Current and emerging pharmacotherapies for opioid dependence treatments in adults: a comprehensive update

Abstract

Introduction:

Opioid use disorder (OUD) is characterized by compulsive opioid seeking and taking, intense drug craving, and intake of opioids despite negative consequences. The prevalence of OUDs has now reached an all-time high, in parallel with peak rates of fatal opioid-related overdoses, where 15 million individuals worldwide meet the criteria for OUD. Further, in 2020, 120,000 opioid-related deaths were reported worldwide with over 75,000 of those deaths occurring within the United States.

Areas covered:

In this review, we highlight pharmacotherapies utilized in patients with OUDs, including opioid replacement therapies, and opioid antagonists utilized for opioid overdoses and deterrent of opioid use. We also highlight newer treatments, such as those targeting the neuroimmune system, which are potential new directions for research given the recently established role of opioids in activating neuroinflammatory pathways, as well as over the counter remedies, including kratom, that may mitigate withdrawal.

Expert opinion:

To effectively treat OUDs, a deeper understanding of the current therapeutics being utilized, their additive effects, and the added involvement of the neuroimmune system are essential. Additionally, a complete understanding of opioid-induced neuronal alterations and therapeutics that target these abnormalities – including the neuroimmune system – is required to develop effective treatments for OUDs.

1. Historical aspects of opioid use and the current epidemic

Opium is a naturally occurring substance derived from the opium poppy Papaver somniferum, and contains various bioactive opioid alkaloids such as morphine, codeine, thebaine, papaverine, and others. Recorded history of use of opium for relief of pain and a variety of other medical ailments date back more than six millennia. In the latter half of the 19^th century, chemical isolation of morphine from opium, the discovery of its conversion to diacetylmorphine (heroin) by boiling in acetic anhydride, and the invention of the hypodermic syringe, collectively led to widespread intravenous opioid use which revealed the high abuse dependence of these otherwise therapeutic compounds [1]. Over the next century, a multitude of synthetic and semisynthetic opioids were developed for use in the treatment of chronic pain, cough, and diarrhea, the most commonly prescribed being hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl, tramadol, and meperidine.

Over the past 40 years, on a global scale there has been a steady rise in the number of people diagnosed with seeking treatment for opioid use disorder (OUD, defined below), and the number of opioid-related overdoses, both fatal and non-fatal. This surge is now widely considered an epidemic, and has been characterized as having three distinct contributing phases, or “waves”, each with unique primary underlying factors [2]. The first wave was primarily fueled by miseducation of medical professionals and the public at large regarding the high abuse and addiction potential of prescription opioid analgesics, which resulted in extremely large numbers of prescriptions for and dispensing of opioid medications. As a result, many individuals became dependent on prescription opioids, and those who could not maintain a constant supply of the drug commenced use of widely available and inexpensive heroin, constituting the second wave. The third wave of the opioid epidemic consisted of infiltration of synthetic fentanyl and illicitly manufactured analogues of this highly potent opioid into the drug supply, adulterating not only heroin but also illicitly manufactured opioid analgesics, benzodiazepines, and recreational substances such as cannabis, hallucinogens, and psychostimulants. Currently, a fourth wave of the opioid epidemic is now emerging, characterized by co-abuse of opioids with psychostimulants such as cocaine and methamphetamine, which are used to counteract opioid-induced sedation and/or increase the euphorigenic effects of both drug types [3]. Complicating the global opioid epidemic further has been the coronavirus disease 2019 (COVID-19) pandemic, which resulted in significant social isolation and reduced access to OUD treatment [4].

2. Opioid use disorder

Currently it is estimated that over 2 million people within the United States (US) currently suffer from OUD, which includes the misuse of all classes of opioids (prescription pain relievers, synthetic opioids (i.e. fentanyl), and heroin). This number is thought to exceed 15 million worldwide, where opioid related deaths surpass 120,000 annually [5]. OUD is characterized by the inability to limit opioid intake despite negative consequences, intense drug craving and compulsive drug seeking and taking [6]. In 2021, the number of fatal overdoses due to opioids was estimated to be nearly 76,000 in the US alone, nearly a 26% increase from that observed in 2020 [7]. Behind the US, the United Kingdom and Canada ranked second and third for the highest number of fatal opioid overdoses reported in 2020, with 18,000 and 6,500, respectively [8]. Interestingly, France has reported minimal opioid related fatal overdoses, with only 7 opioid related fatalities per population of one million – equating to less than 500 deaths in 2020 [8]. This is likely due to the access to effective opioid addiction treatments, like methadone, where 87% of individuals in France with high-risk opioid use report utilizing their effective access to treatment [8]. Only a small percentage of individuals in Canada and the US report having access to and utilizing effective treatments, with only 23% and 11%, respectively [8]. Interestingly, the US consumes 73% of the world’s oxycodone, followed by Canada [9]. The recent rise in the use of fentanyl has increased opioid related overdoses due to its high potency at opioid receptors, where its affinity for the mu opioid receptor is 50–100 times greater than morphine and 25–40 times more than heroin [10,11]. In addition to the increase in fentanyl use, opioid use throughout the COVID-19 pandemic has continued to rise at an alarming rate [12,13]. Currently, treatment options for those suffering from OUDs include pharmacotherapies aimed at antagonizing opioid receptors, psychotherapy (albeit with limited efficacy alone), and long-term opioid replacement therapy, the latter posing significant concerns of abuse potential. Given that OUDs have limited effective treatments particularly in the long term, and that opioid use levels and overdoses remain an unprecedented crisis, development of useful pharmacotherapies that aid in long-term abstinence remains a critical unmet need for combating the opioid epidemic. In this expert opinion, we will review statistics and phenotypes of OUD, typical usage patterns, pharmacological mechanisms of action, as well as the current treatment options and promising therapeutics that may be beneficial for future use in treating OUDs. It is of note, that given the abundance of fatal opioid overdoses reported and the lack of access to and utilization of effective treatment options in the US, this review primarily focuses on statistics and findings within the US and less on other parts of the world.

