin (16) to increase the perceived tion and marketing of some opioid formulations during the same
potency of the latter. These synthetic compounds have been a ma- period. These factors have led to a marked change in physician pre-
jor cause of recent increases in overdose deaths (see Fig. 3) (18). scription habits, from earlier prescriptions of 3 to 7 days of opioids
for acute pain (such as surgical procedures and fractures) to current
The impact of excessive availability of prescription opioids averages of pain medications up to 3 weeks or even longer (20). This
Medical and nonmedical use of prescription opioids, such as oxycodone, increase has created a large excess of prescription opioids available
have been increasing markedly, especially in the United States (19), for misuse, which can then progress to OUDs and use of illicit drugs
either in the patient to whom the medication was originally pre- such as heroin (21, 22).
scribed or frequently by someone else taking the unused medicine.
This increase has occurred in part as a result of the World Health
Organization’s reduced oversight of international sales and move- EPIDEMIOLOGY
ment of opiates, beginning in the late 1980s. Further exacerbating The most recent data from the federal government, primarily from the
this problem, recent changes in U.S. medical practice have encour- Substance Abuse and Mental Health Services Administration, the
aged physicians to prescribe “as much medication as any patient National Institute on Drug Abuse (NIDA), and the National Household
needs for relief of their pain” (a concept foreign to U.S. medical Survey on Drug Abuse and Health, as well as Monitoring the Future,

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Fig. 3. Opioid overdose deaths in the United States, 1999–2017. Data from
Centers for Disease Control and Prevention, 2018 Annual Surveillance Report of
Drug-Related Risks and Outcomes. Asterisk indicates synthetic opioids other than
methadone, e.g., prescribed or illicit fentanyl, fentanyl analogs, and tramadol.
Number sign indicates natural or semisynthetic opioids other than heroin, e.g.,

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morphine, oxycodone, and hydrocodone.

approximately four overdose deaths each day (25). There have been
substantial increases in opioid-induced overdose deaths in recent
years, especially those involving heroin and fentanyl (18, 26). This
statistic includes a widening “gender gap,” in which overdose
vulnerability in males is increasing more than in females (18).

PUBLIC HEALTH NEED FOR INCREASE IN AVAILABILITY

OF MEDICATION-BASED TREATMENT OF OPIOID ADDICTION
Because of the major stigma of drug abuse, there has been an almost
complete absence in most medical schools of education about
Fig. 2. Heroin addiction contrasted with methadone maintenance. (A) Differ- opioid addiction, its diagnosis, treatment of overdose, and chronic
ence in plasma protein binding and metabolism results in substantially different pharmacotherapy (27, 28). More broadly, most medical schools
pharmacokinetic profiles and bioavailability for heroin versus methadone (55). have only limited education about any other addictive disease
(B) Prototypic administration pattern and subjective state for heroin versus meth- as well.
adone. Multiple doses of heroin are self-administered daily to achieve a state of
The number of persons in methadone maintenance treatment
“high” (euphoria) or, in cases with a depleted supply, to avoid a feeling of “sick”
(withdrawal). Methadone, at steady state with single daily administration, leads
programs (MMTPs) in the United States is approximately 382,000,
neither to subjective states of high nor sick (43). while the number of persons in buprenorphine-naloxone treatment
is approximately 112,000 (see Table 2). In the entire world, the
number of people in MMTP is currently roughly 1.4 million (see
show that over 16 million people in the United States suffer from table S1). For the less effective treatment with naltrexone (either as
some addictive disease (see Table 1). The most common addiction a daily oral medication or in depot injection formulation) (29),
is alcoholism, followed by addiction to cannabis, opioids, and cocaine. 23,000 persons are currently in treatment in the United States.
At least 1 million to 2 million persons in the United States suffer Many of these persons entered naltrexone treatment due to the
from addiction to heroin and other short-acting opioids (Table 1). criminal justice system or due to regulations on physicians that
It is estimated that over 37 million persons have misused short-­ exist in some (but not all) states.
acting opioids such as oxycodone and hydrocodone. The number of Studies have shown that fewer than 10% of persons with opioid
persons who have become addicted to these compounds has only addiction are able to achieve long-term abstinence without medication-­
been roughly calculated. Some epidemiological data show that assisted treatment with methadone or buprenorphine maintenance
approximately 20% of persons who self-administer a prescription (30). No behavioral or cognitive treatments alone have been shown
opioid for nonmedical use will develop an OUD (23). In the past to be effective for patients with opioid addiction (or severe OUD).
two decades, increasing numbers of people who started with misuse It is disturbing that the number of persons in medication
of prescription opioids (e.g., oxycodone) then commence the use of treatment overall remains very low, given the numbers afflicted
heroin because it is cheaper than illicit sales of these prescription with opioid addiction. However, in 2017, there appears to have been
opioids (24). In the past 5 years, the number of overdose deaths in the a modest increase in numbers of persons in both MMTP and
United States has risen to approximately 50,000/year. For example, buprenorphine-naloxone treatment, following a decrease in 2016
in New York City alone, it has recently been estimated that there are (see Table 2).

