Fentanyl and Other Opioid Use Disorders: Treatment and Research Needs

The opioid overdose epidemic, which has been markedly exacerbated by fentanyl, highlights the urgency for psychiatrists to be well versed on the proper screening and management of opioid use disorder (OUD). This overview provides a brief review of opioid pharmacology, the neurobiology of opioid addiction (corresponding to moderate and severe OUD), and treatments and promising interventions, and outlines some knowledge gaps and research needs, particularly in relation to fentanyl.

Opioid Pharmacology

Opioid drugs, whether used for their rewarding effects or as analgesics, exert their effects by stimulating opioid receptors, which are constituents of the endogenous opioid system. The three types of opioid receptors—mu (MORs), delta (DORs), and kappa (KORs)—are involved in multiple functions, including reward, analgesia, stress reactivity, and emotions. The rewarding and analgesic effects of opioids are mediated by their agonist effects at MORs, which also underlie their addictiveness. DORs are associated with anxiolytic, antidepressant, and analgesic properties, and KORs with aversive and psychotomimetic effects, and they also contribute to analgesia (1). Overall, the opioid system appears to be geared toward maximizing reward-based learning and minimizing aversive experiences (2).

MORs are expressed throughout various subcortical and cortical regions in the human brain, with the highest concentrations in regions involved with reward, mood, and analgesia (3). Stimulation of MORs in midbrain dopamine nuclei (4, 5) disinhibits dopamine neurons and increases dopamine release in the nucleus accumbens, which is a key brain reward region. Stimulation of MORs in brainstem respiratory nuclei inhibits breathing, which is the mechanism that drives opioid overdoses.

KORs are not associated with opioids’ rewarding effects, but repeated opioid or alcohol exposures upregulate dynorphin signaling via KORs, contributing to the aversive state of drug withdrawal (6). Stressful stimuli also enhance dynorphin KOR signaling, contributing to relapse in addiction (7, 8). KOR activation in the nucleus accumbens inhibits the release of dopamine, and in dorsal raphe the release of serotonin, both of which contribute to anhedonia and negative mood states (9). KORs in the amygdala are also implicated in anxiety and enhanced stress sensitivity (10). KOR antagonists are of interest as targets for OUD medications to mitigate the negative emotional state associated with addiction. Two of the medications used to treat OUD—buprenorphine and naltrexone—have KOR antagonist effects (in addition to their MOR effects), which may contribute to their therapeutic benefits (11).

DORs are widely expressed in brain regions involved in mood and analgesia (12, 13), but less is known about their role in drug reward and addiction (14). DOR agonist drugs have antidepressant, anxiolytic, and analgesic effects (15). DORs also modulate dopamine release in the nucleus accumbens (16) and have been implicated in the influence of cues on decision making (17).

MORs are the target of approved medications to treat OUD and to reverse opioid overdoses, and drugs that target KORs and DORs are being evaluated for their potential benefits in OUD.

Neurobiology of OUD

Opioid use is initially under voluntary control, but in vulnerable individuals, repeated use can result in addiction, leading to loss of control and compulsive drug consumption in a repetitive cycle of intoxication, withdrawal, and craving (18). Addiction progresses along a severity continuum that reflects progressive neurobiological adaptations that persist even years after drug discontinuation. Addiction should be differentiated from physical dependence, which occurs in most individuals even after a few opioid exposures and manifests with the emergence of withdrawal symptoms on opioid discontinuation (19). Physical dependence resolves quickly and can be avoided by slowly tapering opioid medications. Improper management of physical dependence symptoms can result in persistent opioid use to overcome withdrawal that can eventually lead to addiction. Withdrawal symptoms are prominent in opioid-addicted individuals, manifesting as restlessness, anxiety, and irritability and physical symptoms such as sweating, abdominal pain, and tachycardia, triggering drug craving and relapse (20).

Neuroadaptations that result in addiction implicate neuronal networks involved with reward/motivation, stress reactivity/emotion, executive function, and interoception (21). The reward/motivation network, comprising the midbrain dopamine neurons and their projections to cortical and subcortical regions, underlies the rewarding and conditioning effects of drugs, including opioids, and it energizes the motivation to consume them. This network is stimulated during intoxication but becomes hypofunctional during the withdrawal stage, leading to anhedonia and decreased motivation for non-drug rewards (22). Exposure to drug cues and stressors reactivates it, triggering craving, which leads to drug consumption and intoxication, completing the cycle. Opioids are initially used because of their rewarding effects or analgesic actions, but with repeated use, tolerance develops and higher doses are needed to produce the desired effects. The severity of withdrawal symptoms upon opioid interruption increases, and craving begins, in order to avoid withdrawal. The stress reactivity/emotion network includes limbic brain regions and becomes increasingly engaged as addiction progresses, contributing to enhanced stress reactivity and the dominance of negative emotions during the withdrawal stage.