3. Risk factors for OUD

The ability of opioids to induce feelings of intense pleasure and euphoria, while also produce negative reinforcing effects via pain relief, are largely rooted in their neurobiological effects on the central and peripheral nervous systems. Chronic pain conditions vastly increase the risk for opioid misuse and OUD development [14]. Individual susceptibility or resilience to the development of OUD is influenced by genetic and epigenetic factors [15], as well as developmental factors such as age of opioid use initiation, as discussed in the next section. Still, there are profound societal and environmental influences that can confer susceptibility to development of OUD. These include a history of incarceration or early life adversity, low socioeconomic status, unstable housing, employment and family structure, economic stagnation, social despair, and race and ethnicity-based disparities in treatment access [16,17]. Specifically, individuals who have childhood trauma or perceived stress are more likely to abuse opioids and develop an OUD [18]. Trauma in the form of sexual abuse and assault particularly increases prescription opioid use and misuse in both men and women in adulthood [19]. Interestingly, females are more likely to report prescription opioid use and abuse than men, although the reasons behind this are not well understood [20]. In section 9 we highlight sex differences in OUDs, which provides additional insight into this topic.

4. Adult versus adolescent opioid usage

Compared to adults, OUD is less well characterized in younger populations such as adolescents; however misuse of opioids amongst this population appears to be steadily rising in this age group [21,22]. Specifically, a meta-analysis revealed that 0.7% of adolescents and 16.3% of young adults report prescription opioid misuse [23]. However, a more recent study suggests that these metrics may be as high as 3.8% in adolescents and 7.8% in young adults, where users also reported high prevalence of use of other substances, including cocaine, hallucinogens, heroin and inhalants [24]. In the adult population, it is estimated that 2% of all adults meet the criterion for OUD, which roughly translates to 4.3 million individuals in the U.S. alone, a value higher than that reported by the Centers for Disease Control and Prevention (CDC); however, these usage statistics are based on self-report data [25]. Further, with a sample size of nearly 20,000 subjects aged 18 and older, Kelly and colleagues observed that over 10 million adult Americans are taking opioids in a given week, and that more than 4 million are taking them regularly at any given time [25]. Given the sparse literature following adolescent and young adult opioid users into adulthood, future studies highlighting changes in use patterns across life stages is warranted. For the purposes of this article, we will focus on OUD pharmacotherapies utilized in adult subjects.

5. Opioid use patterns – short- vs. long-term

Since their introduction, opioid analgesics were intended for short-term pain relief, with a typical intended duration of one to three weeks [26]. However, chronic pain management using prescription opioids has led to unintended and unforeseen issues with long-term use patterns. Recently, opioid prescriptions have declined in accordance with new prescribing guidelines [27–29]. These guidelines feature three key principles where 1) non-opioid therapy is the preferred approach, 2) when use is necessary, opioids should be given at the lowest possible effective dose, and 3) clinicians should closely monitor all patients undergoing opioid treatment and exercise caution when prescribing opioids to each individual [30]. With these guidelines, reductions in prescription opioid availability have caused long-term users to transition from prescribed opioids to other more available opioids such as heroin and synthetic opioids. An unintended consequence of these guidelines is now a growing reluctance of some physicians to prescribe opioids for long-term pain relief, particularly non-cancer related chronic pain. Such reluctance is accompanied by physicians’ desire to screen for substance use disorders (including urine screens), discontinuation of prescriptions following the appearance of aberrant patterns of opioid use, a reluctance to co-prescribe other medications such as benzodiazepines, and increased stress in managing chronic pain patients, especially among younger physicians [31,32]. Given the high potency and receptor affinity of newly developed synthetic opioids such as fentanyl, an increase in opioid overdoses and fatalities has been observed. In fact, opioid related deaths due to synthetic opioids was found to be more severe in regions of Canada where prescription opioid prescription availability has been more extensive [33]. Of note, the global COVID-19 pandemic has had profound effects on opioid usage, where increased long-term use has been reported; specifically, emergency clinicians were found to have increased the prescribed amount of opioids per prescription during the COVID-19 pandemic compared to the pre-pandemic period [34], an effect compounded by the lack of access to primary care and the reduced ability of emergency clinicians to identify individuals with OUDs [34]. More importantly, the COVID-19 pandemic has increased long-term opioid use through prevented access to healthcare, appropriate pain management services, as well as to opioid use reduction services, such as methadone treatment [35]. Given that opioid use appears to be continuously rising, with the likelihood of long-term use increasing and resulting in OUD, it is important to identify and highlight the current treatment options for individuals with OUDs, which we have discussed below.