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Table 1. Epidemiology of drug use. Prevalence of specific drug abuse Table 2. Status of methadone, buprenorphine, and extended-release
and vulnerability to develop addictions. SAMHSA National Survey on Drug naltrexone treatments for opioid addiction in the United States:
Use and Health, 2017; others 2007–2018. Decrease and then increase in numbers in treatment 2015–2017
(SAMHSA, 2018).
National household survey and related surveys (2007–2016)
U.S. patients in treatment
Heroin use—ever ~5.2 million Treatment
2015 2016 2017
Heroin addiction ~652,000
Methadone 345,443 382,867
~37.1 million (i.e., 14.2% of the 356,843
Illicit use of opiate medication—ever maintenance (−11,400; −3.2%) (+37,424; +10.8%)
population 12 and over)
Dependence on such medication use ~2.1 million Buprenorphine 61,486 112,223
75,723
Opiate (heroin, fentanyl, and other) maintenance (−14,237; −18.8%) (+50,737; +82.5%)
~72,3000 (in 2017)*
overdose deaths
Cocaine use—ever ~40.5 million Extended-release 10,128 23,065
7035
naltrexone (+3093; +44.0%) (+12,937; +128.7%)
Cocaine addiction ~966,000
Alcohol use—ever ~216 million
Alcoholism ~14.5 million
intake, and proneness to relapse unless managed with chronic
Marijuana use—ever ~123 million
medication and related treatment. Several -receptor populations
Marijuana daily use ~4 million in brain, alone or in combination with other receptor systems, may

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Development of addiction after self-exposure mediate these different effects clinically and in translationally
Opiate addiction ~1 in 5 to 1 in 15 (20 to 6.5%) relevant models. Overall, the etiology of OUDs is multifactorial,
and different types of mechanisms can contribute to vulnerability
Alcoholism, marijuana, and cocaine
~1 in 8 to 1 in 15 (12.5 to 6.5%) (see Fig. 4 and fig. S1).
dependency

*National Center for Health Statistics (U.S. Centers for Disease Control and Development of physical dependence and withdrawal
Prevention), 2019.
After repeated exposure to -agonists, either in the context of
medical prescription for analgesia or self-administration for non-
medical uses, a state of dependence develops. Withdrawal signs
The major known factor contributing to the effectiveness of observed upon drug discontinuation include autonomic signs (e.g.,
medication-assisted treatment is compliance in taking the medica- piloerection, diarrhea, and changes in thermoregulation); sensory
tion daily. Compliance is not an issue with methadone maintenance changes, including hyperalgesia; subjective anxiety-like effects; and
treatment because federal regulations mandate that patients in neuroendocrine effects [e.g., increases in circulating levels of stress/
treatment visit the clinic initially daily to receive their methadone hypothalamic-pituitary-adrenal axis hormones, adrenocorticotropic
dose, which can be reduced to weekly or monthly visits when a hormone (ACTH), and cortisol] (33). These diverse signs of with-
patient has been in successful long-term treatment (medical main- drawal can be mediated by different neurobiological systems. Studies
tenance). That said, the strict federal regulations surrounding show that withdrawal can contribute to increased self-administration
methadone maintenance have had the consequence of limiting the of -agonists (34), after the initial chronic exposure period.
number of clinics and therefore reduce the availability of effective The molecular and physiological underpinnings of -agonist
treatment to those in need. Buprenorphine must also be used daily but, dependence and withdrawal have been examined for decades. While
under federal law, can be prescribed for up to 30 daily doses at a time, several medications can be used to medically manage the severity
with the patients responsible for self-administering their daily dose. of withdrawal (including the 2-adrenergic agonists clonidine or
Research over the past 50 years shows that the most critical need lofexidine) (35), the impact of the cycles of self-administration and
in the treatment of opioid addiction is the continued and expanded withdrawal in OUDs remains a challenge and contributes to the con-
availability of treatment with a long-acting steady-state medication tinuation of the disease process. Some findings suggest that changes
(-opioid receptor agonist or partial agonist). Research has docu- in -receptor signal transduction, as well as receptor cycling and
mented that a relative “endorphin deficiency” develops in persons internalization, occur after repeated exposure to -agonists (36).
with long-term opioid addiction (31). Therefore, treatment with However, it is also clear that some withdrawal mechanisms develop on
methadone or buprenorphine maintenance can be considered a the basis of changes to neurobiological networks, which are down-
long-term “replacement” therapy similar to thyroxin treatment for stream from -receptors (37, 38). Withdrawal signs (and other
thyroid deficiency or insulin use for diabetes. interoceptive signs) can function as triggers to drug-taking and changes
in reward function (34, 39). The process of escalation of -agonist
Criteria for OUD diagnosis self-administration has also been examined in preclinical models (40).
OUD is currently defined by the DSM-5 (fifth edition of the Diag-
nostic and Statistical Manual; www.DSM5.org), based on the num- Basic function of -opioid receptors
ber of clinical criteria that are met (32). Increasing numbers of -opioid receptors are G i /G o -coupled receptors [G protein
criteria met can be used to qualify the diagnosis as mild, moderate, (heterotrimeric GTP-binding protein)–coupled receptor], encoded
or severe. These criteria focus primarily on escalating self-exposure, by the gene OPRM1 (41), and their main endogenous ligands are
tolerance, physical dependence, withdrawal, loss of control over -endorphin and enkephalin-derived neuropeptides (encoded by

