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CLINICAL ISSUES: SUBSTANCE USE DISORDERS AND THE BODY doi:10.1111/add.15636

Opioid use disorder and the brain: a clinical perspective

Katherine Herlinger1 & Anne Lingford-Hughes2

MRC Addiction Research Clinical Training Programme, Imperial College London, London, UK1 and Division of Psychiatry at Imperial College London, London, UK2

ABSTRACT

Opioid use disorder (OUD) has gained increasing publicity and interest during recent years, with many countries describing
problems of epidemic proportions with regard to opioid use and deaths related to opioids. While opioids are not themselves
acutely neurotoxic, the chronic relapsing and remitting nature of this disorder means that individuals are often exposed to
exogenous opioids for lengthy periods of time (either illicit or prescribed as treatment). We are increasingly characterizing
the effect of such long-term opioid exposure on the brain. This narrative review aims to summarize the literature regarding
OUD and the brain from a clinical perspective. Alterations of brain structure and function are discussed, as well as neuro-
logical and psychiatric disorders in OUD. Finally, we review current and new directions for assessment and treatment.

Keywords Brain, cognition, neuroimaging, neurological disorders, opioid use disorder, psychiatric disorders, review,
treatment.

Correspondence to: Dr Katherine Herlinger MBChB, BSc (Hons), Clinical Research Fellow and MRC Addiction Research Clinical Training Programme (MARC)
Candidate, Neuropsychopharmacology Unit, Centre for Psychiatry, Imperial College London, 2nd Floor Commonwealth Building, Hammersmith Hospital
Campus, Du Cane Road, London W12 0NN. E-mail: k.herlinger@imperial.ac.uk
Submitted 1 February 2021; initial review completed 16 March 2021; final version accepted 18 June 2021

INTRODUCTION classification systems—the Diagnostic and Statistical

Opioid use disorder (OUD) is a chronic and relapsing
disorder of the brain caused by repeated exposure to
exogenous opioids. Clinically, individuals present with a
compulsion or craving to consume opioids, prioritizing
the use of opioids at the expense of other activities or
responsibilities, and a physiological dependence on opioids
which manifests as increased tolerance and an acute
withdrawal syndrome when opioid use is ceased. OUD
has garnered increasing publicity and concern recently,
with many countries describing problems of epidemic
proportions with regard to opioid use and deaths related
to opioids.
While opioids are not themselves acutely neurotoxic
(unlike alcohol), the chronic relapsing and remitting
nature of this disorder means that individuals are often
exposed to exogenous opioids for lengthy periods of time
(either illicit or prescribed as treatment). In this review
we describe our increasing knowledge of the effects of such
long-term opioid exposure on the brain from a clinical
perspective.
Definitions are key, and therefore it is therefore
important to acknowledge the recent changes and
consequent differences between the clinical diagnostic
Manual of Mental Health Disorders (DSM) [1] and the
International Classification of Diseases (ICD) [2]. OUD in
DSM-5 can be described as mild, moderate or severe. Mild
OUD is equivalent to opioid abuse and moderate and severe
OUD to opioid dependence in DSM-IV. ICD-11 remains
largely unchanged from ICD-10 for addiction disorders,
with categories of harmful opioid use and dependence.
Thus, OUD in DSM-5 is a continuum, rather than
separating-out substance ‘abuse’ and ‘dependence’, as in
ICD. In this article we focus upon and use the term ‘opioid
dependence’ rather than moderate/severe OUD.
It should also be noted that the terms ‘opiate’ and
‘opioid’ are often used interchangeably clinically. An opiate
is a naturally occurring substance that has been derived
from the flowering opium poppy plant (Papaver somniferum)
(e.g. morphine, codeine); an opioid is any substance,
naturally derived or synthetic, that acts upon opioid
receptors (e.g. heroin, fentanyl). Therefore OUD refers not
only to illicit heroin, but to any opioid including prescrip-
tion analgesics. In this review we will use the term ‘opioid’.
The opioid system is widely distributed in the brain and
plays important roles in several functions, including pain,
mood, reward and impulsivity. There are three main recep-
tors with their endogenous ligand, namely μ- and

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provided the original work is properly cited.