6. Mechanisms of action and neuroadaptations

Opioid receptors are classified into three major subtypes: mu, kappa and delta opioid receptors (MOR, KOR and DOR, respectively), each of which are seven transmembrane domain spanning inhibitory G-protein coupled receptors. These receptors provide cell to cell communication utilizing endogenous opioid peptides such as endomorphins, enkephalins, dynorphins and endorphins [1,36]. Of these peptides, endorphins and enkephalins are generally responsible for analgesic effects through their actions at pre- and post-synaptic MORs [37], whereas dynorphins mediate aversive effects through stimulation of KORs [38]. Exogenous opioids, such as heroin, morphine, prescription opioids and synthetic opioids, exert their actions primarily at MOR, though their affinity for individual receptors and extent of receptor stimulation (i.e., full or partial agonism) can vary [39]. Further, antagonism of these receptor reduces opioid intake in both animals and humans, and reduces conditioned rewarding effects in animal models of OUDs [40]. Opioid receptors, especially MORs, are expressed across multiple brain regions. Of relevance to OUDs and other motivated behaviors, MORs are extensively present on GABAergic interneurons within the ventral tegmental area, which allows opioids to disinhibit reward associated mesolimbic dopaminergic neurons when activated. This results in increased dopamine release at downstream targets such as the nucleus accumbens, a brain area heavily implicated in addiction [41–43]. While the role of dopamine in reward areas of the brain has been heavily studied with regard to opioid addiction [16,44–47], recent findings have highlighted the role of microglia in opioid dependence, and the modulatory effects of microglial activation on dopamine release [48]. Microglia are part of the innate immune system of the central nervous system and are capable of releasing signaling molecules/peptides that can act as chemical transmitters and mediate neuroinflammatory processes [49]. Within the last 15 years, research on microglia function in the context of substance abuse has grown given the role of their secreted cytokines in regulating synaptic plasticity, learning and memory. Recent reviews have underscored the role of the neuroimmune system in substance use disorders and readers are directed to these reviews for a more thorough discussion [48,50,51]. In brief, the toll-like receptor 4 (TLR4) plays a crucial role in the rewarding and reinforcing effects of opioids, where opioid-induced activation of TLR4 promotes subsequent release of pro-inflammatory mediators such as brain derived neurotrophic factor (BDNF) and interleukin 1-beta (IL-1β). While BDNF remains the best characterized microglial derived immune factor affecting opioid reward, both IL-1β and BDNF have been shown to increase dopamine levels within the rat brain [52,53]. Interestingly, BDNF polymorphisms in heroin-dependent patients associated with the onset of substance abuse, further suggest that this immune factor plays a critical role in opioid dependence [54–56]. Lastly, blockade of TLR4 reduces opioid-induced dopamine release within the nucleus accumbens, conditioned place preference for opioids, as well as opioid self-administration [57]. For an in-depth review on microglia and opioids, please see [48,51]. Taken together, these studies highlight that there are complex interactions between opioids, dopamine and microglia activation that likely contribute to drug seeking and dependence. Given the role of each, utilizing pharmacotherapies that target these various pathways is desired in hopes of achieving complete abstinence and preventing relapse in patients with OUD.

7. Current pharmacotherapies for adults with OUDs

7.1. Naloxone

Fatal overdoses due to opioid use are currently at an all-time high. With increased dosages, opioids can suppress heart rate as well as respiration, resulting in death. Originally approved by the US Food and Drug Administration (FDA) in 1970, naloxone is a broad-spectrum opioid receptor antagonist that has the ability to reverse opioid overdose by preventing opioid receptor binding by other opioids either injected or consumed. In fact, naloxone is identified as a key measure to help mitigate the opioid crisis and prevent overdose fatalities by increasing distribution and making naloxone an over-the-counter treatment for those with OUD or individuals who have close contact with an individual prone to overdose [58,59]. Naloxone is used as a harm reduction strategy, meaning that this compound alone does not prevent opioid usage but reduces the immediate dangers associated with an overdose such as accidental death. However, while primarily used to prevent opioid overdose fatalities, naloxone has also proven beneficial for long term treatment of OUD in patients when given simultaneously in combination with buprenorphine, a partial MOR agonist known to promote opioid abstinence and prevent relapse [60]. Combined use of naloxone and buprenorphine has become a common therapeutic for patients with OUD over the last few years, and is further discussed below.