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Fig. 4. Model of the progression from misuse of opioids toward moderate or severe OUD (i.e., opioid addiction).

POMC and PENK, respectively) (42, 43). -receptors are located in unbiased analysis of all targets affected after 14-day chronic oxy-
several areas of the central nervous system (CNS) and also the codone self-administration in adult mice (50–52). Focusing on neuro­
gastrointestinal tract, where they can modulate diverse biobehavioral transmitter and neuropeptide systems, RNA-seq studies demonstrate
functions including reward, mood, anxiety, neuroendocrine func- that chronic oxycodone self-administration caused a change in
tion, and also gastrointestinal motility (44). -receptor systems pro-opiomelanocortin (Pomc), 5HT2a and 5HT7 receptors, galanin
also interact with other major neurobiological systems, such as receptor, and glycine receptor. RNA-seq also shows that chronic
dopaminergic, glutamatergic, and neuropeptide systems, including oxycodone self-administration causes up-regulation of 54 and
the -opioid receptor/dynorphin system (encoded by OPRK1 and 126 genes involved in neuroinflammation/immunomodulation in
PDYN, respectively). the dorsal and ventral striatum, respectively (50). In addition, genes
involved in axon guidance, in the integrin, semaphorin, and ephrin
Molecular changes in brain after repeated exposure to systems, were differentially altered in both the dorsal and ventral
short-acting -opioid agonists striatum, after chronic oxycodone self-administration (51). These
Several studies have shown that repeated exposure to -agonists RNA-seq data describe the complex gene regulation that occurs in
such as morphine, heroin, or oxycodone can cause changes to the brain of subjects, which self-administered oxycodone over a
mRNA expression of numerous targets, including prodynorphin and relatively prolonged period, and indicates some of the brain pro-
-receptor genes (Pdyn and Oprk1, respectively) (45, 46). Using an cesses that could be affected in persons with severe OUD.
mRNA array, it was found that several genes encoding neuro­ Furthermore, some of the aforementioned molecular changes can
transmitter receptors (especially the -aminobutyric acid type A persist or even emerge well after exposure to the -agonist is
receptor 2 subunit; Gabrb2) were altered in the striatum after chronic discontinued (46). The aforementioned studies show that repeated
oxycodone self-administration in adult mice (47). Other studies also -agonist exposure results in complex and potentially long-lasting
show that molecular adaptations in the striatum and hippocampus neuroadaptations that could underlie different aspects of opioid
differ between adult and adolescent mice, after chronic oxycodone addiction and its relapsing features. Interventions on some of these
self-administration (48, 49). For example, expression of some genes, molecular targets may be fruitful avenues for the development of
such as monoamine oxidase a (Maoa), was up-regulated in the dorsal mechanism-based prevention of opioid addiction or to minimize neural
striatum of both adult and adolescent mice, after chronic oxycodone remodeling that may occur after iatrogenic exposure to -agonists.
self-administration. However, other striatal genes, especially gastrin-­
releasing peptide receptor (Grpr), were differentially regulated after
chronic oxycodone self-administration in adults and adolescents CURRENT TREATMENT FOR OPIOID ADDICTION
(48, 49). -opioid agonist and partial agonist medications
Our laboratory has also recently reported RNA sequencing Methadone
(RNA-seq) studies in the dorsal and ventral striatum (i.e., caudate-­ Research on developing a treatment for opiate addiction came to
putamen and nucleus accumbens, respectively), which allowed an fruition at the Hospital of the Rockefeller Institute for Medical

