Opioid use disorder: current trends and potential treatments

Opioid use disorder (OUD) is a major public health threat, contributing to morbidity and mortality from addiction, overdose, and related medical conditions. Despite our increasing knowledge about the pathophysiology and existing medical treatments of OUD, it has remained a relapsing and remitting disorder for decades, with rising deaths from overdoses, rather than declining. The COVID-19 pandemic has accelerated the increase in overall substance use and interrupted access to treatment. If increased naloxone access, more buprenorphine prescribers, greater access to treatment, enhanced reimbursement, less stigma and various harm reduction strategies were effective for OUD, overdose deaths would not be at an all-time high. Different prevention and treatment approaches are needed to reverse the concerning trend in OUD. This article will review the recent trends and limitations on existing medications for OUD and briefly review novel approaches to treatment that have the potential to be more durable and effective than existing medications. The focus will be on promising interventional treatments, psychedelics, neuroimmune, neutraceutical, and electromagnetic therapies. At different phases of investigation and FDA approval, these novel approaches have the potential to not just reduce overdoses and deaths, but attenuate OUD, as well as address existing comorbid disorders.


Introduction
Opioid use disorder (OUD) is a complex physical and emotional disease with important mood and anhedonic impacts.It also contributes to comorbid medical and infectious diseases that require evaluation and treatment (1).Drug use changes the brain, behavior, and motivational hierarchy via induction of neuroplasticity; the patient with OUD acquires a chronic, progressive neurodysregulation that shortens life, reduces career opportunities and earning potential, increases the risks of other diseases, and often ends in death.Fentanyl is becoming increasingly common.Fentanyl is highly effective at producing OUD and contributing to anhedonia and overdose.Many with OUD also use methamphetamine and cocaine for their euphoric mood effects, but when used regularly, these drugs can lead to alterations in brain function to trigger negative effects, such as dysphoria, anhedonia, and depression (2).Unfortunately, polysubstance use and relapses are the norm rather than the exception (3,4).OUD is part of the substance use disorder (SUD) spectrum but is unique among other SUDs in that there is a solid understanding of its neurobiology and there are Food and Drug Administration (FDA) approved treatments (5).Medical management of OUD has not changed much since the 1970s, with agonists like methadone and antagonists like naltrexone.The addition of the partial agonist buprenorphine and extended-release naltrexone (XR-NTX) were important milestones.

Opioid use in the context of worsening substance use
Substance use disorder (SUD) is one of the nation's most pressing public health challenges.According to the 2021 World Drug Report by the United Nations Office on Drugs and Crime (UNODC), at least 275 million people worldwide used controlled substances in the previous year, with more than 36 million meeting the criteria for a substance use disorder (6).Among controlled substances contributing to the burden of disease, opioids stand out as the primary driver of drug-related fatalities, comprising 69% of deaths directly associated with drug use.
Recent data show the evidence-based and FDA-approved treatments for OUD reduce stigma and improve treatment access.Although more people are currently being treated with medications for opioid use disorder (MOUD), deaths continue to increase.Nationally, over the past 15 years, at least 500,000 deaths have been attributed to opioid overdoses, contributing to the decrease in US life expectancy.This concerning trend has worsened during the COVID-19 pandemic (7,8).Those with SUDs are highly dependent on traditional in-person and often emergent care (9).However, pandemic policies--such as the quarantine--to save lives from the COVID-19 virus, have led to disruptions in such care, leading to worsening opioid overdoses and deaths during the lockdown (10,11).The Centers for Disease Control and Prevention estimated that for the first time ever, over 100,000 deaths occurred due to overdoses during a 12-month period, and the current Director of the Office of National Drug Control Policy suggested that annual opioid-induced deaths could reach 165,000 by 2025 (12).
By necessity, the opioid crisis has shifted the focus to addressing overdose deaths rather than treatment and recovery.A considerable proportion of opioid overdose fatalities are now linked to synthetic opioids, particularly fentanyl.The opioid epidemic has transitioned from being primarily of prescription opioids to heroin and now subsequently fentanyl.Concerningly, with the increase in synthetic opioid use, the trend shows that more and more individuals are also consuming other substances, sometimes inadvertently from contamination and others from co-ingestion of other prescription or psychostimulant drugs.Although SUDs are often discussed in isolation, the reality is that many individuals are combining multiple drugs, often in fatal combinations.For example, in more than half of all methamphetamine-related deaths and about three-quarters of all cocaine-related deaths in 2019, there were co-ingestion of opioids (7).Illicitly manufactured fentanyl is implicated in the increase in overdose deaths in cocaine use, and co-ingestion of fentanyl and other substances, such as methamphetamine, cocaine, and ecstasy, have been shown in postmortem examinations of overdose deaths (13,14).
Patients in the psychiatric emergency rooms often test positive for fentanyl while testing positive for other psychostimulants; unknown contamination with fentanyl puts opioid-naïve psychostimulant users at an increased risk of overdose (15,16).While the public attention remains on opioid-related deaths, a concerning upsurge in fatalities linked to stimulant drugs suggests that the opioid crisis may be entering a new phase.The ongoing substance use crisis is constantly evolving, marked by changing patterns of substance use and availability, as well as concurrent use of multiple drugs across drug classes.

