The Use of Oxytocin for the Treatment of Opioid Use Disorder

Abstract

Nearly 27 million people have an opioid use disorder (OUD) according to the 2016 Global Burden of Disease study, most of which occur in the US where opioids are a common class of medication used to treat acute and chronic pain. In 2016 alone, more than 60 million patients had at least one prescription for opioids filled or refilled. Over the past decade, prescription rates have risen astronomically and have created an epidemic in the US dubbed the “opioid crisis.” In this regard, there has been an increase in overdoses and OUD diagnoses. Several studies have found dysregulation of balance between several neurotransmitters involved in the neural circuitry that subserves several behavioral domains, such as reward recognition, motivation, learning, and memory, affect, stress, and executive function, that contribute to the manifestation of craving. On the horizon is a new treatment approach consisting of the neuropeptide oxytocin, which may be involved in the overlapping mechanisms of stable attachment formation and coping with stress. Through this mechanism, it can shift processing from novelty and reward-seeking to an appreciation of familiarity and thus reduce stress and increase resilience in the face of addiction. It has been hypothesized that there is a connection between the glutaminergic and oxytocinergic systems, making oxytocin a possible therapeutic agent in reducing drug-induced actions seen in OUD patients. This manuscript will review the potential and feasible use of oxytocin in treating OUD.

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Vol.:(0123456789)
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Current Pain and Headache Reports (2023) 27:89–97
https://doi.org/10.1007/s11916-023-01105-6
ACUTE PAIN MEDICINE (R URMAN, SECTION EDITOR)
The Use ofOxytocin fortheTreatment ofOpioid Use Disorder
AmberN.Edinoff1,2· SaveenSall3· LaurynG.Honore4· RossM.Dies4· AlexaR.Zaheri4· SaurabhKataria5·
EricD.Jackson6· SaharShekoohi7· ElyseM.Cornett2,7,8· KevinS.Murnane2,3,8· AdamM.Kaye9· AlanD.Kaye2,7
Accepted: 21 February 2023 / Published online: 6 April 2023
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023
Abstract
Nearly 27 million people have an opioid use disorder (OUD) according to the 2016 Global Burden of Disease study, most of
which occur in the US where opioids are a common class of medication used to treat acute and chronic pain. In 2016 alone,
more than 60 million patients had at least one prescription for opioids filled or refilled. Over the past decade, prescription
rates have risen astronomically and have created an epidemic in the US dubbed the “opioid crisis.” In this regard, there has
been an increase in overdoses and OUD diagnoses. Several studies have found dysregulation of balance between several
neurotransmitters involved in the neural circuitry that subserves several behavioral domains, such as reward recognition,
motivation, learning, and memory, affect, stress, and executive function, that contribute to the manifestation of craving. On
the horizon is a new treatment approach consisting of the neuropeptide oxytocin, which may be involved in the overlapping
mechanisms of stable attachment formation and coping with stress. Through this mechanism, it can shift processing from
novelty and reward-seeking to an appreciation of familiarity and thus reduce stress and increase resilience in the face of
addiction. It has been hypothesized that there is a connection between the glutaminergic and oxytocinergic systems, making
oxytocin a possible therapeutic agent in reducing drug-induced actions seen in OUD patients. This manuscript will review
the potential and feasible use of oxytocin in treating OUD.
Keywords Opioids· Opioid use disorder· Dependence· Addiction· Oxytocin
Introduction
In the US, opioids are a common class of medication used
to treat acute and chronic pain. In 2016 alone, more than
60 million patients had at least one prescription for opi-
oids filled or refilled [1]. Opioids work by acting on opioid
receptors found throughout the body, and these receptors are
found anywhere from the GI tract to the brain. These pain
medications work by attaching to these receptors and thus
reducing the perception of pain. However, opioids have a
large addictive potential and should not be used in the long
term, outside of cancer pain. Despite this, prescription rates
have risen astronomically and created an epidemic in the
US dubbed as the “opioid crisis” and has seen an increase in
overdoses and opioid use disorder (OUD) diagnoses.
OUD has emerged as one of the most profound public
health crises. In 2015 alone, 52,000 people died of drug
overdoses, with over 30,000 dying from opioid drugs [2].