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Research in 1964 by Dole et al. (53). The treatment developed was cient cross-tolerance to “blockade” the euphoric effects by super-
methadone maintenance treatment, approved by the FDA in 1972, imposed short-acting -agonists.
which remains the most widely used effective therapeutic approach Methadone, when administered orally, has a slow onset and
for opioid addiction (Table 3) (54–56). offset of action. When used to treat opioid addiction, moderate
In good-quality MMTPs, which provide adequate counseling, doses of methadone should be used initially (30 to 40 mg/day) and
medical, and psychiatric care (which pertains in most local and slowly increased, usually at the rate of 10 to 20 mg/week up to a
national legislations and rules), 60 to 80% of persons can respond daily dose that provides cross-tolerance to the effects of any super-
well, stay voluntarily in treatment for more than 1 year, and imposed short-acting -agonist, i.e., “narcotic blockade,” while
progressively decrease the use of illicit opioids over the first 3 to preventing opioid withdrawal signs without causing euphoria (Fig. 2B)
6 months (57). However, approximately 20 to 40% of persons may drop (53). With the increasing purity of heroin over the past two to three
out of treatment. In individuals receiving chronic oral methadone, decades, the optimal treatment dose in most patients with opiate
intravenous or parenteral methadone does not cause euphoria (or addiction is 80 to 150 mg/day, with higher doses needed in a small
high) because it rapidly binds to plasma proteins (53). percentage of patients. These doses of methadone are markedly
Methadone maintenance has greater retention than buprenorphine higher than those used to treat chronic pain, which usually range
maintenance (see below), probably because the former is a full from 10 to 45 total mg/day, delivered in divided doses. Because of
agonist at the -opioid receptor and also has modest N-methyl-­d- extensive binding to plasma protein, as well as to tissues, metha-
aspartate receptor antagonist activity, which may further retard done enters the brain slowly and exits the brain slowly, allowing a
the development of tolerance (58, 59). Methadone needs to be used steady state to develop (60). The half-life of racemic methadone (the
in moderate to high doses, usually 80 to 150 mg/day, to create suffi- usual form) in humans is approximately 24 hours (±4 hours). The
half-life of the active enantiomer (l or R, Fig. 1E) is around 48 hours,

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and the half-life of the inactive enantiomer (d or S) is around
Table 3. FDA-approved medications for OUD, with typical dosing 16 hours (61–63). Methadone is biotransformed to pyrolline and
paradigms for each of the approved formulations. PO, per os (oral); SL, pyrrolidine metabolites, both inactive and excreted primarily not
subligual; BUC, buccal; SQ, subcutaneous; IM, intramuscular. only in urine but also in feces. Methadone does not cause enhanced
Treatment Dose range Considerations or inhibited microsomal activity. Therefore, doses of methadone
can be kept constant for at least 10 years with little need for change.
Methadone (PO) 80–150 mg/day Maintenance dosing
(typical range) is determined With a half-life for the racemic formulation of 24 hours, steady-state
during the early methadone can be achieved with once daily dosing of a specific dose
weeks of treatment within 1 week. PET investigations of formerly heroin-addicted indi-
following upward viduals, maintained on steady-state methadone at an effective treat-
titration. Individual
genetic and drug
ment dose, indicate that the occupancy of the -opioid receptor is
history differences not close to 100% but rather 30 to 40% (64).
may lead to Buprenorphine
requirement of Buprenorphine was originally developed in the 1970s as an analgesic
higher doses than
(Fig. 1F) in the laboratory of J. Lewis, at Reckitt-Colman in the
the typical range.
FDA approved in United Kingdom. When used as a maintenance medication for OUD,
1972. buprenorphine must be used by the sublingual, but not oral route,
Buprenorphine- 8–24 mg/day 4:1 ratio (w/w) of due to rapid liver biotransformation. Unfortunately, when used
naloxone (SL or BUC) buprenorphine buprenorphine- parenterally or injected intravenously, buprenorphine can have
(1–6 mg/day naloxone. Because euphoric effects. However, it has also been shown that the addition
naltrexone) of partial agonist of naloxone in the sublingual formulation of buprenorphine, if
(typical range) nature of
buprenorphine, no
self-administered parenterally, prevents this euphoria for at least
further treatment 30 min (i.e., the half-life of naloxone) (65). Very recently, sustained
effect to be gained release implants of buprenorphine have been developed that last up
by doses greater to 30 days (Table 3) (66).
than 24 mg/day. Buprenorphine and buprenorphine-naloxone are also effective
FDA approved in
2002. for at least 6 months in at least 40 to 50% of unselected patients (67).
The sublingual formulation with the largest buprenorphine dose
Buprenorphine 80–300 mg/monthly Two formulations
extended-release injection available. FDA
(12 mg) is combined with 3 mg of naloxone. The FDA-approved
formulation (SQ) approved in 2016 package insert states that sublingual doses of buprenorphine larger
and 2017. than 24 mg have not been shown to have a further clinical advantage.
Naltrexone tablets 50 or 100 mg/day Requires a patient As above for methadone, it is critical that buprenorphine mainte-
(PO)/extended- orally; 380 mg/ to be opioid free for nance doses should be sufficient to achieve blockade of short-acting
release formulation monthly IM 7–10 days before -opioid agonists (68).
(IM) injection administration. FDA
Buprenorphine administered by the sublingual route has an extended
approved in 1984
(tablets, no longer half-life compared to the half-life of intravenous buprenorphine, which
marketed); 2010 is similar to short-acting opiates, and has also been shown to bind
(extended release). to the -opioid receptor with slow dissociation kinetics (69).
Therefore, in treatment of addiction, buprenorphine has a sustained