496 Katherine Herlinger & Anne Lingford-Hughes
β-endorphin, kappa and dynorphin and delta and enkeph-
alins. The μ receptor system is key in addiction as it medi-
ates reward, analgesia and also respiratory depression with
the kappa system contributing to dysphoria and aversive
states seen in withdrawal (see [3] for more information).
Opioid receptors are present in all the brain regions that
play an important role in addiction, e.g. mesolimbic path-
way, prefrontal cortex (see [4] for more information regard-
ing the neurocircuitry of opioid addiction) (Table 1).
EPIDEMIOLOGY
After cannabis, opioids are the second most commonly
used controlled substance world-wide, with an estimated
58 million past-year users of either illicit opioids (30.4 mil-
lion) or pharmaceutical opioids (28 million) in 2018. This
equates to a prevalence of approximately 1.2% of the global
population aged 15–64 years [5]. Compared with other il-
licitly used substances, opioids cause the greatest harm to
the health of users due to the severe health consequences
associated with their use. This is reflected in statistics indi-
cating that opioids account for 68% of all drug-related
deaths globally, approximately 128 000 yearly and 80%
of the 42 million years of life lost annually due to drug
use disorders [6].
Opioid-related deaths have been steadily increasing
since the 1990s, and many countries are now recording
record-breaking numbers of deaths. The areas most af-
fected are North America, Australasia, the Middle East
and South Asia, where opioid use is higher than the global
average. In North America and Australasia pharmaceuti-
cal opioids are the main opioid used, while in the Middle
East and South Asia heroin is predominantly used [5].
While illicit pharmaceutical opioid use remains relatively
low in Europe compared with heroin use (16.4% of overall
opioid use), its use has increased from 10% in 2015 [7,8].
Of growing concern is the number of deaths attribute to
fentanyl, an extremely potent synthetic opioid, which is in-
creasingly being added to heroin and counterfeit prescrip-
tion opioids and benzodiazepines. In 2018 it was
Table 1 Common drugs targeting opioid receptors and type of
effect.
Full agonists Partial agonists Antagonists
Heroin Buprenorphine Naloxone
Morphine Tramadol Naltrexone
Fentanyl
Methadone
Codeine
Hydrocodone
Oxycodone
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estimated that 67% of opioid deaths in North America
were attributed to fentanyl or fentanyl analogues [9].
The global prevalence of OUD is approximately equal in
males and females, with a prevalence rate of 276 per 100
000 for both sexes. This is consistent with prevalence rates
in North America: 1944 and 1780 per 100 000 for males
and females, respectively. However, OUD in Australasia ap-
pears to be more common in males than females, with
rates of 510 and 350 per 100 000, respectively. A similar
male predominance is seen in the United Kingdom, with
a prevalence of OUD at 518 and 320 per 100 000 for
males and females, respectively [6].
Regarding age, in North America the greatest past-year
use of non-prescribed opioids is in those aged 18–25 years,
with the highest death rates in males under 50 years [10].
In Australia illicit opioid use appears to be similar across all
age groups (14–65 years), with the highest death rates oc-
curring in males aged 35–44 years [11]. However, in
Europe, including the United Kingdom, drug deaths among
individuals aged over 50 years have increased by 75% be-
tween 2012 and 2018, reflecting an ageing
opioid-dependent cohort [8].
CLINICAL PRESENTATIONS AND
UNDERLYING MECHANISMS
Brain structure
Differences in grey and white matter have been found in in-
dividuals with OUD compared with healthy controls irre-
spective of the opioid abused. This may explain the range
of neural network dysregulation and cognitive impair-
ments seen in OUD (discussed below). Executive dysfunc-
tion in particular has been linked to frontal lobe
pathology; however, changes in other brain regions have
been reported [12].
Grey matter
A meta-analysis of neuroimaging studies in OUD identified
atrophy of the fronto-temporal region, including the supe-
rior frontal gyrus, inferior frontal gyrus, superior temporal
gyrus, orbitofrontal gyrus and insula in opioid-dependent
individuals compared with controls. Further regression
analysis has indicated that these grey matter changes were
negatively associated with opioid use duration and length
of abstinence [13]. More recently, a study of individuals
prescribed long-term opioid agonist treatment reported en-
largement of the right caudate nucleus and reduced vol-
ume in the right amygdala, anterior cingulate cortex and
orbitofrontal cortex. These changes were reportedly more
pronounced in those with longer duration of OUD [14].
Several causal mechanisms may account for these
changes, although hypoxia secondary to respiratory
Addiction, 117, 495–505