OUD is treatable with episodes of remission and recur-
rence characterized by loss of control of opioid use. The
pathophysiology is initially driven by the activation of brain
reward neurocircuits while increasingly engaging anti-
reward neurocircuits that drive adverse emotional states and
relapse [3]. Individuals taking opioids can become tolerant,
which later develops into dependence and addiction. Well-
conducted trials have demonstrated that long-term opioid
agonist therapy with methadone and buprenorphine has effi-
cacy for OUD treatment and can save lives [4]. However,
many individuals remain refractory to these therapies, and
there is a great need for new treatment options, such as new
formulations and drug targets for OUD [5, 6]. The clini-
cal need for new treatments for OUD has been worsened in
the era of fentanyl, however, as the existing medications are
starting to have even more limitations on their outcomes for
the treatment of OUD.
This article is part of theTopical Collection on Acute Pain Medicine
* Sahar Shekoohi
sahar.shekoohi@lsuhs.edu
Extended author information available on the last page of the article

90 Current Pain and Headache Reports (2023) 27:89–97
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On the horizon is a new treatment approach consisting
of the neuropeptide oxytocin, which may be involved in the
overlapping mechanisms of stable attachment formation and
coping with stress. Through this mechanism, it can shift pro-
cessing from novelty and reward-seeking to an appreciation
of familiarity and thus reduce stress and increase resilience
in the face of addiction. This neurobiological model has
been gaining traction as a potential method for increasing
the resilience patients face while undergoing the addiction,
dependence, and stress of OUD [7]. If untreated, OUD is
associated with significant morbidity and mortality. It is
vitally important that new, effective treatments be imple-
mented, to combat, improve, and prevent the current opioid
epidemic, which has substantially strained individual health,
families, and financial burdens. This manuscript will review
the potential and feasible use of oxytocin in treating OUD.
Opioid Use Disorder Overview andEpidemiology
inBrief
It is now a well-known fact that the epidemic of opioid use
has led to a crisis in many countries and has become a topic
of debate in the United States (US) for more than two dec-
ades now [4, 8, 9]. Nearly 27 million people were identified
as having some sort of OUD in the 2016 Global Burden
of Disease study, and the peak prevalence was observed in
the US [4, 10]. According to the 2017 census, people aged
25–44 had the recorded highest rates of overdose deaths
[11]. To add to that, approximately 3% of the children who
were < 17years of age lived with at least one parent with a
history of substance use disorder between 2009 and 2014
[12]. This calamity of OUD has unfolded in such a way that
almost 50,000 deaths in 2017 were related to opioid over-
dose [13].
Insights intoCraving: anOverview
oftheNeurobiology andNeuropathology
The opioid crisis has led to the curiosity to dig deep into
the understanding of craving and the mechanisms of addic-
tion. Several studies have found a dysregulation of balance
between several neurotransmitters involved in the neural
circuitry that subserves several behavioral domains, such
as reward recognition, motivation, learning, and memory,
affect, stress, and executive function, that contribute to the
manifestation of craving [14]. Two well-known models,
studied by Robinson and Koob, respectively, are based on
positive and negative reinforcement and their role in drug
seeking and drug taking. Several changes in dopamine neu-
ral circuitry result in a hyper-dopaminergic state after con-
sistent opioid use, leading to enhanced craving [15, 16]. On
the other hand, negative reinforcement drives the develop-
ment of an “anti-reward” state as a driving force in OUD.
For example, people combating acute or chronic pain use
an opioid, which gives them relief from their pain almost
instantly, thus creating a seeking behavior every time they
experience pain [14, 17]. Once physiologic dependence
occurs, negative reinforcement also results from the dis-
comfort and sickness that come with the withdrawal from
opioids. The use of opioids mitigates these symptoms, and
therefore, they are removed, and the opioid use is negatively
reinforced.
Current Treatment ofOpioid Use Disorder
OUD affects 26 million individuals worldwide and thus
is deemed a “worldwide disease” [18]. Due to this, treat-
ment efforts must focus on expanding access to lifesaving,
evidence-based OUD pharmacotherapy. Pharmacotherapy is
the evidence-based mainstay of OUD treatment, and many
studies support its integration into primary care settings
[19]. Currently, there are three FDA-approved medications
for OUD: the full opioid agonist methadone, the partial opi-
oid agonist buprenorphine, and the opioid receptor antago-
nist naltrexone. Methadone works by binding and fully acti-
vating the opioid receptor.