OUD overdose reversal starts with naloxone
Among all potential interventions, increasing the access to naloxone would have the most significant effect in reducing opioid-use related deaths, according to Pitt et al. (17).While important to implement other strategies, no other harm reduction approach has had as significant of an impact.Naloxone is classified as a "pure" antagonist, meaning it lacks opioid agonistic traits seen in other opioid antagonists, and it displaces other full and/or partial opioid agonists that engage opioid receptors to reverse the effects of euphoria, analgesia, as well as respiratory depression, sedation, and bradycardia.Naloxone is a rapid-acting, easy-to-administer agent that can be given in the setting of opioid intoxication and overdose, to provide swift, life-saving reversal (18).Within minutes, naloxone can fully reverse the effects of opioids.Regardless of the substance use history, naloxone offers substantial potential benefits and minimal risk when overdose is suspected.Thus, the importance of promoting access to naloxone in those who use opioids as well as in potential bystanders who can intervene in an overdose setting cannot be understated.However, it is also important to note that naloxone serves as an intervention rather than a remedy for the underlying condition.Naloxone can treat the overdose acutely, but it does not treat the OUD.Existing evidence does not indicate that experiencing an overdose and subsequent reversal with naloxone alters the trajectory of those with OUD; patients must be connected to subsequent treatment services that include MOUDs for improved outcomes (1).Thus, access to both is critical to reduce OUD related deaths.
Transition with urgency: from overdose reversal to treatment of the whole patient with OUD It is difficult to accurately estimate the total economic burden associated with substance use, encompassing factors from the cost of treatment as well as reduced productivity, loss of life, and the emotional toll on those left behind (19).Although it has been suggested that mortality can be reduced by evidenced-based treatment approaches, OUD is characterized by a chronic and relapsing courseinitially driven by activation of the brain's reward system, but later increasingly dominated by anti-reward neural circuits that trigger negative emotional states and relapses (3, 20).It is noteworthy that one important anti-reward neurocircuit phenomena is the subsequent opioid-induced reduction of functional connectivity (21).
No single treatment approach has proven to be universally effective, as many have other medical and psychiatric comorbidities that often hinder successful treatment.Furthermore, racial and economic disparities in morbidity and mortality point to inequalities that must be addressed and rectified (22).Even harm reduction strategy of naloxone is a limited strategy in that it often requires someone else other than the patient to help administer the reversal agent (23).
The current mainstay of treatment for OUD is MOUDs.Buprenorphine, extended-release naltrexone (XR-NTX), and methadone are all FDA-approved and have been shown to be effective in reducing the number of overdoses in those who remain adherent to treatment-which remains a challenge in access and retention (24)(25)(26).Buprenorphine is the most prescribed of the MOUDs and it may help mitigate anhedonia and withdrawal symptoms associated with fentanyl use (27,28).However, treatment dropouts are common, and patients are often re-initiated on the same buprenorphine (29).Once an overdose is reversed, the patient remains at high risk for overdose, which has led to initiation of buprenorphine in hospitals, emergency rooms, and immediately after rescue.This has not decreased the overall number of deaths, but provides another opportunity to successfully treat the patient.
XR-NTX is a monthly injectable opioid antagonist that acts to block other opioids from activating receptors.Despite the monthly injectable formulation of the drug, transition and compliance to treatment remain an issue, as patients need to go through detoxification to start the medication.Therefore, despite similar efficacy of XR-NTX to buprenorphine shown in the XBOT trial, buprenorphine is more often initiated (30).Augmentation of naltrexone therapy with other agents such as clonidine, lofexidine, and buprenorphine are often tried in outpatient detoxification settings.With augmentation of non-opioid agents like clonidine, patients are able to successful initiate and maintain an opioid antagonist, rather than a partial agonist.This is particularly important for those in occupations related to public for whom methadone or buprenorphine is not prescribed and for those who may be mandated to treatment for their OUD (26,31).
While MOUDs are highly effective and FDA approved, they are not a "magic bullet", and the entire scientific community should continue their pursuit to develop alternative non-addictive and safe treatments (32, 33).Despite best efforts, the existing strategies for preventing and treating OUD will still result in more than 700,000 deaths in the US between 2016 and 2025, from both prescription and non-prescription opioids such as fentanyl (34).
The most favorable outcomes are associated with extended duration of MOUD therapy.However, treatment drop out and relapses are common.When OUD treatment with a MOUD ends or is discontinued by the patient, they often relapse, overdose, and rarely have the disease remitted.Risk of overdose appears to persist even after completion of buprenorphine treatment, and stopping MOUD is associated with an elevated overdose risk, raising a controversial question about whether opioid agonist treatment can lead to opioid deficiency or opioid system dysregulation (3,35).This risk of relapse and overdose persists even several years of recovery; thus, recovery can be akin to a "remission" of OUD symptoms rather than a complete cure or elimination.While it may be true that prolonged MOUD is the most effective in preventing relapse, it is also true that the quality of life on MOUD treatment can be negatively impacted and most patients do not remain on lifelong treatment for OUD.One study revealed that patients on long-term Suboxone exhibited significantly flat affect (p < 0.01) and reported diminished sense of feelings of happiness, sadness, and anxiety compared to both the general population and Alcoholics Anonymous (AA) groups (36).Despite the limitations, treatment of OUD is still linked to improved outcomes in morbidity and mortality, and integration of MOUD with effective, evidence-based therapy and contingency management lead to enhanced outcomes (37).It is thought that achieving successful treatment of OUD requires not just medications but a comprehensive approach that addresses the psychosocial factors that predispose and perpetuate individuals toward opioid use disorder.
Brain and behavioral recovery take hope, patience, time, and effort.No one knows if or when the brain will return to its pre-morbid function.Interestingly, research from China revealed that even after 10 months of heroin abstinence, there were changes in resting state of functional connectivity (RSFC) patterns between the midbrain and various cortical regions, such as diminished RSFC of the medial orbitofrontal cortex (mOFC) and anterior cingulate cortex compared to non-heroin using controls.Persistent reward circuitry abnormalities were present after 16 months, but enhancement of RSFC in certain circuits were seen in long-term abstinence compared with short-term (38,39).Abstinence from substance use, as well as adopting a healthy diet, and other regenerative treatments, including exercise and transcranial magnetic stimulation may all help expedite brain recovery (40, 41).