depression is most commonly cited (discussed in further de-
tail below).
There is mixed evidence to suggest that abstinence from
opioids allows for structural recovery of grey matter. In one
study investigating grey matter changes in heroin depen-
dence, decreased grey matter density was reported in the
middle frontal gyrus, superior frontal gyrus, posterior cin-
gulate and inferior occipital gyrus in the dependent group
(after 3 days’ abstinence) compared with controls. After
30 days’ abstinence there was no significant difference in
the superior frontal gyrus between heroin dependence
and control groups; however, other regions remained
unchanged. This highlights the potential for structural
changes to return to normal after a month of
abstinence [15]. Another study looking at longer-term
abstinence (average 4.5 years since opioid use or opioid
substitute treatment [OST]) in heroin-dependent individ-
uals noted decreased grey matter parieto-occipital region
without changes in the frontal region [16].
White matter
Significant damage to white matter is also seen in OUD in
several areas. One preliminary meta-analysis reported sig-
nificant reductions in fractional anisotropy in the bilateral
frontal subgyral regions extending from the limbic struc-
tures to the prefrontal cortex [17]. These changes have
been hypothesized as secondary to degradation of myelin
sheath through alteration of myelin-specific genes, mito-
chondrial dysfunction and neuronal apoptosis [18].
Cognition
It is widely accepted that impaired neuropsychological
function is associated with chronic opioid use. In particu-
lar, several aspects of executive functioning appear to be af-
fected. One meta-analysis reported that, compared with
age-, gender- and education-matched controls, current
chronic opioid users (mean 10.5 years using) have im-
paired verbal working memory, cognitive impulsivity and
cognitive flexibility with medium effect sizes. The studies
used for this analysis included users of a range of opioids,
including those used for analgesia and OST [19].
Of growing interest has been the effect of OST on cogni-
tive functioning. One meta-analysis of methadone-
maintained individuals reported neurocognitive deficits in
working memory, attention, cognitive flexibility and other
areas compared with controls [20]. In another study both
methadone and buprenorphine users exhibited deficits in
visuospatial working memory, which were strongly corre-
lated with higher mood and anxiety symptom scores
[21]. This highlights the potential need to pursue
abstinence-based therapy in OUD.
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Opioid use disorder and the brain 497
Following periods of abstinence enduring cognitive im-
pairments are reported, although not consistently, varying
with domain examined and the abstinence length. Mea-
sures of executive function, information processing speed,
verbal learning and non-verbal learning were reportedly
no different between abstinent opioid users and healthy
controls following 3–6 months abstinence, while
methadone-maintained individuals exhibited deficits in all
these domains [22]. In contrast to this, one meta-analysis
assessing decision-making in heroin users has shown that
chronic users exhibited consistent deficits on a range of
decision-making tasks, and that these deficits were still
present after 1.5 years abstinence [23]. Impairments of
these domains probably explain the high rates of relapse
in OUD, as poor decision-making will drive drug-seeking
and relapse.
Network dysregulation and relapse vulnerability
Several neural networks are thought to become dysregu-
lated as a consequence of chronic opioid abuse and to un-
derpin drug-seeking behaviour and vulnerability to relapse.
Non-drug reward
Over time, drugs of abuse are thought to hijack the reward
system, such that drug rewards are inappropriately
favoured over non-drug rewards (e.g. food, money). In
the absence of a drug reward, individuals are hypothesized
to be in a reward-deficient state where conventional re-
wards have lost salience, leaving the individual vulnerable
to drug use and to relapse [24].
While the dopaminergic mesolimbic system is seen as
an important pathway in addiction, it has been more diffi-
cult to show changes in the dopaminergic system in OUD
in humans similar to dopaminergic deficits seen in other
addictions [25–27]. This suggests that other systems may
be more important, such as the endogenous opioid system.
Our group and others using positron emission tomography
(PET) imaging have shown that alcohol and stimulants in-
crease endogenous opioids (endorphins) levels which are
associated with feelings of pleasure [28–30]. We have also
shown that endogenous opioid release is blunted in absti-
nent alcohol dependence and in pathological gamblers,
supporting the theory that addiction is associated with an
endorphin deficit in the reward pathway [31,32]. Also con-
sistent with this endorphin deficit is that PET studies have
shown higher opioid receptor availability in opioid addic-
tion [33].
Results from functional magnetic resonance imaging
(fMRI) studies have also indicated that chronic opioid use
is associated with decreased non-drug reward anticipation.
In one study, cocaine-dependent participants who were
maintained on methadone had decreased blood oxygen
level-dependent (BOLD) responses during anticipatory
Addiction, 117, 495–505