7.2. Buprenorphine

Buprenorphine was approved by the FDA in 2000 as a replacement therapy for OUD [61]. Buprenorphine is a partial MOR agonist, making it less likely to cause respiratory distress or euphoria, as this “ceiling effect” diminishes its abuse liability while patients benefit from decreased opioid craving [62–64]. Abuse potential of buprenorphine is further decreased by its co-delivery with naloxone, which acts as a harm reduction strategy in combination with therapeutic effects of buprenorphine. Naloxone has low efficacy if taken orally, and thus the full effects of buprenorphine are retained. However, absorption of naloxone into the bloodstream is increased if delivered via the intravenous or intranasal route, thereby antagonizing the effects of buprenorphine and decreasing the likelihood of medication tampering and misuse [64]. Effects of buprenorphine last between 6–72 hours due to its long half-life and slow dissociation from opioid receptors [63,64]. In terms of efficacy, patients receiving buprenorphine to treat OUD are more likely to continue treatment and have negative opioid urine tests if given buprenorphine early during the course of treatment and in combination with psychological or other forms of therapy [61,65]. Additionally, a study that followed approximately 30,000 US Veterans with OUD for 5 years after treatment initiation showed that those who did not receive buprenorphine were over 4 times as likely to commit suicide or experience overdose than those taking buprenorphine, even if they were taking other medications to address their OUD [66]. One criticism of buprenorphine is that due to its high receptor affinity, it can displace full MOR agonists and precipitate withdrawal in patients under the influence of other opioids. For this reason, it is recommended that the patient is not under the influence of other opioids in order to minimize withdrawal effects and maintain patient retention [62,63]. However, it is of note that abstinence is not required for the initiation of buprenorphine treatment. In fact, there is emerging evidence that buprenorphine “microinduction” or “microdosing” is a promising approach to address the issue of buprenorphine-induced withdrawal in patients currently still using other opioids. In several published case studies, very low dose buprenorphine microinduction was initially overlapped with full agonist use, followed by either abrupt discontinuation or tapering of the full agonist. This resulted in decreased symptoms of withdrawal and increased treatment retention [62,63,67]. Another emerging buprenorphine administration strategy is the use of long-acting injectable formulations that can be administered weekly or monthly, greatly benefitting patients who live in rural areas with little access to pharmacy or clinical care and those who struggle with daily dosing [68]. Currently, extended-release injections of buprenorphine are in the clinical trial phase with an estimated completion date in December of 2022. This clinical trial is also exploring the formulation of sublingual buprenorphine (24 mg) that is administered once daily as a treatment option for patients with OUD. Results from this clinical study could lead to substantial improvements in treatment outcomes in patients with OUD, especially those who have limited clinical access [69].

7.3. Efficacy of naloxone and buprenorphine co-administration

Cotreatment with sublingual buprenorphine and naloxone has been recently utilized for opioid use disorder. The combination of buprenorphine and naloxone capitalizes on the partial MOR agonism with buprenorphine, that has a safety profile superior to methadone (discussed below), as well as the harm reduction strategy of naloxone. Specifically, this combination achieves a ‘ceiling effect’ on its opioid agonistic properties, especially on respiratory depression, and limits drug-drug interactions making buprenorphine+naloxone a safer treatment option than methadone alone [70]. Additionally, the combination discourages diversion to intravenous use and aids in hindering the abuse potential. However, as discussed above, buprenorphine can displace full MOR agonists and precipitate withdrawal; thus, it is recommended that the patient should not be under the influence of other opioids in order to minimize withdrawal effects and maintain patient retention. This is also true for buprenorphrine+naloxone, however abstinence is not required but may help treatment retention. When maintenance is achieved, buprenorphine+naloxone has shown promising effects for achieving complete abstinence from opioids [71] and reduces the risk of relapse 10-fold [72]. In fact, the use of buprenorphine+naloxone has been shown to be as effective as methadone maintenance in reducing opioid use [73], increases quality of life [74] and reduces rates of mortality in patients with OUDs [75]. Recent evidence even suggests that six months of buprenorphine+naloxone treatment is effective at improving neurocognitive function in patients with OUDs [76]. Yet, even with this promising evidence, the use of buprenorphine+naloxone is hindered due to patient maintenance and access to treatment. Additional studies highlighting the benefits and pitfalls of this treatment initiation and maintenance are essential, especially given its success in previous studies in hindering opioid use in patients with OUD.

7.4. Naltrexone

Similar to naloxone, naltrexone acts as a broad spectrum competitive opioid receptor antagonist that is predominantly used as a deterrent of opioid use and to sustain abstinence and is used following an initial abstinence phase of typically a week or longer. Naltrexone is also widely used as a pharmacotherapy for alcohol use disorder [77]. Interestingly, naltrexone can rapidly induce or amplify withdrawal symptoms in those currently using opioids or in an initial withdrawal period [78]. While pharmacologically effective, naltrexone efficacy has been hindered due to poor medication compliance [79]. Thus, it is not surprising that naltrexone is the least utilized for treatment initiation and short durations of OUD treatment, at least based on insurance submissions within the United States [80]. However, recent clinical trials have yielded promising results demonstrating that extended-release naltrexone had similar effectiveness to the more commonly used buprenorphine for OUD treatment [81,82]. These studies have however yielded conflicting results, where extended release naltrexone significantly reduced risk of first and any relapse to heroin use in opioid-dependent patients compared to buprenorphine-naloxone combination [78,83], while others report that the use of both buprenorphine and naloxone has better efficacy than extended naltrexone at preventing relapse in OUD [84]. Given that naltrexone has a large safety margin and a mechanism of action beneficial in not only adults, but also adolescents [85], future studies demonstrating its effectiveness alone and in combination with other medications, such as buprenorphine, in preventing relapse are pertinent.