The executive control network, which underlies various cognitive processes such as decision making and self-regulation (21), is disrupted by the repeated use of licit (alcohol and nicotine) and illicit drugs (i.e., opioids, stimulants), resulting in increased impulsivity and risky behaviors. This network includes various regions in the prefrontal cortex whose functions are modulated by dopamine directly through cortical D₁ and D₂ receptors and indirectly through striato-thalamo-cortical circuits (23). To the extent that certain psychiatric disorders (e.g., ADHD) or adverse developmental exposures (e.g., stress, poverty) can interfere with the development of the prefrontal cortex, this constitutes an increased vulnerability for drug use and for transitioning into addiction (24).

Finally, the interoceptive network, which enables self-awareness of mental state, engages the default mode network’s coordination of internal versus external attention, and its disruption focuses consciousness on the negative emotional state of withdrawal and craving stages, driving behavioral choices to escape them (25).

Medication for Opioid Use Disorder

Medication for opioid use disorder (MOUD) is the gold standard for OUD treatment, as it significantly reduces risks of overdose deaths, infections, and criminal behavior while helping patients achieve recovery (26–33).

There are currently three medications approved by the U.S. Food and Drug Administration (FDA) for OUD treatment: methadone, buprenorphine, and naltrexone (34–37), each with distinct effects at MORs. Methadone, a full opioid agonist, has the strongest intrinsic efficacy, and as such it requires lower levels of MOR occupancy for therapeutic benefits in OUD, whereas buprenorphine, a partial opioid agonist, has lower intrinsic efficacy, requiring almost complete MOR occupancy for OUD treatment. Naltrexone, an opioid antagonist, is devoid of signaling when it occupies MORs, but it blocks other opioids from binding (38).

Methadone, which was approved by the FDA in 1973, has the longest history among the OUD medications and is the most extensively used worldwide (36, 39, 40). Methadone is typically dispensed daily as an oral solution, and dosages above 80 mg/day are recommended (41, 42). As a full MOR agonist, methadone lacks a ceiling effect and can result in overdoses when used at doses above the patient’s tolerance or when combined with other opioid drugs. As with other opioid drugs, the risk of overdose also increases when methadone is combined with other depressant drugs, such as alcohol or benzodiazepines. A challenge for the use of methadone is that it must be administered in licensed outpatient treatment programs. There are around 1,700 such programs in the United States, mostly in large urban areas, and patients from suburban or rural areas may have to travel large distances to attend treatment (43). Alternative service models, including office-based practices or dispensing through pharmacies, for which there is evidence of safety and effectiveness, would increase access and facilitate methadone treatment (44). Studies should also evaluate the potential of telehealth for monitoring adherence to methadone treatment.

Buprenorphine is often prescribed in a sublingual formulation that includes naloxone (an opioid antagonist with poor oral bioavailability) to minimize injection misuse. As a partial opioid agonist, buprenorphine is less likely to induce severe respiratory depression unless combined with other CNS depressants (45). Moreover, its high affinity for MORs, combined with its low intrinsic efficacy, protects against overdoses even from fentanyl, provided that adequate doses are given (46, 47). Buprenorphine’s KOR antagonist effects may help improve mood symptoms (48, 49). Daily dosing is recommended for sublingual administration. Although some providers favor multiple daily dosing, evidence indicates that it is associated with worse outcomes (47). The target dosage for most patients is 16 mg/day, with dosages ranging from 8 to 24 mg/day (32). Sustained plasma buprenorphine concentrations above 1 ng/mL were initially recommended to prevent withdrawal and cravings (50), but recent estimates that take into account possible fentanyl exposures recommend 2–3 ng/mL (51). Daily dosing can limit adherence (52) and could result in suboptimal buprenorphine plasma levels at the end of the 24-hour interval (50). Extended-release formulations of buprenorphine, including a monthly injection approved in 2018 (53) and a once-a-week formulation awaiting FDA approval, may help overcome these challenges.

An extended-release monthly formulation of naltrexone (naltrexone-XR) significantly reduces relapses and overdoses and shows improved outcomes (34, 35, 54) compared to immediate-release naltrexone. Naltrexone-XR is favored by patients with OUD who do not want to receive an opioid agonist and by treatment programs in jails and prisons. A major challenge for naltrexone-XR is that patients must be abstinent for 1 week prior to treatment induction, to avoid withdrawal. Naltrexone is also a KOR antagonist (55), which could contribute to mood improvement.