498 Katherine Herlinger & Anne Lingford-Hughes
reward to money in the posterior cingulate cortex,
precuneus, inferior frontal gyrus and dorsolateral prefron-
tal cortex (PFC) compared with controls. There was no sig-
nificant difference in BOLD response between the
cocaine-dependent group and the healthy controls or the
cocaine-dependent group taking methadone, suggesting
that this blunted response may be specific to methadone
dosing in the cocaine and methadone group [34]. Another
study reported no significant difference in BOLD activation
between methadone-maintained individuals and controls
during reward anticipation; however, there was a blunted
response in the dorsal caudate during the reward outcome
phase of the task compared with controls [35]. We have
similarly reported blunted striatal response to reward an-
ticipation in abstinent polydrug-dependent (including opi-
oid) individuals who relapsed at 1 year compared with
those who did not relapse [36].
Inhibitory control
Impulsivity refers to action in the absence of
pre-meditation or forethought. This can be divided into
several domains, including trait and choice impulsivity
and response inhibition. Elevated impulsivity is generally
associated with poorer psychopathological outcomes, in-
cluding increased risk of developing substance dependence
and relapse during abstinence [37]. Impairments of several
domains of impulsivity have been reported in OUD [38,39].
Interestingly, while heroin and methadone users exhibited
impairments of impulsivity measures compared with con-
trols, chronic opioid analgesic users did not differ in these
measures compared with controls. Therefore, while the
type of opioid may be important, impulsivity may only fea-
ture alongside the other complex behaviours seen with ad-
diction. The impairments seen were not associated with
other risky behaviours such as injecting [38].
Of growing interest has been the association between
blunted non-drug reward processing and increased impul-
sivity measures in substance dependence populations. Our
group has found that blunted activation of the ventral stri-
atum during non-drug reward anticipation correlates with
increased behavioural measures of impulsivity in abstinent
polydrug (including opioid) users [40]. In line with this,
heroin-dependent individuals display weaker tract strength
of the left striatum–medial orbitofrontal cortex compared
with matched controls. This deficit was also correlated
with higher behavioural impulsivity measures [41].
Drug cues and craving
In contrast to hyporesponsivity to conventional rewards,
hyperactivation to drug-related salient stimuli is seen in ad-
dictions, including OUD. Such stimuli or cues are com-
monly cited to trigger drug craving and relapse in
addiction [42].
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Notably, methadone-maintained individuals display
increased BOLD responses to drug versus neutral cues
in several regions, including the prefrontal cortex,
anterior cingulate cortex, thalamus and caudate [43].
Similarly increased activation of the orbitofrontal cortex
has been reported in heroin-dependent individuals
following administration of heroin, despite a reduction
in perceived craving [44]. These enduring brain
responses despite OST probably underpin continuing risk
of relapse.
There is also evidence to suggest this dysregulation
extends into abstinence in OUD. Using PET, we have
previously shown that abstinent heroin-dependent
individuals exhibit increased blood flow in the left
medial prefrontal cortex and left anterior cingulate cortex
(ACC) in response to a personalized autobiographical script
of a craving episode compared with a neutral episode. Du-
ration of abstinence was positively correlated with blood
flow in the ACC [45]. Functional magnetic resonance im-
aging (fMRI) studies have reported similar findings, with
abstinent heroin-dependent individuals exhibiting
increased BOLD signals to heroin cues in several regions.
Changes in craving here positively correlated with
activation in the nucleus accumbens, caudate, putamen
and ACC, while the abstinence duration positively
correlated with activation of the left caudate and right
parahippocampal gyrus [46].
Negative emotional processing
Chronic opioid use induces negative affect states,
including depression, dysphoria, anxiety and irritability,
most notably in acute withdrawal. This is thought to
be due to activation of the brain stress system, mediated
by the hypothalamic–pituitary axis and other hormones
[47]. As dependence develops, motivation to consume
addictive substances for their rewarding effects (positive
reinforcement) is replaced by consuming substances to
avoid withdrawal (negative reinforcement). For
example, heroin administration in heroin-dependent
individuals significantly decreases anxiety, cortisol and
adrenocorticotrophic hormone (ACTH) concentrations
to the levels found in healthy controls, while saline
administration leads to no such reduction [48]. This
avoidance of negative states confers vulnerability to
developing dependence and to relapse once substance
use has ceased.
fMRI studies have characterized this further using aver-
sive stimuli paradigms. When presented with fearful faces,
heroin-dependent individuals exhibit significantly in-
creased BOLD responses in the amygdala compared with
controls, and this is attenuated by administration of heroin.
Increased levels of state anxiety, ACTH and cortisol were
also seen [49].
Addiction, 117, 495–505