7.5. Methadone

Methadone acts as a full MOR agonist. Although methadone exhibits high affinity for MOR, it has a slow onset of action and a long elimination half-life, upwards of 120 hr in some individuals [86]. While methadone itself is active, when metabolized it is converted to two primary inactive metabolites which include 2-ethylidene-1,5-dimethyl-3 and 3-diphenylpyrrolidine (EDDP). Methadone is currently a treatment option to diminish usage of opioids by controlling the ability to taper usage, where dosages are started high and tapered down over the course of many weeks to months [77]. Until 2020, methadone treatment was prescribed and administered at federally certified opioid treatment programs within the US, where patients had to travel to certified locations to receive treatment. However, in light of the COVID-19 pandemic, an exemption from the federal requirements was approved, where patients were able to obtain 28 days of take-home dosages home if deemed stable. Interestingly, this led to almost double the methadone doses distributed during the exemption period compared to pre-exemption times. However, this increase in methadone dosages was not associated with negative treatment outcomes in adherent patients [87]. When compared to buprenorphine, methadone has higher outpatient retention rates at 2 weeks, 30 days and 12 weeks after initiation in hospitalized patients [88]. Furthermore, when used in combination with counseling, the efficacy of methadone treatment is increased, an effect that is particularly apparent in women who identified as Latinas [89]. However, individual and group therapy for patients with OUD, where peer support and mental health professionals are available, has proven extremely beneficial [90], where patients report increased self-control and restraint over drug seeking [91]. The benefits of individual and group therapy for individuals with OUD have been discussed in depth [5,92,93]. Despite its abuse potential, methadone has yielded beneficial results for treating OUD. However, the apparent sex dependent effects on treatment as well as the outcomes of combined treatment plans (i.e. methadone + counseling; methadone + naltrexone etc.) should be further explored. Lastly, it is of note that methadone has the ability to induce serotonin toxicity by hindering serotonin uptake and increasing serotonin synthesis and release when delivered in conjunction with other serotoninergic medications including monoamine oxidase inhibitors [94]. As such, the use of methadone should be carefully selected as treatment of use in patients currently on other medications that may promote serotonin toxicity [94].

7.6. L-alpha-acetylmethadol

Levo-alpha-acetylmethadol (LAAM), a full MOR agonist, was approved for OUD treatment in 1993, but was withdrawn from the market in 2004 [95,96] for reasons that are discussed below. However, given its promising effects while on the market, researchers continue to probe its efficacy and safety, as well as other structurally similar compounds. At the time when LAAM was under development, methadone was the only FDA approved medication for OUD. Since methadone was intended to be taken daily, LAAM was originally formulated to be taken 3 times a week to decrease the need for frequent clinic visits [95,97–99]. However, several issues emerged regarding LAAM that explain its short-lived clinical use. First, some clinics would require an initial period of methadone treatment before switching to LAAM, which led to problematic symptomology as patients adjusted to LAAM, potentially driving a preference for methadone. Further, patients who ceased using LAAM did so due to inadequate withdrawal relief, possibly as a result of inflexible dosing and a lack of availability of take-home formulations [99]. The most compelling issue with LAAM was that it produced cardiac symptomology in the form of arrhythmias which could lead to mortality, although rare. As result of all of these concerns, the FDA changed LAAM’s status from front-line therapy to recommended use only when other therapies were unsuccessful, which was later followed by its discontinuation [97]. Since its discontinuation, researchers have reported that the cardiac symptoms observed in LAAM may not have been any worse than those observed with methadone [96]. Indeed, two comparison studies between methadone and LAAM showed no adverse cardiac events in patients using either drug, but similar or better retention of those taking LAAM as compared to those prescribed methadone. Additionally, both studies reported fewer opioid positive urine tests upon follow up with LAAM patients in comparison to those taking methadone. A shared observation by the authors of both studies is that the physicians overseeing patient care were able to adjust doses of LAAM based on patient characteristics, which is likely responsible for the observed positive outcomes [97,100]. Thus, while LAAM is not currently being utilized its formulation has shown promising results in the past and may prove beneficial if a reintroduction of the therapy were to be initiated.