Regarding OUD, methadone prescriptions are primar-
ily for detoxification and maintenance therapy. Methadone
is an effective agent for opioid withdrawal symptoms such
as tachycardia, diaphoresis, nausea, and vomiting. Fur-
thermore, it shows increased retention in treatment and
decreased mortality rates [20].
Buprenorphine is a partial agonist of the opioid receptor,
and it binds with high affinity but only partially activates
the opioid receptor. Related to these pharmacological prop-
erties, buprenorphine can mitigate negative reinforcement
related to withdrawal of opioids and significantly decrease
the positive reinforcing effects of full efficacy opioids, such
as heroin or fentanyl.
Compared to methadone, buprenorphine is considered
the “medication of choice for many patients with OUD”
due to its decreased risk of adverse effects [21]. Although
preferred by many patients related to the flexibility of the
treatment setting (i.e., can be prescribed in office-based set-
tings), buprenorphine is seen with limited use due to a lack
of physician certification [21]. Physicians, however, now can
treat under 30 patients without the certification. However,
there are still issues with the pharmacy recognizing these
prescriptions due to the lack of the x waiver linked to the
physician’s prescribing abilities, as well as a lack of training
for clinicians in general in the ever-changing clinical, regula-
tory, use patterns, emerging designed drugs, and legal issues
around opioids [22].
Lastly, naltrexone is an opioid receptor antagonist, and
this means it fully binds and inhibits opioid receptors. The

91Current Pain and Headache Reports (2023) 27:89–97
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idea is to block opioids from inducing their intoxicating and
rewarding effects, which can be affected in short-term and
long-acting formulations [6]. One stipulation regarding this
treatment is patients must have undergone complete detoxi-
fication of opioids before being administered naltrexone to
prevent precipitated withdrawal. In many studies, naltrexone
injections are shown to be just as efficient as buprenorphine
in patients that underwent complete detox before its initia-
tion. However, it is often difficult for those with active OUD
to fully complete the detoxification requirement needed
before the naltrexone injections [21].
Methadone for years was the gold standard of treatment.
Still, it came with heavy federal regulations requiring many
early in treatment to present to the clinic for their daily dose.
Suboxone changed the clinical scenario since it allowed for
office-based treatment and freed patients from presenting
to a clinic daily. The clinical conditions changed again with
the introduction of fentanyl as an illicit drug. It was previ-
ously the case that 60mg of methadone was enough to stave
off the cravings and withdrawal of heroin users. However,
since fentanyl is more potent than heroin, patients are now
requiring higher doses of methadone to have the same effect.
The current titration schedule is starting at 30mg and titrat-
ing methadone of 5 to 10mg every 3 to 5days, which may
not be fast enough for those who use fentanyl to reach that
effective dose for cravings in a quick fashion [23]. This can
lead to people returning to use and leaving treatment. It can
also lead to people needing larger doses of methadone and,
therefore, could lead to more adverse events for patients.
Suboxone comes with its challenges, as inductions are
harder to perform with fentanyl. Since fentanyl is more lipo-
philic, it distributes to the peripheral tissues dose-depend-
ently [24]. This causes more precipitated withdrawal in
fentanyl use, and can make patients weary of starting this
medication [24]. This is why, at present, newer treatments
are so greatly needed to help those who suffer from OUD,
and oxytocin could potentially be one of them.
Mechanism ofAction ofOxytocin
Oxytocin is a neuropeptide associated with multimodal roles,
including childbirth, lactation, social interactions, reward,
bonding, and even decisions and memories. Oxytocin is ini-
tially produced in the paraventricular and supraoptic nuclei
of the hypothalamus and eventually stored in the posterior
pituitary gland. As a hormone, it will be secreted into the
bloodstream via signals from the central nervous system.
Oxytocin also undergoes central release in the brain, includ-
ing in dopamine brain circuitry important for opioids. Once
released, the sole oxytocin receptor is widely expressed in
the brain, including in the amygdala, which is important
for stress and anxiety, and the nucleus accumbens, which is
important for positive reinforcing effects. The wide expres-
sion of the oxytocin receptor contributes to its diverse roles
in physiology, emotions, and social functions.