Neurological disorders
Hypoxic brain injury
Stimulation of μ opioid receptors in central chemorecep-
tors in the medulla result in respiratory depression [50].
In cases of opioid toxicity and overdose this can be fatal, es-
pecially if compounded with vomiting and aspiration, in-
creasing the likelihood of cardiorespiratory arrest. Studies
in rats have indicated that heroin-induced respiratory de-
pression leads to brain hypoxia, hyperglycaemia, a tran-
sient hypothermic response (due to heat dissipation
through vasodilation) followed by a delayed rebound hy-
perthermic response, which is destructive to neural cells
[51,52]. Similar responses are reported for other opioids,
including fentanyl, morphine and oxycodone, suggesting
that this is a common mechanism for opioids [53–55].
Whether fatal or not, opioid overdose results in
hypoxic/ischaemic changes with generalized cerebral oe-
dema, ischaemic neuronal damage and ischaemic neuro-
nal loss. There is evidence to suggest that these changes
result in decreased neuronal density, particularly in the
global pallidus (GP), with bilateral lesions seen 5–10% of
heroin users at autopsy [56,57]. Clinically, GP lesions can
present as acute cognitive impairment, personality
changes and parkinsonism [58].
Box 1. OUD and polysubstance use.
• Polysubstance abuse and dependence are extremely
common in OUD. Not only does this complicate treatment
and aftercare, but there can be serious clinical implications
during acute intoxication involving other sedative drugs
• Alcohol and benzodiazepines are commonly found as
concurrent substances in opioid deaths [59]
• Both alcohol and benzodiazepines enhance the effects of
inhibitory GABA neurones through GABAA receptors.
GABA neurones are found in the chemoreceptors in the
brain and can alter respiration as a result
• Sedation and muscle relaxant effects of these drugs may
increase the risk of airway occlusion and respiratory arrest
in opioid overdose [60]
• Concomitant tobacco use is also extremely common in
OUD. Smokers may have an increased risk of chronic pain,
may need higher opioid analgesic doses and are more likely
to be on long-term opioid therapy, increasing risk of
prescription opioid abuse [61]
OUD = opioid use disorder; GABA = gamma
aminobutyric acid.
Cerebrovascular disease
Opioids cause vasodilation and hypotension, and therefore
are unlikely to directly cause cerebrovascular disease
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Opioid use disorder and the brain 499
unless secondary to a hypoxic/ischaemic insult, as
described above [62]. Injecting heroin users are, however,
at risk of several cerebrovascular complications, including
ischaemic stroke, haemorrhagic stroke and subarachnoid
haemorrhage secondary to ruptured mycotic (infective)
aneurysms [63]. These are generally due to infective
thromboembolism secondary to infective endocarditis or
an embolus caused by substances such as talcum powder
added to dilute heroin by dealers. Vasculitis and
arteritis have also been implicated [64]. Intravenous users
who share or use non-sterile paraphernalia are more at
risk, as are individuals with HIV (see Box 2). It has also
been hypothesized that the recurrent hypotension
and hypoxaemia seen with heroin use may lead to
pathological cerebral vascular wall remodelling and
weakening [65,66].
Box 2. OUD and HIV
• Injecting drug users are estimated to be 22x more likely to
acquire HIV compared to the general population [67].
Globally the most widely injected drugs are opioids and
stimulants which are often used together [68].
• Whilst all opioids do not share the same
immunosuppressant effects, there is evidence to suggest
that chronic use of opioids causes immunosuppression
[69]. This compounded with HIV leads to an increased risk
of opportunistic infection and neurological sequalae.
• HIV is also thought to cause neurodegeneration and
neuronal injury due to persistent activation of glial cells
[70]. There is evidence to suggest that opioid use
accelerates this neuropathogenesis [71]. The prevalence of
cognitive disorders amongst individuals with HIV ranges
from 20–-60%, with mild-–moderate severity and this may
be increased with concurrent opioid use [72].
Intracranial infections
Intracranial infections such as meningitis, encephalitis and
brain abscess can all occur as a result of injecting opioids
and atypical organisms should form part of the differential
diagnosis [73]. Modulation by HIV or other immunosup-
pressive diseases should also be considered (see Box 2).
Dementia
As previously stated, OUD is associated with cognitive im-
pairments that may persist into abstinence. In addition to
frequent and recurrent hypoxic–ischaemic injury, OUD
has also been associated with increased microglial activa-
tion which suggests a neuroinflammatory response [74].
Both these factors may increase predisposition to develop-
ing neurodegenerative disease in later life. Post-mortem
studies have revealed that young opioid users (age
Addiction, 117, 495–505