7.7. Mitragyna speciosa (Kratom)

Mitragyna speciosa is a plant species native to portions of southeast Asia, and contains several alkaloid molecules such as mitragynine and 7-hydroxymitragynine which exert partial MOR agonist effects [101]. Given the street name kratom, this botanical product has analgesic properties, is generally widely available, and has recently been proposed as a potential treatment option for those currently suffering from OUDs, especially those with limited access to other regulated therapeutics such as buprenorphine, naltrexone and naloxone. Specifically, some studies suggest that kratom could be beneficial for the treatment of opioid withdrawal symptoms and chronic pain management [102], and a variety of reports confirm that kratom is typically utilized to self-manage opioid withdrawal and abstinence from classical opioids [103], and is less used for recreational purposes [102]. In addition to its affinity for MOR, it has been proposed that mitragynines and other alkaloids in kratom exert noradrenergic and serotonergic receptor mediated effects [104,105] while also having reported anti-inflammatory and anti-parasympathetic effects [106], which may aide in its analgesic mechanisms of action. However, kratom may pose some abuse potential, caused at least in part by the metabolite mitragynine pseuodoindoxyl which is also a potent opioid receptor agonist [107] with higher affinity than mitragynine alkaloids alone. Kratom was recently evaluated by the US Drug Enforcement Administration and Food and Drug Administration to determine whether it would be placed into the Schedule I act of the Controlled Substances Act [108]. However, this evaluation concluded that there is no documented threat to public health warranting class I scheduling [108]. It is of note that abuse of kratom can be treated with buprenorphine-naloxone maintenance [109–111]. In addition to its abuse potential, an increasing number of adverse effects including liver damage [112], seizures [113], coma and death [114] have been reported with kratom use, particularly when used in combination with alcohol. Despite this abuse potential and usage warnings issued by the FDA, kratom is currently not FDA regulated in the US. Interestingly, treatment with buprenorphine/naloxone has been beneficial for patients with kratom dependence [115]. Given its relatively recent rise in popularity, future studies are warranted to distinguish the longevity of kratom as a treatment option for OUDs, as well as its optimal dosages to alleviate concerns of abuse potential and toxicity.

7.8. Tramadol

Tramadol was approved for antinociceptive use in the US by the FDA in 1995 has been classified as a Schedule IV drug since 2014. There are several routes of tramadol administration, with oral preparations available in the US but other countries additionally offering suppository and injectable preparations. Immediate release tablets have a 6-hour elimination half-life whereas extended-release tablets have a half-life of 12 hours [116]. Tramadol acts as an adrenergic and serotonergic reuptake inhibitor, similar to an SNRI antidepressant, along with its action as a weak μ-opioid receptor agonist. A pro-drug, tramadol is metabolized to its most active metabolite, O-desmethyltramadol, by the enzyme CYP2D6. Importantly, recent work has shown that variations in the expression of the CYP2D6 gene may result in differing therapeutic outcomes in patients [116,117]. Though there is evidence that there may be less risk of adverse effects and incidence of dependence than with other opioids, this may not be the case for certain individuals and groups. Prescribers should be cautious of drug interactions, particularly to avoid serotonin syndrome in patients taking medications that elevate levels of serotonin. Toxicity may also occur in patients with impaired hepatic function [116]. Further, case studies have shown that patients can exhibit symptoms of dependence and withdrawal from tramadol following long-term use [117,118]. Importantly, there are regional differences in the expression of abuse liability for tramadol. In a comparison analysis of four European countries, tramadol was much less likely to be abused than other opioids. However, the United Nations Office on Drugs and Crime reported in 2017 that the rise in non-medical use of tramadol was “serious” in West Africa and playing a direct role in destabilizing the region through trafficking and other sociocultural mechanisms [119]. Though tramadol might pose more abuse liability than originally thought, its use is still supported in patients detoxifying from opioids and in patients with mild to moderate opioid use disorders who are not planning on long term use but rather a monitored tapering schedule [117,120].

8. Targeting neuroimmune signaling as a treatment for OUDs

As discussed earlier, microglia and the neuroimmune system have been recently implicated in driving opioid use and OUDs. In light of this, compounds targeting neuroimmune mechanisms and microglia have gained traction for possible treatments of substance use disorders, especially OUDs. These mechanisms as they relate to addiction are extensively discussed in our previous review [50] as well as in others [51,121]. For example, in preclinical studies the antioxidant N-acetylcysteine has been shown to reduce heroin-seeking behaviors [122], whereas the microglial inhibitor minocycline prevents drug-primed morphine conditioned place preference in rats [123]. Clinical studies have also found that ibudilast, a phosphodiesterase inhibitor, reduced cravings for heroin in patients with OUD [124] and reduces withdrawal symptoms in patients undergoing detoxification [125]. Lastly, inhibition of cyclooxygenase-2 (COX-2), a prostaglandin endoperoxide synthase that promotes tumor growth, reduces the formation of proinflammatory prostaglandins and has been shown to reduce opioid cravings in dependent individuals [126]. More recently, cannabidiol which has anti-inflammatory properties has been shown to reduce opioid-induced inflammatory responses, which may have profound effects in preventing opioid intake [127], though additional studies exploring this hypothesis are necessary. Taken together, these preclinical and clinical findings demonstrate that opioid craving and withdrawal symptomology can be alleviated by targeting opioid-induced neuroinflammatory pathways and may prove as a promising avenue for future treatment for OUDs.