Pro-dopamine regulation and assessment of preaddiction
At the population health level, a "preaddiction" model, like prediabetes, has been suggested to ring the alarm bell for an early intervention before the addiction progresses to cause more severe symptoms and engender chronic changes in the brain's neural circuitry.SUD is currently defined by the DSM-5 based on 11 symptoms of impaired control, and severity is determined by the number of symptoms patients endorse.The term addiction specifically refers to severe SUD, which is defined as having six or more symptoms.This occurs in about 4-5% of adults, compared to 13% of the adult population who have mild to moderate SUD, defined as having 2-5 symptoms (42).Although larger proportion of the population suffer from mild to moderate SUD, public health policies and treatment focus on those with severe, often chronic addictions, to prevent overdoses and deaths, rather than the much larger population grappling with early-stage SUDs.By focusing on those with earlystage addiction, McLellan et al. argue that a preaddiction model that looks for early signs of addiction increases public awareness and allows early intervention that can increase disease detection, shorten delays to treatment, and prevent progression (42,43).Directors of the National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism have also advocated for the integration of "preaddiction" to the conceptualization of addiction in the DSM.
Although the term preaddiction borrows from the advances made in diabetes, but it is best conceptualized as dopamine or reward dysregulation, where there is a net hypodopaminergia within the meso-limbic reward circuitry from inappropriate or dysregulated neurotransmitter systems (44,45).Therefore, the terms "reward deficiency" or "reward dysregulation" have also been proposed (46,47).Reward deficiency syndrome (RDS) refers to behavioral dysfunctions resulting from the disruption of the reward circuitry, due to both genetic and epigenetic factors, and can describe a wide spectrum of psychiatric disorders, from various addictions to obsessive and compulsive disorders and other behavioral conditions (47).