More recently, oxytocin has been undergoing research
on its involvement as a potential therapy for addiction,
such as methamphetamine use [25]. Not much is thor-
oughly understood about how oxytocin particularly exerts
its effects. What is understood is that the many facets of
oxytocin are, on a molecular basis, brought about by a single
receptor [26]. The oxytocin receptor, a 7-transmembrane G
protein–coupled receptor capable of binding to Gαi or Gαq
proteins, activates a set of signaling cascades, such as the
MAPK, PKC, PLC, or CaMK pathways, which converge on
transcription factors like CREB or MEF-2 [26]. This signal-
ing cascade has been a major target for better understanding
the oxytocin system on a basic level.
Furthermore, research is looking into how glutamate is
related to oxytocin. Glutamic acid is one of the most excita-
tory neurotransmitters in the central nervous system, and it
also has a major role in how rewarding stimuli are processed.
It has been hypothesized that there is a connection between
the glutaminergic and oxytocinergic systems, making oxy-
tocin a possible treatment agent in reducing drug-induced
actions seen in OUD patients [27]. More evidence suggests
a connection between oxytocin and opioids. A 1995 study
examined the connection in which endogenous opioids
regulated oxytocin levels in morphine-tolerant rats. Dur-
ing chronic morphine exposure, tolerance and dependence
develop in oxytocin neurons, thus reducing the excitability
of oxytocin neurons and the availability of oxytocin recep-
tors. As a result, the connection between oxytocin and opi-
oids needs to be explored more to become a viable treatment
option for OUD patients [28].
Preclinical andClinical Studies
Animal Studies
A quantitative animal study was performed over 27days
on Sprague–Dawley rats, including 48 male rats weigh-
ing between 200 and 250g [29]. This study was conducted
using the conditioned place preference (CPP) assay, a widely
used behavioral assay of the appetitive conditioned effects of
drugs. It was shown in previous studies that giving oxytocin
directly into the brain ventricles could block the oxycodone
CPP [30], which is an important finding as oxycodone is
one of the more widely medically used and illicitly diverted
opioids [31]. The rats were housed in cages with a 12:12
light/dark cycle. The rats were randomly divided into four
groups: saline + artificial cerebrospinal fluid (aCSF) (Sa),
oxycodone + aCSF (Oa), oxycodone + oxytocin (OO), and
saline + oxytocin (SO). Oxycodone and other injections

92 Current Pain and Headache Reports (2023) 27:89–97
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were administered to the rats through intracerebroventricu-
lar injections targeting the right lateral ventricle [29]. After
the injections, rats were given 7days to recover and then
underwent habituation to the conditioning chamber com-
posed of two compartments (the side paired with saline and
the side paired with oxycodone). If any rats preferred one
side of the chamber, they were eliminated. On days 4, 6, 8,
and 10, groups Oa and OO were injected with oxycodone,
while groups Sa and SO were injected with saline. The rats
were then conditioned to associate one side of the chamber
with being given the injection. Half of the rats were placed
in the side of the chamber with vertical stripes, while the
other half were placed in the side with transverse stripes
after their respective injections. Every rat, on days 5, 7, 9,
and 11, was injected with saline and placed in the oppo-
site chamber. Then, for another 7days, the rats were free
from any injection and placed back in the same box in which
they were originally housed. Groups OO and SO were then
administered oxytocin while groups Oa and Sa were admin-
istered aCSF. The rats were then given the opportunity to
explore both sides of the chamber. After this experiment,
the rats’ brains were harvested for testing. The rats’ RNA
and DNA were extracted from the dorsal hippocampus to
be tested for both DNA methylation and mRNA expression
using transmission electron microscopy. Methylation of the
DNA was determined by using a 5-(h)mC. The results of the
study showed that the saline-treated group spent much less
time in the drug-associated side of the chamber compared
to the oxycodone groups (Oa and OO). Though, after the
administration of oxytocin, there was an overall decrease in
the amount of time spent in the drug-paired side [29]. It was
found that treating the rats with oxytocin before the oxyco-
done entirely blocks oxycodone-induced changes in synaptic
function. However, using oxytocin by itself to treat the rats
after oxycodone administration showed no capacity to block
oxycodone-induced place conditioning [29].