9. Sex differences in treatment of adults with OUDs

Recent work has shown that biological sex is an important variable to consider when evaluating both the prevalence and treatment of OUDs. As in the past, women continue to be more likely to misuse prescription opioids, whereas men with OUDs are more likely to use heroin [128,129]. The higher prescription opioid misuse observed in women may be attributed to their increased likelihood of receiving an opioid prescription to treat chronic and acute pain [130,131]. Further, women with OUDs generally have poorer health outcomes, including chronic health problems [132]. Even though both sexes report a high incidence of anxiety and depression, women have consistently shown more psychiatric comorbidities than men, with more interpersonal issues in social and family settings. In adolescent populations, anxiety, stress, and trauma as well as a history of self-harm and suicide attempts have emerged as risk factors for young women. Further, women are more likely than men to report substance use to cope with negative feelings, emotional abuse, and physical abuse [131]. Men, on the other hand, were more likely to have a greater number of comorbid substance use disorders, which is reflected in both mature and juvenile populations [128,132–134]. Although some studies suggest that women suffer from more perceived stigma about their OUD in healthcare settings than men, others report similar levels of stigma and discrimination between the sexes [128,133]. Other factors that affect women are that they tend to be younger at the onset of opioid use and have a faster disease progression. It is also more likely that women are unemployed and live alone with children, which affects their ability to pursue and maintain treatment [128, 133,135].

It is of importance that pregnancy is an opportunity for women with OUDs to implement lifestyle changes to remain abstinent from opioid use [136]. However, while complete abstinence is ideal the World Health Organization and National Institute for Health and Clinical Excellence have recommended that pregnant women should not undergo withdrawal as it can have detrimental effects on the maternal and fetal health [137]. For this reason, and to prevent the risk of neonatal abstinence syndrome (NAS), opioid agonist therapies during pregnancy have been implemented, where methadone is most commonly utilized [138]. However, more recently buprenorphine has been utilized as an alternative, which has a more favorable neonatal opioid withdrawal profile when compared to the methadone alternative [139]. In fact, buprenorphine was found to increase gestational age, birth weight, as well as reduce NAS, congenital anomalies and stillbirths [138]. Postpartum breast feeding by those women who have undergone methadone or buprenorphine therapy has also shown to have a positive impact on fetal health, where breastfeeding was associated with less severe neonatal opioid withdrawal syndrome and shorter hospital stays. In addition, mothers experienced a decreased risk of postpartum depression and improved bonding and infant attachment as well as maternal confidence [140]. Taken together, these studies demonstrate that utilizing current treatment options for OUD may be extremely beneficial for both maternal and fetal health not only during pregnancy but when breastfeeding is implemented.

There are also sex differences in treatment outcomes. In terms of relapse, youth is a risk factor for both sexes. For women, the severity of symptoms of withdrawal in combination with untreated psychiatric comorbidities are the most important variables for the likelihood of relapse. Men tend to be at a higher risk if they have multiple substance use disorders and if they exhibit more externalizing symptoms, such as ones observed in conduct disorder [141]. Medication assisted therapy has been shown to be beneficial to both sexes, with similar retention in treatment programs that use buprenorphine, methadone, and naltrexone [142]. However, women are less likely than men to relapse when taking buprenorphine and are also less likely to relapse than women taking methadone [143]. Women are also more likely to experience more severe symptoms of withdrawal in the early stages of naltrexone use, making it particularly hard to retain them in treatment [131]. Though treatment retention is an important outcome measure, other measures are important for patient outcomes. Outpatient information gathered from just over 2700 patients with OUD showed that although men reported more criminal activity than women overall, each year on medication assisted therapy conferred a 7% annual increase in the likelihood of women also engaging in criminal activity. This increase was mostly regarding drug dealing and may be linked to high unemployment rates in women as compared to men [135]. It is becoming increasingly clear that physicians who treat patients for OUDs should consider biological sex when putting together a treatment plan. Women would benefit from employment and childcare assistance, addressing untreated psychiatric disorders and better management of symptoms of withdrawal whereas men would be better served by addressing their polysubstance abuse [135,141].

It is also of great importance to highlight that despite the large body of literature on sex differences in opioid use and treatment strategies, less is known about the influence of gender biases on opioid prescribing in the clinical setting and subsequent use. Gender norms about men and women have led to women being prescribed opioids at a higher rate than ‘brave men’, who report less pain than ‘emotional women’, which has been described in detail by Samulowitz and colleagues [144]. In fact, such gender biases in pain treatment were found to be driven in part by the patient-provider encounter, whereby gender role expectations can influence the perception of pain by a clinician. Such gender biases can significantly alter a clinician’s ability and likelihood to prescribe opioids, and may contribute to the elevated number of women compared to men that report using opioids, as discussed above. As part of treating patients with chronic pain, and those that go on to develop OUDs, we must fully understand how gender biases in the clinic may contribute to sex differences highlighted above.