Ways to improve on existing treatment approaches
Public health solutions proposed to address the worsening opioid epidemic include: relaxing the restrictions for physicians to be able to prescribe MOUD; increasing insurance coverage to increase access to treatment for patients (48)(49)(50)(51); inducting patients on high-dose buprenorphine in the emergency department (52, 53); and implementing contingency management along with medical treatment to address other key issues of patients undergoing treatment, such as other concurrent substance use (50).Widespread adoption of these practices may help improve treatment retention and reduce overdoses and deaths, to address critical gaps in delivery of existing treatments (37,(54)(55)(56).
All these measures would be helpful to curb damage of the OUD at the population level, but still does not address the intrinsic limitations of existing treatments.Limited effectiveness of existing pharmacologic treatments and harm reduction approaches leaves a desire for more durable, novel treatment approaches especially as they relate to the required induction of "dopamine homeostasis" (57-59).
Novel treatments for SUDs are being investigated, most notably interventional neuromodulatory interventions such as transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS), as well as psychedelics and neuroimmune therapies.Rather than working at modulating specific opioid receptors as existing MOUDs do, these proposed treatments target other aspects of substance use pathophysiology, such as the mesolimbic neural circuitry modulating reward and dorsolateral prefrontal and orbitofrontal cortex involved in craving, or the neuroimmune and epigenetic modulations that occur in response to substances (60,61).

Developments in interventional neuromodulation treatments for OUD
Interventional neuromodulational treatments such as TMS and DBS work by modulating neural circuits and synaptic plasticity, and several neuromodulating modalities have been investigated for use in various neurologic and psychiatric conditions (62).TMS is a noninvasive treatment that utilizes an extracranial magnetic coil to induce a magnetic field that can stimulate or inhibit targeted cortical and subcortical structures.It is currently FDA-approved for treatment of psychiatric conditions including major depressive disorder and obsessive-compulsive disorder.Clinical trials have shown its effectiveness in reducing substance craving via targeting of the dorsolateral prefrontal cortex, with effects on curbing substance use lasting greater than the immediate treatment period, with various substances such as cocaine, methamphetamine, alcohol, heroin, and cigarette use (63)(64)(65)(66)(67)(68)(69)(70).A meta-analysis of repetitive TMS (rTMS) on addiction has found a small, persistent effect on stimulant and behavioral addiction, but not on depressants such as alcohol, opioids, and cannabis (71).However, currently multiple randomized controlled trials are being conducted for various TMS protocols to treat patients with opioid use as well as uncover mechanisms (72)(73)(74)(75)(76)(77)(78)(79)(80)(81)(82)(83).Further understanding of the exact mechanism and optimization is needed to implement TMS as treatment for OUD (84).One important aspect regarding TMS relates to the concept of utilizing QEEG to determine individualized or personalized signatures termed PRTMS, first coined and developed by Kevin T. Murphy (85).
Similarly, DBS is a neuromodulatory treatment method that can directly stimulate targeted brain regions, but unlike TMS, it typically relies on surgically implanted electrodes.It has FDA approval for various neurologic conditions, such as Parkinson's disease, tremors, dystonia, as well as epilepsy and OCD.With its ability to reach deeper subcortical structures, DBS is also being investigated for other psychiatric conditions, such as treatment-resistant depression, pain, multiple sclerosis, and addiction.Specifically for addiction, animal models have shown that modulation of nucleus accumbens (NAc) can reverse synaptic changes from cocaine and alcohol use (60,62), and small case studies in humans have shown effectiveness in treating alcohol use and heroin use (86).More registered clinical trials are examining DBS's effect in various substance use, including both randomized and non-randomized clinical trials on DBS of NAc of the mesolimbic system as well as DBS specifically for the treatment for severe OUD (87-94).
Beyond TMS and DBS, other similar modalities such as vagus nerve stimulation (VNS), focused ultrasound (FUS), and transcranial direct current stimulation (tDCS) are being investigated, with varying degrees of invasiveness and spatial resolution.VNS is FDA-approved for treatment-resistant depression and epilepsy, and FUS is approved for use in treatment-resistant Parkinson's disease as well as essential tremor (95,96), while tDCS does not have any FDA-approved indications.A small randomized clinical trial on transcutaneous VNS has found significant improvement in behavioral and physiologic opioid withdrawal symptoms, indicating potential utility as adjunct treatment for OUD (93).Although not FDA-approved, tDCS has some evidence for utility in depression and addiction, and multiple clinical trials are ongoing for its use in neuropsychiatric conditions (81,(97)(98)(99)(100)(101).FUS is also being investigated in a small, open-label clinical trial for feasibility in treatment for OUD (102).
Overall, more evidence is needed before neuromodulatory modalities are adopted in OUD treatment, but the strength of these proposed therapies is that they work via modulating neural circuitries and synaptic plasticity, rather than maintaining patients on opioid maintenance treatments, as well as treat other comorbid neuropsychiatric conditions, such as other SUDs and mood disorders.