An additional animal study was performed on 309
7-week-old male C57BL/6J mice weighing an average of
20–25g [32]. These mice were used in two related studies
reported in the same manuscript. The mice were exposed
to a 12:12-h light/dark cycle and were allowed to habitu-
ate to their environment for 7days before the experiment
began. After chronic saline or chronic morphine treatment,
mice were left untreated in their cages for 7days to induce
withdrawal symptoms. A group of 5 from the 309 mice
were then euthanized, and their brains were analyzed for
oxytocinergic receptor binding. Another group of mice of
the 309 was euthanized, and their brains were observed for
changes in oxytocin peptide levels. In the same experiment,
the CPP assay was used to test a different small group of
mice to examine the effects of carbetocin (CBT), an oxy-
tocin analog, on morphine-seeking behavior. A group of 14
mice was pretreated with saline, while the other group of 12
was pretreated with CBT. The mice were then put through a
6-min swimming stress test and placed directly into the CPP
apparatus for 20min.
The group of mice administered morphine demonstrated
an increase in oxytocinergic receptor levels in different areas
of their brains compared to the saline group [32]. These
areas included the piriform cortex, medial septum, and verti-
cal limb of the diagonal band of Broca, as well as the ante-
rior olfactory nucleus ventral and lateral [32]. In the second
experiment, using the forced swimming assay, a reduction
in swimming is used as a measure of depressive-like behav-
ior or alternatively described as behavior despair, which is
operationally assessed by a decrease in the amount of time
from the beginning of the swim to each mouse’s first attempt
to stop swimming (latency to stop swimming) as well as a
decrease in the amount of time each mouse spent swimming
[32]. An additional measurement of anxiety-like behavior
included looking at the number of fecal boli produced by
each mouse, with an increase in fecal boli indicating more
anxiety-like behavior [32]. The study found that the mice
given CBT and morphine showed less depressive-like fea-
tures than those given the saline and morphine; the mice
demonstrated increased swim times, decreased fecal boli
production, and an increased latency time to motionless
floating behavior [32]. The mice given the CBT and mor-
phine showed results similar to those given saline and those
given saline with CBT [32].
Human Studies
A previous study conducted in Maine included opioid-
dependent mothers along with their infants and non-opioid-
dependent mothers along with their infants [33]. Every
infant was between 4 and 6months of age. Fourteen dyads
were recruited, which included seven dyads from opioid-
dependent mothers and seven from non-opioid-dependent
mothers. The opioid-dependent mothers were recruited from
a local opioid treatment program while the other group was
recruited from a family medicine practice and a Women,
Infants, and Children program. Groups were tested monthly
for alcohol and drugs [33, 34]. Both groups were matched
for socioeconomic status (SES), verbal ability, psychiat-
ric status (beyond substance use disorder), and substances
including alcohol, tobacco, and cannabis use during preg-
nancy [33]. Dyads of premature infants (born at < 37weeks)
were avoided.