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effect, as does methadone, but for different reasons. Rapid “on-off” Long-acting medications allow normalization of functions in humans
effects of a -agonist affect signal transduction and result in that are disrupted by short-acting -agonists, including stress
adaptations including desensitization and tolerance (70). Mainte- responsivity and hormone-regulated reproductive function (specifi-
nance with methadone orally or buprenorphine sublingually pro- cally normalization of the hypothalamic-pituitary-adrenal and
vides steady-state occupancy at -opioid receptors (12, 64), with hypothalamic-pituitary-gonadal axes) (81, 82).
limited tolerance, as shown by stable doses in the clinic, over pro-
longed periods. Since buprenorphine is a -receptor partial Human molecular genetics related to opioid use disorders
agonist with dissociation kinetics, it can block binding of other Variants of the -receptor gene, Oprm1
self-administered -opioid agonists. PET studies reveal that In 1998, we reported on an important and fairly common single-­
buprenorphine maintenance results in submaximal occupancy of brain nucleotide polymorphism (SNP) of the -opioid receptor, the
-receptors (40 to 60%) (12). This maintenance treatment is able to A118G variant, which changes an amino acid in the N terminus (83).
block the effects of challenge with short-acting -agonists (68). In collaboration with Yu and colleagues (83), we showed that the
A118G variant results in increased binding affinity of the endogenous
Opioid antagonist medications neuropeptide, -endorphin. We and others also showed that with
As mentioned previously, naltrexone (Fig. 1G) has been approved this variant, there is greater signal transduction to the G protein–
as a treatment for opioid addiction, both with oral tablet adminis- coupled inwardly rectifying potassium channel system.
tration and more recently intramuscular depot injections with sus- In the initial clinical studies, we and others learned (83) that this
tained release for approximately 1 month (Table 3) (71). Naltrexone A118G variant occurs in around 8 to 30% of European Caucasian
is primarily a -antagonist and is also a -opioid receptor partial populations and occurs in 40 to 60% of Asian populations. However,
agonist (72). Acute administration of naltrexone to a person who is it is not present in African populations, unless admixture has