500 Katherine Herlinger & Anne Lingford-Hughes
< 40 years) have increased hyphosphorylated tau contain-
ing neurofibrillary tangles with more brain areas affected
compared to age-matched controls [75,76]. Increased
beta-amyloid precursor proteins have also been cited, but
this is not consistent throughout the literature [75,77].
In one study, the level of tau proteins seen in the OUD
matched those of elderly controls [78]. Both proteins are
associated with neurodegenerative conditions including
Alzheimer’s disease and frontotemporal dementia, al-
though this relationship is still not fully understood.
Box 3. Rare neurological presentations in OUD
Toxic leucoencephalopathy
Heroin-induced leucoencephalopathy is a rare toxic
leucoencephalopathy which is thought to be caused by
contaminants added to illicit heroin [79]. Toxic
leucoencephalopathy caused by other opioids is even rarer
still [80]. Clinically this condition usually presents as three
stages of irreversible progressive neurological symptoms
occurring over weeks/months. There have also been cases
reported with abrupt symptom onset, presenting as
confusion, behavioural changes, ataxia, stupor and
dementia [81]. As a result there have been instances
where cases are misdiagnosed as psychiatric patients, and
it is likely that this is a common occurrence [82]
Movement disorders
Myoclonus (quick, involuntary muscle jerks) are known
side-effects of high-dose opioid analgesics and as a result are
often encountered in the palliative care setting. The cause
is thought to be neuroexcytotoxicity secondary to an
accumulation of several metabolites, such as morphine-3-
glucuronide or hydromorphone-3-glucuronide, rather
than due to the opioids themselves [83]. As a result,
opioid-induced myoclonus does not occur with all opioids,
but depends upon individual metabolites. Similarly,
methadone-induced chorea is a rare movement disorder
that resolves after switching to an alternative opioid,
suggesting a mechanism that is not opioid-specific [84,85]
OUD = opioid use disorder.
Psychiatric conditions
Mood and anxiety disorders
OUD is associated with an increased prevalence of mood
and anxiety disorders compared with that of the general
population. Clinically, most opioid users will present with
symptoms of anxiety and depression requiring assessment.
It should be remembered that opioids are potent anxio-
lytics. The prevalence of depression in opioid users is
thought to range between 10 and 30% for current inci-
dence and 19 and 74% for life-time incidence [86]. Anxiety
disorders are also common; one study estimated 46% of
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their methadone-maintained cohort suffered with an anx-
iety disorder [87].
Post-traumatic stress disorder (PTSD)
OUD has the highest prevalence of PTSD compared with all
other substances of abuse. An estimated 14–19% life-time
incidence and 20–31% current prevalence of PTSD has
been reported for heroin dependence [88]. Not only is it
likely that individual may turn to opioids as a result of trau-
matic experience(s), often in childhood, but individuals are
also at an increased risk of experiencing trauma due to the
high-risk life-style associated with opioid use [89].
Psychotic disorders
An increased prevalence (~3–6%) of OUD with schizophre-
nia and schizotypal disorders compared with the general
population has been reported [90,91]. In particular, kappa
receptors have been implicated in schizophrenia, and
kappa opioid receptor (KOR) agonists have psychotomi-
metic effects in healthy individuals [92]. Previous trials of
medications that antagonize kappa receptors such as nal-
oxone, naltrexone and buprenorphine have improved both
positive and negative symptoms in patients with schizo-
phrenia, although results have been mixed [92]. Opioids
are also associated with an increased risk of conversion to
schizophrenia in high-risk individuals (i.e. high genetic
risk, schizotypal personality disorder, subpsychotic symp-
toms, etc.) [93]. Studies have indicated that this risk is com-
parable or higher than for cannabis, stimulants and
alcohol [94,95].
ASSESSMENT AND TREATMENT
Treatment for opioid dependence may vary depending
upon the opioid used and the individual’s treatment goals.
Following assessment, ongoing treatment can be broadly
categorized as either harm reduction or abstinence-
orientated. In heroin dependence, early access to OST med-
ication is a key factor in engagement; however, developing
a strong therapeutic alliance is thought to be more impor-
tant for long-term recovery [96].
Psychosocial interventions
Psychosocial interventions are extremely useful for build-
ing a therapeutic relationship, identifying specific goals
and risks and creating a care-plan with the patient to en-
sure that care can be delivered in a structured and cooper-
ative manner. Motivational interviewing, contingency
management, cognitive behavioural therapy, cue exposure
therapy, social behaviour network therapy and couples
therapy are all interventions that can be beneficial during
the initial stabilization period. Ongoing engagement will in-
clude one-to-one keywork sessions in addition to a group
Addiction, 117, 495–505