Renewed interest in psychedelics for SUD
Psychedelic medicine has seen a resurgence of interest in recent years as potential therapeutics, including for SUDs (103,104).Prior to the passage of the Controlled Substance Act of 1970, psychedelics had been studied and utilized as potential therapeutic adjuncts, with anecdotal evidence and small clinical trials showing positive impact on mood and decreased substance use, with effect appearing to last longer than the duration of use.Many psychedelic agents are derivatives of natural substances that had traditional medicinal and spiritual uses, and they are generally considered to have low potential for dependence and low risk of serious adverse effects, even at high doses.Classic psychedelics are agents that have serotonergic activity via 5-hydroxytryptamine 2A receptors, whereas non-classic agents have lesser-known neuropharmacology.But overall, psychedelic agents appear to increase neuroplasticity, demonstrating increased synapses in key brain areas involved in emotion processing and social cognition (105-109).Being classified as schedule I controlled substances had hindered subsequent research on psychedelics, until the need for better treatments of psychiatric conditions such as treatment resistant mood, anxiety, and SUDs led to renewed interest in these agents.
Of the psychedelic agents, only esketamine-the S enantiomer of ketamine, an anesthetic that acts as an NMDA receptor antagonist-currently has FDA approval for use in treatmentresistant depression, with durable effects on depression symptoms, including suicidality (110,111).Ketamine enhances connections between the brain regions involved in dopamine production and regulation, which may help explain its antidepressant effects (112).Interests in ketamine for other uses are expanding, and ketamine is currently being investigated with plans for a phase 3 clinical trial for use in alcohol use disorder after a phase 2 trial showed on average 86% of days abstinent in the 6 months after treatment, compared to 2% before the trial (113).
Psilocybin, an active ingredient in mushrooms, and MDMA, a synthetic drug also known as ecstasy, are also next in the pipelines for FDA approval, with mounting evidence in phase 2 clinical trials leading to phase 3 trials.Psilocybin completed its largest randomized controlled trial on treatment-resistant depression to date, with phase 2 study evidence showing about 36% of patients with improved depression symptoms by at least 50% at 3 weeks and 24% experiencing sustained effect at 3 months after treatment, compared to control (114).Currently, a phase 3 trial for psilocybin for cancer-associated anxiety, depression, and distress is planned (115).Similar to psilocybin, MDMA has shown promising results for treating neuropsychiatric disorders in phase 2 trials (116), and in 2021, a phase 3 trial showed that MDMA-assisted therapy led to significant reduction in severe PTSD symptoms, even when patients had comorbidities such as SUDs; 88% of patients saw more than 50% reduction in symptoms and 67% no longer qualifying for a PTSD diagnosis (117).The second phase 3 trial is ongoing (118).
With mounting evidence of potential therapeutic use of these agents, FDA approval of MDMA, psilocybin, and ketamine can pave the way for greater exploration and application of psychedelics as therapy for SUDs, including opioid use.Existing evidence on psychedelics on SUDs are anecdotally reported reduction in substance use and small clinical cases or trials (119).Previous open label studies on psilocybin have shown improved abstinence in cigarette and alcohol use (120)(121)(122), and a meta-analysis on ketamine's effect on substance use showed reduced craving and increased abstinence (123).Multiple open-label as well as randomized clinical trials are investigating psilocybin, ketamine, and MDMA-assisted treatment for patients who also have opioid dependence (124-130).Other psychedelic agents, such as LSD, ibogaine, kratom, and mescaline are also of interest as a potential therapeutic for OUD, for their role in reducing craving and substance use (104,(131)(132)(133)(134)(135)(136)(137)(138)(139)(140).