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actively dependent on -agonists results in precipitated with- occurred. Further work from our laboratory, carried out in collab-
drawal symptoms, which are aversive. Thus, prior to naltrexone oration with the Karolinska Institute (Stockholm, Sweden), showed
induction, patients must be withdrawn from -agonists first, with that A118G is strongly associated with opioid addiction (84) and
several days of abstinence, initiated with or without tapering. with alcoholism (85). Each of these findings was made in a European
Daily oral naltrexone has been of only limited utility in the treat- Caucasian population. Several other groups have also studied this
ment of OUD-related morbidity (29). So far, only a few studies of variant in healthy humans and have found that one or two copies of
limited duration have been performed on intramuscular depot nal- the G nucleotide result in altered stress responsivity, including
trexone, designed to provide stable levels of naltrexone for approx- altered responsivity to a challenge with a -receptor antagonist,
imately 1 month [for example, (73–75)]. The long-term clinical impact is which normally activates this system (86, 87). Further, it has been
still unclear (29). Depot naltrexone can block the effects of short-acting shown that one or two copies of this variant markedly alter the
-agonists (76). However, to our knowledge, depot naltrexone has response in normal volunteers to metyrapone, a neuroendocrine
not been shown to normalize the persistent neurobiological changes test compound that cuts off the production of cortisol by the adrenal
that result from long-term exposure to illicit opioids. cortex for about 8 hours, resulting usually in a surge of -endorphin
Depot naltrexone could be potentially useful as a therapeutic and ACTH (88). This effect arises because the normal negative feed-
modality before onset of multiple daily opioid use (a characteristic back system by cortisol or other glucocorticoids is temporarily
of dependence and addiction) before the development of persistent blocked. Thus, in persons with one or two copies of the A118G variant,
neurobiological disruptions. There is some concern that hepatotoxicity a subnormal response to metyrapone testing was observed. This
may result from chronic long-term naltrexone use, at least in a subset response is likely due to changes in -endorphin binding to the
of patients. As an alternative, a similar compound, nalmefene (Fig. 1H), -receptor in carriers of this variant, as this neuropeptide is part
may also be useful in a depot formulation in the future. At this time, of the modulation of stress responsivity. Thus, with higher affinity
nalmefene is administered in oral formulation, as an “as-needed” binding of -endorphin to the G variant–carrying -opioid receptor,
medication for the treatment of alcohol use disorder, and approved one sees less activation of the stress axis, resulting in lower ACTH
for use in Europe and Japan. Nalmefene, similar to naltrexone, is a (and likely -endorphin) levels after metyrapone challenge.
-opioid receptor antagonist and also has -partial agonist effects, In addition, transgenic mice homozygous for the G variant self-­
primarily through G protein signaling (77, 78). administer over twice as much heroin (than the wild-type) (89). These
The most commonly used opioid antagonist against overdose is findings show that even a single amino acid change in the coding
currently naloxone, which is of lower potency and shorter duration region of the -opioid receptor can significantly increase the amount of
of action, compared to its congeners, naltrexone, and nalmefene. self-administered short-acting -agonist.
Naloxone has been of major importance for saving thousands of Methadone and buprenorphine-naloxone maintenance treatment
lives in overdose situations. With the recent availability of illicit fentanyl has been found to be effective in individuals with the Oprm1 A118G
and its analogs, due to their enhanced potency and longer duration polymorphism and with several other polymorphisms in genes
of action, single doses of naloxone are not always effective in rescuing expressed in brain (90). The effectiveness of this treatment is prob-
opioid-induced respiratory depression (79). Multiple sequential ably due to the relatively high dose of both medications that are
injections of naloxone are sometimes necessary, particularly with used in the treatment of opioid addiction. However, polymorphisms
fentanyl analogs. Naltrexone and nalmefene, which have longer of genes involved in methadone pharmacokinetics are associated
durations of action, are therefore receiving current attention as with differences in the dose required for effective maintenance
anti-overdose medications against potent fentanyl analogs (80). (91, 92). Some studies have suggested that patients with one or
Long-acting medications such as methadone and buprenorphine-­ two copies of the A118G variant may respond differently from
naloxone can be used on a long-term basis with little dose change. those with the prototype both to pain and to analgesic treatment

Kreek et al., Sci. Adv. 2019; 5 : eaax9140 2 October 2019 7 of 11

SCIENCE ADVANCES | REVIEW

with a -opioid receptor agonist (93). Both methadone and chemistry and pharmacology (both in vitro and in vivo, in rodents
buprenorphine can be effectively used in the treatment of pain at and nonhuman primates).
relatively low doses, compared to maintenance doses used in OUDs. Current areas of development include the examination of
To our knowledge, no study has shown a difference in analgesic effects “biased” -agonists, which may potentially have an improved pro-
of these two compounds in persons with one or two copies of the file (e.g., a relatively lower propensity to cause constipation, respiratory
A118G variant. depression, or abuse potential) compared to classic -agonists such
Variants of the -opioid receptor (Oprk1) and prodynorphin as fentanyl (103, 104). At this time, the superior characteristics of these
(Pdyn) genes agonists have not been demonstrated unequivocally (105). A second
A second group of gene variants that have been shown to be associ- approach examined recently in preclinical models involves novel
ated with different addictive diseases is the functional 68–base pair -agonists that would be active preferentially at the local site of
(bp) repeat present in one to four copies in the promoter of the injury or inflammation (e.g., at -receptors in the periphery) (106),
prodynorphin (PDYN) gene, which encodes for the endogenous thus diminishing risk of overdose and abuse potential, as the latter
neuropeptide at -opioid receptors (94). Some studies have found effects are mediated by receptors in the CNS.
an association of this polymorphism with aspects of opioid addiction A third approach has examined dual targeting of -opioid
(95, 96) in Caucasian populations, and similar findings of associa- receptors and other receptors. One recent notable example, studied
tion of the number of 68-bp repeats have been reported in studies of preclinically, is a dual -agonist/orphanin-agonist compound,
the genetic determinants of cocaine addiction (97). which shows enhanced analgesia with a reduced burden of both
Variants of cannabinoid system genes respiratory depression and abuse potential (107).
One laboratory has reported an association of fatty acid amide More broadly, it has been shown that classic -agonists are not
hydrolase gene variant 385C > A with opioid addiction (98). However, optimal for the chronic treatment of pain that is mediated by neuro-