recovery programme or mutual support group. Treatment
in combination with mutual support groups has been asso-
ciated with better outcomes, improved functioning, im-
proved long-term recovery rates and an overall reduction
in cost to society [97].
Pharmacological interventions
Pharmacological interventions for OUD can be used as sub-
stitutes for illicit opioids, for detoxification and for relapse
prevention [98]. For substitution, methadone, a μ opioid
receptor (MOR) agonist, is the most commonly used opioid
substitution medication globally [99]. Buprenorphine is
also commonly used and is a long-acting partial MOR ago-
nist. Buprenorphine has high affinity at the MOR, so in the
presence of other opioids it will displace and antagonize
their effects. Therefore, if buprenorphine is consumed in
the presence of another opioid agonist, withdrawal is
precipitated.
There is no evidence to suggest that detoxification is
better tolerated or provides better outcomes from either
methadone or buprenorphine [98]. Lofexidine, an
alpha-2 agonist, can be used to support detoxification by
attentuating the noradrenergic storm seen in opioid with-
drawal [98]. Naltrexone, a long-acting non-selective an-
tagonist, blocks the effects of illicit opioids and is approved
for relapse prevention, although is rarely used clinically
[100,101].
In cases of acute overdose the fast-acting opioid
receptor antagonist, naloxone, is used parenterally to
rapidly reverse opioid-induced respiratory depression and
is therefore life-saving in such situations [102]. As
many people with OUD have witnessed an overdose, in
some regions those with OUD and/or family/friends are
given ‘take-home’ naloxone for use while calling for
medical help.
PROGNOSIS
OST, in combination with psychosocial interventions,
remains the mainstay of treatment OUD. In heroin
dependence, OST has been effective in improving health
and social functioning, particularly concerning infection
rates and survival from HIV and hepatitis [98,103,104].
There is evidence to suggest that individuals who were
initially introduced to opioids via prescription have better
health outcomes than those who were introduced to
opioids illicitly [105].
Despite this improvement, prognosis in OUD remains
poor. For example, the most recent data from England in-
dicate that individuals with opioid dependence have the
lowest rate of ‘successful exits’ (i.e. leaving treatment
drug-free) in 2018–19 at 25%. For comparison, the
© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.
13600443, 2022, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/add.15636 by Cochrane Romania, Wiley Online Library on [15/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Opioid use disorder and the brain 501
highest rate of ‘successful exits’ was for alcohol at 60%
in 2018 [106].
Box 4. Dual diagnosis and OUD
• ‘Dual diagnosis’ is a term used to describe patients with
substance dependence and a co-occurring mental health
disorder
• Dual diagnosis patients have poorer outcomes compared to
other psychiatric patients, with polypharmacy and