10. Medication assisted therapy and the collaborative care treatment model

Medication assisted therapy uses medication to decrease symptoms of withdrawal and cravings (buprenorphine, methadone, and naltrexone) and to prevent overdose fatality (naloxone) as a supplement to counseling and/or behavioral therapies for opioid use disorder. Medications are intended to allow the psychological and behavioral work needed for recovery and sustained abstinence to occur by preventing overdose, decreasing the need for rapid detoxification, lowering the risk of disease transmission, and increasing patient retention in treatment [145]. As such, the dosage and duration should be tailored to the individual, with a robust plan for deprescribing and ambulatory care put in place early in treatment. A deprescribing plan should provide a schedule to taper and ultimately wean the patient off opioid use while monitoring signs of withdrawal that may include nausea, vomiting, cramping, perspiration, and anxiety. Gastrointestinal and other physiological signs and symptoms should be addressed with supplementary medications, whereas PT, OT, exercise and other nonpharmaceutical interventions should be utilized as alternative pain management strategies when pain is involved [146]. Additionally, ambulatory care should include education on safe opioid use, storage, and disposal as well as regular follow-ups and interventions as needed [147]. These services may be administered by a single care provider or multiple care providers working together.

The collaborative care model for opioid use disorder, which incorporates input from multiple physicians from different disciplines, has emerged as a more efficacious treatment model than the traditional model of care [148]. One strength of the collaborative care model is the incorporation of a care manager who is responsible for coordinating communication between the patient, primary care physician, therapist or social worker, and psychiatrist. The success of such groups of treatment professionals is largely dependent on their availability and cohesion, which is especially advantageous in dedicated facilities containing Addiction Behavior Units. They also are responsible for following up on treatment progress, incorporating recommendations and adjustments to treatment, and assisting with challenges that might arise regarding logistics and access to care[149]. This model acknowledges that primary care physicians are the healthcare providers most likely to be approached for help and aims to provide training and support to both physician and patient in the primary care setting [148].

11. Conclusion

OUD is a chronic disease prone to relapse that can be, in many cases, ameliorated with pharmacological interventions. While current treatment options are not successful for every individual affected by OUD, there are options available to increase the likelihood of abstinence and decrease the propensity of relapse. Yet, because current treatment options rely heavily on targeting the opioid system as opposed to other contributing mechanistic factors such as the neuroimmune system, treatment options have much room for improvement. Above we have highlighted the use of multiple OUD pharmacotherapies including methadone, tramadol, and buprenorphine and their use as replacement therapies, naltrexone and naloxone and their ability to prevent activation of MORs and promote detoxification, as well as non-FDA-regulated, over-the-counter substances such as kratom and N-acetylcysteine, which have shown some promising results for reducing opioid craving. We have also highlighted the effectiveness of combining treatments such as buprenorphine and naloxone, which serves as a novel approach for treating OUDs and suggests that further research be conducted on the combination of pharmacotherapies to increase treatment efficacy. Taken together, this review highlights the current treatment strategies for individuals suffering from OUD and provides insight into new treatment strategies that may prove beneficial for improving treatment outcomes in these patients.

12. Expert opinion

Opioid use and overdoses within the US are continuously rising, which has been perpetuated by the COVID-19 pandemic as well as newly available synthetic opioids, where overdoses have risen by over 25% in the last year alone. However, while the current treatment options for OUD offer some efficacy, limitations exist, especially given that treatment initiation and maintenance is hindered by unequal access to treatment. While there are reversal treatments for overdose, diminishing withdrawal symptoms and cravings, and preventing withdrawal, an effective universal treatment for all of these phases and characteristics exhibited by patients with OUD is severely lacking. Specifically, treatments have heavily relied on either opioid replacement therapies (buprenorphine and methadone) or antagonism at opioid receptors for therapeutic effects, which disregard other potentially targetable cellular mechanisms underlying OUD. Newer studies uncovering the role of the neuroimmune system and opioid-induced microglial activation could serve as a basis for promising avenues for future therapeutic developments, as pharmaceuticals targeting these pathways have been beneficial for treatment of alcohol and nicotine use disorders [50,150,151]. Additionally, while the combination of commonly used treatments (i.e. buprenorphine + naloxone) have only recently become mainstream, they appear to be promising for improved treatment over either drug alone, which we also believe could be beneficial for future treatment developments. Thus, we believe that in order to effectively treat OUDs, a deeper understanding of the therapeutics being utilized, their additive effects when given together, and the added involvement of the neuroimmune system are necessary. A complete understanding of the opioid-induced neuronal alterations and the therapeutics that target these abnormalities – including the neuroimmune system – should be deemed necessary for the advancement of the field and the development of treatments that address all phases and characteristics exhibited by patients with OUD that make them prone to relapse.

Article highlights:

1. Opioid use disorder (OUD) impacts all parts of the world, with highest prevalence and number of fatal overdoses reported within the United States.

2. Opioids elicit their rewarding effects by binding to opioid receptors across several brain regions and altering neuroimmune signaling, contributing to enhanced dopamine release in reward-related regions.

3. Opioid replacement therapies (methadone and buprenorphine) are shown to be effective for decreasing opioid craving and relapse propensity.

4. Targeting the neuroimmune pathways altered by opioids has shown promising preclinical efficacy and may prove beneficial for future treatment development.

5. The use of medication assisted therapy and the collaborative care treatment model has emerged as a more effective treatment model than the traditional model of care, furthering treatment efficacy for OUD.

6. Additional preclinical findings on the effects of pharmacotherapies and the neuroimmune system are essential to fully understand OUDs and effective treatments.