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our laboratory was unable to confirm this finding in a larger sample pathic or inflammatory mechanisms (108). Therefore, there has been
of normal volunteer Caucasians, compared with those with opioid a continued focus on novel pharmacological targets (i.e., not directed
addiction, although we found several intriguing associations of to the -receptors) for the chronic treatment of these kinds of pain.
polymorphisms of the cannabinoid receptor type 1 and opioid
addiction (99). Across three different ethnicities studied (Caucasian Gaps in scientific knowledge and research directions that
Europeans, African-Americans, and Hispanics), a highly significant are likely critical for advancing the effectiveness
association was found of long repeats with heroin addiction (P = 0.009). in treatment and recovery
Further, pointwise significant association of the allele 1359A The goals and rationale for pharmacotherapy for opioid addiction
(P = 0.006) and genotype 1359AA (P = 0.034) was associated with (53) are for a pharmacotherapeutic agent (preferably used orally or
protection from heroin addiction in Caucasians. sublingually) to prevent withdrawal symptoms, to reverse drug
Variants of nociceptin/orphanin FQ receptor genes craving, and to normalize any functions that have been disrupted by
Our laboratory investigated the nociceptin/orphanin FQ receptor chronic drug use, especially brain function (54). Further, the medi-
gene (OPRL1) with respect to genetic variants that might be associ- cation should be targeted to a specific site of action, a specific phys-
ated with opioid addiction (100). In Caucasians, but not in African-­ iological system affected or deranged directly by the drug of abuse,
Americans, we found that rs6090041 and rs6090043 variants of the and not simply symptomatically directed. Opioid addiction is often
OPRL1 gene were significantly associated pointwise with opioid comorbid with other addictions (e.g., to cocaine and alcohol).
addiction. Of the haplotypes formed by these two variants, one was Currently, we are also investigating development of medications to
associated with vulnerability to develop opioid addiction in Caucasians treat cocaine addiction and alcoholism, with the -opioid receptor
(pointwise P = 0.020), and another haplotype of these variants as one major potential target (109–111).
was associated with protection from developing opioid addiction in One current goal would be the discovery of targets and approaches
African-Americans (pointwise P = 0.04). that may prevent the onset of OUDs after relatively brief exposure
Recent human genetics of opioid addiction to -agonists (e.g., after short-term iatrogenic exposure for analgesia),
Our laboratory conducted a very early (2010) genome-wide associ- with the aim of preventing the development of severe OUDs.
ation study to identify gene variants that might contribute to the Studies have also shown that persons with OUD show persistently
risk for developing heroin addiction (101). SNPs in several genes changed neuroendocrine stress–axis systems, which may contribute
encoding for components of the endogenous opioid system, neuro­ to continued risk of relapse (112). Recent work also shows that pain
transmitter systems, and the stress hormone system were associ- exposure per se (e.g., neuropathic or inflammatory pain) can result
ated with heroin addiction in multiple ethnicities (see table S2) in neurobiological changes that could also increase the susceptibility
(101, 102). of the individual to OUDs or to psychiatric comorbidities, such as
anxiety or depression (113, 114).
Current research areas that have clear translational Novel technologies such as RNA interference and CRISPR (for
potential for the development of new treatments somatic, not germ cells) may be explored in the future, for preven-
or interventions tion or therapeutic uses, both for analgesia and for the treatment of
In addition to the aforementioned approved medications, some OUD. These approaches could include targeting of particular neuro-
current research areas may have translational potential. Promising anatomical areas and mechanisms that may underlie specific facets
research areas include the development of novel analgesic moieties of analgesia and of OUD treatment. As with all “gene therapy”–based
with decreased abuse potential or with reduced risk of toxicity or approaches for CNS disorders, the development of vectors that can
overdose. These developments are the product of decade-long be expressed in a human relatively noninvasively and effectively will
research efforts in public and privately funded research in medicinal be crucial, as it is the avoidance of “off-target” effects (115).