A sample salivary collection was obtained from all of the
mothers and was analyzed by ELISA methods to determine
oxytocin levels in each mother. Upon arrival, each mother
was instructed to complete a series of surveys regarding
their infant. The mothers were also instructed to participate
in the Still Face paradigm. Before participating in the Still
Face paradigm, the mothers are separated from their infants

93Current Pain and Headache Reports (2023) 27:89–97
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Table 1 Summary of preclinical and clinical studies regarding oxytocin and opioids
Author/date Focus Groups studied Results and findings Conclusions
Daigle etal. (2019) [33] To find out “the impact of continued
maternal opioid treatment in the post-
natal period on maternal responsiv-
ity” [33]
14 dyads of mother and infant
Opioid-dependent mothers were
recruited from local opioid treatment
programs
Opioid independent mothers (demo-
graphically similar) recruited from
EMMC family medicine practice and
WIC program
In the opioid-exposed group, oxytocin
difference from pre-exposure to
their infant to post-exposure to their
infant was smaller (Mdiff = 11.32,
SD = 33.81) than the non-opioid
group (Mdiff = 40.01, SD = 20.51;
t(12) = 1.93, p = 0.03, d = 1.03). Non-
opioid group mothers who showed a
higher post-exposure oxytocin level
were also associated with a more
positive post-exposure reaction (dura-
tion: r (12) = 0.43, p = 0.03)
The trial supports that opioid main-
tenance therapy correlates with
decreased positive emotional respon-
siveness. Moreover, opioids potentially
influence oxytocin levels causing this
decreased response
Woolley etal. (2016) [36] To explore “the tolerability of intrana-
sal oxytocin and its effects on heroin
craving” [36]
36 male patients with a history of her-
oin abuse recruited from SFVAMC
ORT clinic on a stable does of metha-
done or buprenorphine
34 non-heroin user males recruited
from Craigslist in the San Francisco
Bay Area
The patients on opioid replace-
ment therapy showed significant
association with feelings of “bad”
[Z = −2.19, p = 0.029] and “high”
[Z = −1.97, p = 0.049] drug effects
post oxytocin administration relative
to no oxytocin administration. There
was no significant reduction in opioid
cravings due to administration of
intranasal oxytocin
The effects of single-dose oxytocin
administration on drug effects were
attributed to outlier effects rather than
reduced opioid tolerance
Moeini etal. (2019) [35] To observe how the administration of
oxytocin affects withdrawal symp-
toms along with “craving, anxiety
scores, and neuroadaptive stress
hormones levels in the male heroin-
dependent individuals” [35]
58 males (20–60years old) were
recruited and selected via a blindness
method from an inpatient treatment
center
Subjects performed a period of absti-
nence in which no illicit drugs were
to be consumed, verified by a urine
drug screening
All subjects met the DSM-IV criteria
for heroin dependence
Subjects were either administered an
intranasal dose of oxytocin or the
placebo
The results demonstrated that one
intranasal dose of oxytocin correlated
with a decreased craving for heroin,
conveyed by the Desire for Drug
questionnaire results (−17.16 ± 4.36
vs. 3.51 ± 1.24, p < 0.001) and Visual
Analog Scale results (−8.42 ± 3.86
vs. 2.1 ± 5.11, p < 0.005). The
results also reported a correlation
between oxytocin administration
and decreased withdrawal symp-
toms (−10.45 ± 2.99 vs. 2.45 ± 2.71,
p < 0.001)
A single dose of intranasal oxytocin
correlated with an effective decrease in
craving and withdrawal symptoms in
patients addicted to heroin. Oxytocin
did not significantly reduce anxiety
symptoms in heroin users

94 Current Pain and Headache Reports (2023) 27:89–97
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Table 1 (continued)
Author/date Focus Groups studied Results and findings Conclusions
Zanos etal. (2014) [32] To observe the correlation between
oxytocinergic receptor binding and
negative feelings during opioid-free
periods [32]
309 male C57BL/6J mice (7weeks
old)
Mice were injected with either saline
or morphine and left in the cage for
7days to induce withdrawal
After giving a structural analog of oxy-
tocin, CBT, the 7-day morphine with-
drawn group and the chronic mor-
phine administration group showed
an increase in oxytocinergic receptor
binding in the amygdala compared
to the saline group. After administra-
tion of CBT to the 7-day morphine
withdrawn group, the group showed
an increased time spent in open arms,
indicating decreased anxiety
Giving a structural analog of oxytocin,
CBT correlates with the relief of
the encompassing negative feel-
ings, including anxiety, along with
an increased receptor binding in the
amygdala during opioid abstinence
Fan etal. (2021) [29] To observe the levels of oxytocin in
both addicted and control groups and
the association of those levels with
other factors including “psychiatric
symptoms, aggressiveness and per-
ception of parental neglect.” [29]
48 male Sprague–Dawley rats
Rats divided into 4 groups:
-Saline + aCSF
-Oxycodone + aCSF
-Oxycodone + oxytocin
-Saline + oxytocin
A statistically significant negative asso-
ciation was found between oxytocin
treatment and time in the drug-
paired chamber (p < 0.05). Results
demonstrated that only pretreatment,
no treatment, with oxytocin blocked
oxycodone-induced synaptic function
changes. Furthermore, pretreatment
with oxytocin correlated with statisti-
cally significant increased methyla-
tion of genes originally downregu-
lated by oxycodone
Oxytocin, or an analog of it, has poten-
tial to suppress biological changes to
the brain caused by oxycodone that
could potentially lead to addictive
patterns. Therefore, it is suggested
that oxytocin has potential to dampen
opioid-seeking behavior

95Current Pain and Headache Reports (2023) 27:89–97
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[33, 34]. During separation, their pre-test oxytocin levels are
measured through salivary collection and were taken around
10min after maternal and infant separation [33]. The first
step of the Still Face paradigm consists of the infant and the
mother being placed in the same room for 2min and allowed
to engage in normal play as if they were at home. The next
step was for the mother to look straight at the ground for
15s and not interact with her child. This is called the “reset”
period. Then, the mother was instructed to continue not to
touch or interact with her infant. The mother was then told to
look at her infant for 2min with a “still face.” After this, the
mother was instructed to participate in another reset period
by looking at the ground and not interacting with her infant.