Potential neuroimmune modulatory approaches to treating OUD
Changes to brain's synaptic plasticity via neuroimmune modulation seen in addiction suggest the role of agents that can disrupt and/or mitigate the changes from substance use and addiction as potential therapeutics (141,142).Existing medications may be applicable to OUD and substance use treatment in this manner, by modulating or reversing synaptic plasticity.For example, N-Acetylcysteine, an antioxidant medication with multiple clinical applications, has shown to reverse cocaine-induced metaplasticity in in rats (143), and ceftriaxone, a third generation cephalosporine antibiotic, has shown to downregulate glutamate transporter 1 (EEAT2) and reduce drug seeking behavior (144, 145).Similarly, spironolactone, a mineralocorticoid receptor antagonist, has been shown to reduce alcohol consumption in both mice and humans, but to a greater degree in humans (146).Novel immune-modulating agents can also be developed to target known signaling pathways involved in addiction and OUD, such as TLR4, a transmembrane protein that plays a role in rewarding effects of substances, leading to reinforcement of use (147-149).
Other neuroimmune modulatory agents are of interest, including biologic agents, such as antibodies, and vaccines that block the effect of substances of abuse (150-154), but low immunogenicity remains a major challenge to being effective in humans.Overall, much more evidence is needed to develop novel neuroimmunotherapeutics as effective treatments for SUDs.However, the potential benefit of the proposed approaches is that they may modulate or even reverse the lasting damages substance use imposes on the brain.

Summary
The nation has had a series of drug overdose epidemics, starting with prescription opioids, moving to injectable heroin and then fentanyl.Addiction policy experts have suggested a number of policy changes that increase access and reduce stigma along with many harm reduction strategies that have been enthusiastically adopted.Despite this, the actual effects on OUD & drug overdose rates have been difficult to demonstrate.
The efficacy of OUD treatments is limited by poor adherence and it is unclear if recovery to premorbid levels is even possible.Comorbid psychiatric, addictive, or medical disorders often contribute to recidivism.While expanding access to treatment and adopting harm reduction approaches are important in saving lives, to reverse the concerning trends in OUD, there must also be novel treatments that are more durable, non-addicting, safe, and effective.Promising potential treatments include neuromodulating modalities such as TMS and DBS, which target different areas of the neural circuitry involved in addiction.Some of these modalities are already FDA-approved for other neuropsychiatric conditions and have evidence of effectiveness in reducing substance use, with several clinical trials in progress.In addition to neuromodulation, psychedelics has been gaining much interest in potential for use in various SUD, with mounting evidence for use of psychedelics in psychiatric conditions.If the FDA approves psilocybin and MDMA after successful phase 3 trials, there will be reduced barriers to investigate applications of psychedelics despite their current classification as Schedule I substances.Like psychedelics, but with less evidence, are neuroimmune modulating approaches to treating addiction.Without new inventions for pain treatment, new treatments for OUD and SUD which might offer the hope of a re-setting of the brain to pre-use functionality and cures we will not make the kind of progress that we need to reverse this crisis.

Conclusion
By using agents that target pathways that lead to changes in synaptic plasticity seen in addiction, this approach can prevent addiction and/or reverse damages caused by addiction.All of these proposed approaches to treating OUD are at various stages in investigation and development.However, the potential benefits of these approaches are their ability to target structural changes that occur in the brain in addiction and treat comorbid conditions, such as other addictions and mood disorders.If successful, they will shift the paradigm of OUD treatment away from the opioid receptor and have the potential to cure, not just manage, OUD.