Kreek et al., Sci. Adv. 2019; 5 : eaax9140 2 October 2019 8 of 11

SCIENCE ADVANCES | REVIEW

SUMMARY AND CONCLUSIONS 20. N. Volkow, H. Benveniste, A. T. McLellan, Use and misuse of opioids in chronic pain.
Annu. Rev. Med. 69, 451–465 (2017).
OUDs, including their most severe form, opioid addiction, are
21. G. Banerjee, E. J. Edelman, D. T. Barry, W. C. Becker, M. Cerda, S. Crystal, J. R. Gaither,
chronic relapsing diseases of the brain with multifactorial origins. A. J. Gordon, K. S. Gordon, R. D. Kerns, S. S. Martins, D. A. Fiellin, B. D. Marshall,
Standard-of-care maintenance medications (methadone and Non-medical use of prescription opioids is associated with heroin initiation among US
buprenorphine-naloxone) are effective for the treatment of these veterans: A prospective cohort study. Addiction 111, 2021–2031 (2016).
diseases. However, the appropriate therapeutic use of these medica- 22. K. T. Brady, J. L. McCauley, S. E. Back, Prescription opioid misuse, abuse, and treatment
in the United States: An update. Am. J. Psychiatry 173, 18–26 (2016).
tions has been limited by stigma, insufficient medical education,
23. T. D. Saha, B. T. Kerridge, R. B. Goldstein, S. P. Chou, H. Zhang, J. Jung, R. P. Pickering,
and lack of resources. Ongoing research includes development of W. J. Ruan, S. M. Smith, B. Huang, D. S. Hasin, B. F. Grant, Nonmedical prescription opioid
novel analgesic approaches that have greater effectiveness for chronic use and DSM-5 nonmedical prescription opioid use disorder in the united states.
pain states (e.g., neuropathic and inflammatory pain), with a de- J. Clin. Psychiatry 77, 772–780 (2016).
creased burden of overdose risk and of abuse potential. Other 24. S. G. Mars, P. Bourgois, G. Karandinos, F. Montero, D. Ciccarone, “Every ‘never’ I ever said
came true”: Transitions from opioid pills to heroin injecting. Int. J. Drug Policy 25, 257–266
approaches may also focus on mitigating the development of opioid
(2014).
addiction, before the emergence of substantial neurobiological changes 25. M. Cerda, Y. Ransome, K. M. Keyes, K. C. Koenen, M. Tracy, K. J. Tardiff, D. Vlahov, S. Galea,
and compulsive-like drug-taking behaviors. Prescription opioid mortality trends in New York City, 1990-2006: Examining
the emergence of an epidemic. Drug Alcohol Depend. 132, 53–62 (2013).
SUPPLEMENTARY MATERIALS 26. H. Hedegaard, B. A. Bastian, J. P. Trinidad, M. Spencer, M. Warner, Drugs most frequently
Supplementary material for this article is available at http://advances.sciencemag.org/cgi/ involved in drug overdose deaths: United States, 2011-2016. Natl. Vital. Stat. Rep. 67, 1–15
content/full/5/10/eaax9140/DC1 (2018).
Table S1. Methadone maintenance treatment for opiate (heroin) addiction. 27. E. Wood, J. H. Samet, N. D. Volkow, Physician education in addiction medicine. JAMA 310,
Table S2. SNPs of genes related to endocrine stress responsivity that has been found to be 1673–1674 (2013).
associated with opioid addiction (101, 102, 116). 28. Surgeon General, Facing Addiction in America (2016); https://addiction.surgeongeneral.gov/
29. J. R. Morgan, B. R. Schackman, Z. M. Weinstein, A. Y. Walley, B. P. Linas, Overdose

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Fig. S1. Model for the contribution of pain states and pain treatment to the development of OUD.
following initiation of naltrexone and buprenorphine medication treatment for opioid
use disorder in a United States commercially insured cohort. Drug Alcohol Depend. 200,
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65–72 (2010). Acknowledgments: We would like to thank O. Levran for consultation with the genetics
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study identifies genes that may contribute to risk for developing heroin addiction. illustration, and reference support. Funding: We acknowledge funding for our laboratory
Psychiatr. Genet. 20, 207–214 (2010). research from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to M.J.K.),
102. O. Levran, O. Awolesi, S. Linzy, M. Adelson, M. J. Kreek, Haplotype block structure as well as the Robertson Therapeutic Discovery Fund, NIH NIDA grants DA018151 (subcontract
of the genomic region of the mu opioid receptor gene. J. Hum. Genet. 56, 147–155 to E.R.B.) and DA041730 (subcontract to B.R.). Author contributions: M.J.K. conceptualized
(2011). the paper and wrote portions related to the history and pharmacology of methadone and
103. N. Singla, H. S. Minkowitz, D. G. Soergel, D. A. Burt, R. A. Subach, M. Y. Salamea, buprenorphine, as well as the genetics work. E.R.B. also contributed to the conceptualization
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(TRV130), a novel -receptor G-protein pathway selective (-GPS) modulator, epidemic. B.R. wrote portions comprising the pharmacology and chemistry of the opioids. All
for the management of moderate to severe acute pain following abdominoplasty. authors put sustained effort into the illustrations, tables, references, and final composition.
J. Pain Res. 10, 2413–2424 (2017). Competing interests: All authors are inventors on a patent related to this work filed by
104. C. L. Schmid, N. M. Kennedy, N. C. Ross, K. M. Lovell, Z. Yue, J. Morgenweck, Rockefeller University (no. WO/2019/113419, published 13 June 2019). The authors declare that
M. D. Cameron, T. D. Bannister, L. M. Bohn, Bias factor and therapeutic window correlate they have no other competing interests. Data and materials availability: All data needed to
to predict safer opioid analgesics. Cell 171, 1165–1175.e13 (2017). evaluate the conclusions in the paper are present in the paper and/or in the references cited
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