After this reset period, the mothers were allowed to resume
play with their children again as they did in the beginning.
Once the paradigm is over, mothers were given 10 more min-
utes to play with their children, and then, their oxytocin levels
were measured again through salivary collection. To compare
the mothers’ oxytocin scores, the researchers calculated oxy-
tocin levels on a curve [33]. The experiment results showed
that the oxytocin difference from beginning to end of the Still
Face paradigm in the non-opioid use group was much larger
than in the opioid use group [33, 34]. This conveys that it is
likely that opioid use mothers may have a lessened emotional/
oxytocin response to the paradigm [33]. This could lead to
the theory that oxytocin is lower in those with OUD.
An additional randomized, double-blind, placebo-con-
trolled study was conducted in Iran to look at the effects of
oxytocin on withdrawal [35]. Originally, the study consisted
of 68 male participants recruited from an inpatient reha-
bilitation center. Five participants were eliminated due to
medical conditions, and another five were eliminated due
to inability to provide a urine drug screening (N = 58). The
participants were required to meet the DSM-IV criteria for
opioid dependence to be chosen. Females were excluded
from the study due to the small amount (n = 4) of opioid-
dependent females. The male participants were between the
ages of 20 and 60years old. The subjects were randomized
to receive 40 international units (IU) of intranasal oxytocin
or 40IU of intranasal saline. Urine drug screenings were
conducted to ensure participants were not using other sub-
stances. A blood sample was collected from the participants
at the beginning of the study to analyze their cortisol and
DHEA-S levels. Each participants’ anxiety and craving lev-
els were measured through the Hamilton checklist and the
Visual Analog Scale and Desire for Drugs questionnaire,
respectively. After all levels were assessed, the participants
were administered either 40IU of intranasal oxytocin or
40IU of intranasal saline. An hour after administration, par-
ticipants were instructed to participate in a craving task with
opioid-related stimuli, and then, all levels were remeasured.
During the study, seven participants could not complete all
tasks, so they were excluded from the final analysis. Thus,
the total number of participants analyzed was 51. Twenty-
seven received intranasal oxytocin, while 24 received intra-
nasal saline. The results of the study showed that adminis-
tration of oxytocin showed a significant difference in the
Desire for Drug questionnaire (p < 0.01), which was seen
as an improved score correlating with a decreased desire
for drugs [35]. The participants administered intranasal
oxytocin also noted that they experienced less withdrawal
symptoms from opioid use than participants administered
intranasal saline [35]. However, intranasal oxytocin showed
no significant effects on participants’ anxiety or cortisol lev-
els [35]. Table1 summarizes the studies discussed in this
section.
Conclusion
With the increase of opioid-related fatalities, the need to
increase access to opioid-related treatment and other opi-
oid use disorder treatment options has become imperative
to save lives. For decades, methadone has been the gold
standard of medical treatment for OUD but has limitations
since it is strictly regulated to methadone treatment clinics
and patients are usually required to go daily for their medica-
tion. Only after a long period of treatment can one earn the
privilege to dose themselves with methadone from home
with what is called “take home doses.” Buprenorphine is
another medication approved in the early 2000s that led to
another revolution in treating OUD. Patients could now have
office-based treatment and did not have to come daily to a
clinic for medication or travel to a clinic that could be far
away from their homes. Buprenorphine also allows patients
to be better shielded from the stigma of receiving treatment
as they did not have to go to a clinic specifically for OUD.