medication adherence commonly cited as ongoing issues
[87]
• Integrative approaches to treatment with all disorders
being considered are essential in order to improve
outcomes for these patients [107]. Nevertheless,
establishing an individual on OST is a critical aspect to
recovery
OUD = opioid use disorder; OST = opioid substitute
treatment.
NEW DEVELOPMENTS AND FUTURE
DIRECTIONS
As detailed above, understanding the underlying neurobi-
ology of OUD has been transformative for informing cur-
rent treatment and improving outcomes. Nevertheless,
despite the fact OUD is characterized by periods of relapse
there are still few abstinence aids or relapse prevention
medications available. Even with the availability of naltrex-
one, its augmentation of brain processes in opioid addicts is
poorly understood. This reflects the broad trend both clini-
cally and in research of a heavy reliance upon OST, with
limited attention paid to either opioid detoxification or re-
lapse prevention and lack of innovations in recent decades.
As a result, the needs of patients with OUD are not being
met with the current treatment options available. This is
of particular importance in countries with a growing age-
ing opioid-dependent population who are more likely to
have significant health consequences as a result of chronic
opioid use and who would probably benefit from detoxifica-
tion and abstinence [3].
Imaging research is now focusing upon identifying
neural ‘biomarkers’, which may clarify under what cir-
cumstances treatments are effective as well as expose fac-
tors affecting individual vulnerability to relapse [108].
This will provide evidence to inform treatment (pharmaco-
logical and psychological) development, as well as
informing how to use treatments more effectively (i.e. pre-
cision medicine) in the future.
The National Institute on Drug Abuse (NIDA) recently
published its top 10 ‘medication development priorities in
Addiction, 117, 495–505

502 Katherine Herlinger & Anne Lingford-Hughes
response to the opioid crisis’ that include orexin, kappa opi-
oid, nociceptin opioid peptide, GABA-B, muscarinic M5,
glutamate (AMPA, mGluR2/3), ghrelin, dopamine D3
and cannabinoid [109]. This focus upon ‘the development
of novel therapeutics to treat opioid overdose and OUD’ is
very welcome, and reflects awareness of the need for inno-
vation within the field. Furthermore, medications already
exist for these targets but are licensed for another indica-
tion, so ‘repurposing’ such medications will hopefully speed
translation and provide more tools for tackling the current
crisis.
Declaration of interests
K.H. is currently funded by the Medical Research Council
(MRC) Addiction Research Clinical (MARC) Fellowship to
complete her PhD. A.L.-H. has received support from GSK
for research studies, grants and personal fees from
Lundbeck; personal fees from Silence Therapeutics,
Janssen-Cliag, Pfizer, Sanofi-Aventis; consultancy but no
fees from Opiant, Lightlake, Astra Zeneca and support for
a PhD from Alcarelle have been received outside the sub-
mitted work.
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