In the era of fentanyl and other high potency designer opi-
oids, new challenges are being presented that are now push-
ing these life-saving medications to their limits. Due to the
potency of fentanyl, higher and higher doses are required to
stabilize patients on methadone. Higher doses come with the
increased changes of side effects such as respiratory depres-
sion and overdose given that methadone is also a full agonist.
Buprenorphine is also starting to reach its limits as 24mg
of buprenorphine was able to stabilize both withdrawal and
cravings in patients that had used heroin but again given the
potency of fentanyl even this medication treatment is not able
to decrease cravings in patients who use fentanyl.
Given these new challenges, new ways of combating
this public health crisis are greatly needed. Oxytocin could
be one of these new tools. In preclinical studies, it shows
promise in blocking the effects of oxycodone if given before
administration and decreasing the dysphoria associated
with morphine administration. In human studies, it can be
suggested that those who have an OUD may be deficit in

96 Current Pain and Headache Reports (2023) 27:89–97
1 3
oxytocin as evidenced by looking at mother infant dyads
and that it could decrease drug cravings. Putting these two
together makes sense that oxytocin could be feasible as part
of the treatment of OUD. More studies in the human popula-
tion that are both larger and more generalizable need to be
performed to further look at this possible link and oxytocin’s
clinical use in the OUD population. Given the severity of
OUD’s morality, it is worth a shot as time may be running
out with new and more deadly fentanyl analogs entering the
drug supply.
Author Contribution All authors listed have made a direct and intel-
lectual contribution to the work and approved for publication.
Funding This work was supported by the National Institutes of Health
grant RO1 NS120676 to K.S.M.
Compliance with Ethical Standards
Conflict of Interest None.
Human and Animal Rights and Informed Consent statement This arti-
cle is based on previously conducted studies and does not contain
any new studies with human participants or animals performed by
any of the authors.
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Authors and Affiliations
AmberN.Edinoff1,2· SaveenSall3· LaurynG.Honore4· RossM.Dies4· AlexaR.Zaheri4· SaurabhKataria5·
EricD.Jackson6· SaharShekoohi7· ElyseM.Cornett2,7,8· KevinS.Murnane2,3,8· AdamM.Kaye9· AlanD.Kaye2,7
Amber N. Edinoff
AEDINOFF@mgh.harvard.edu
Saveen Sall
saveen.sall@lsuhs.edu
Lauryn G. Honore
lho003@lsuhs.edu
Ross M. Dies
rmd001@lsuhs.edu
Alexa R. Zaheri
arz001@lsuhs.edu
Saurabh Kataria
saurabh.kataria@lsuhs.edu
Eric D. Jackson
ericdanieljack@arizona.edu
Elyse M. Cornett
elyse.bradley@lsuhs.edu
Kevin S. Murnane
kevin.murnane@lsuhs.edu
Adam M. Kaye
akaye@PACIFIC.EDU
Alan D. Kaye
alan.kaye@lsuhs.edu
1 Department ofPsychiatry, Massachusetts General Hospital,
Harvard Medical School, Boston, MA02114, USA
2 Louisiana Addiction Research Center, Shreveport, LA71103,
USA
3 Department ofPsychiatry andBehavioral Medicine,
Louisiana State University Health Sciences Center
atShreveport, Shreveport, LA71103, USA
4 School ofMedicine, Louisiana State University Health
Sciences Center atShreveport, Shreveport, LA71103, USA
5 Department ofNeurology, Louisiana State University Health
Sciences Center atShreveport, Shreveport, LA71103, USA
6 College ofMedicine-Phoenix, University ofArizona,
Phoenix, AZ85004, USA
7 Department ofAnesthesiology, Louisiana State University
Health Sciences Center atShreveport, Shreveport, LA71103,
USA
8 Department ofPharmacology, Louisiana State University
Health Sciences Center atShreveport, Toxicology &
Neuroscience, Shreveport, LA71103, USA
9 Department ofPharmacy Practice, Thomas J. Long School
ofPharmacy andHealth Sciences, University ofthePacific,
Stockton, CA95211, USA
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