Medication Selection

There is limited information regarding the comparative effectiveness of the medications used in MOUD. A Cochrane review found that flexible-dose methadone leads to greater retention in treatment than sublingual buprenorphine (37), but studies are needed to determine how retention rates compare between methadone and extended-release buprenorphine. There are no published Cochrane reviews of naltrexone-XR versus buprenorphine. The results of two randomized clinical trials suggest that among adults with OUD who were abstinent at the time of randomization, the two medications were equally effective in retention and reduction of illicit opioid use. However, the high dropout rates with naltrexone-XR, prior to induction, make it less effective overall compared to sublingual buprenorphine.

The decision of which MOUD treatment to select is often based on practical considerations, such as access to an outpatient treatment program or insurance coverage for buprenorphine or naltrexone-XR, rather than patient characteristics. Despite some attempts at identifying them, the characteristics that might predict greater benefit for one MOUD treatment over another are currently unknown (32).

Methadone and buprenorphine are recommended for OUD treatment during pregnancy (32, 56), as there is no evidence of birth defects or neurodevelopmental delays with their use, and they lead to better maternal and infant outcomes than no MOUD treatment (57). Naltrexone-XR induction is currently contraindicated during pregnancy because of the risk of precipitated withdrawal. Whether pregnant women already on naltrexone-XR should continue or switch to another MOUD treatment is less clear (32).

There is very limited knowledge on the treatment of OUD in adolescents. Buprenorphine is approved for treatment of OUD in individuals age 16 or older (58), and although methadone is not, it can be prescribed for patients under age 18 if they had two previous unsuccessful treatment attempts and with proper consent of a parent or guardian (59). However, less than 3% of adolescents treated for their OUD receive these medications (60), and MOUD is used mostly for short-term detoxification in this population (61). Small clinical trials have shown preliminary evidence of efficacy for naltrexone-XR in adolescents, although retention is a challenge (62). Treatment of OUD in adolescents is an area that requires further investigation.

Although clinical management should be part of any pharmacological treatment, the current evidence does not support adjunctive psychotherapy in increasing retention or abstinence with buprenorphine (63–65). By contrast, interim methadone and buprenorphine (i.e., without concomitant counseling [66]) are associated with significantly better outcomes than no treatment (67). Thus, lack of access to ongoing therapy should not constitute a reason to delay MOUD (68). Nevertheless, concurrent psychotherapy may benefit certain patients, such as those with co-occurring psychiatric disorders. Contingency management and cognitive therapy are among the most widely used adjunctive behavioral interventions in OUD (69).

Treating Opioid-Related Overdoses

The treatment of an overdose is immediate administration of naloxone, either intravenously, intramuscularly, or intranasally (70, 71). Naloxone is safe and devoid of effects in persons not using opioids. However, it can precipitate an acute opioid withdrawal in those who have recently used opioids. A single dose of naloxone (4 mg intranasal spray or 0.4–2 mg intramuscular injection) is sufficient to reverse most overdoses, but multiple doses may be necessary with fentanyl overdoses (32) because of the shorter duration of naloxone (60–90 minutes) compared with fentanyl’s (2–4 hours). A higher-dose intranasal naloxone formulation (8 mg) that results in higher naloxone plasma concentrations and longer duration was recently approved by the FDA. Failure to reverse an overdose with naloxone may reflect the contribution from other substances (i.e., alcohol, benzodiazepines, xylazine). After an overdose reversal, patients should be transported to an emergency department to assess additional medical support needs, such as readministration of naloxone, need for lofexidine or clonidine to control withdrawal symptoms, or the delivery of oxygen and intubation if necessary (72). The emergency department can also be used to initiate buprenorphine treatment or to link with an outpatient treatment program and other services (73).

Treating Opioid Withdrawal

Detoxification (medically supervised withdrawal) is not recommended as OUD treatment, as most patients relapse, and their risk of overdose is particularly high due to reversal of tolerance (74). Detoxification may be indicated when initiating treatment with naltrexone-XR, which requires 1 week of abstinence. Buprenorphine and methadone can be used to facilitate detoxification through daily tapering to lower doses. A taper protocol for faster naltrexone-XR induction relies on a single day of buprenorphine followed by ascending doses of oral naltrexone along with clonidine and other adjunctive medications, such as clonazepam and prochlorperazine (75).

Alpha-2 adrenergic agonists such as lofexidine and clonidine reduce withdrawal symptoms from noradrenergic hyperactivity but do not address other withdrawal symptoms, such as craving and anhedonia (72). It is essential that withdrawal be followed by ongoing MOUD treatment (76).

Knowledge Gaps and Research Needs

The changes in the patterns of opioids misused, along with the increase in polysubstance use, identify areas for which research could be valuable both in the development of alternative medications and other therapeutics (Table 1) and in clinical management (Table 2).

Therapeutics for OUD and Overdose

Although available medications for OUD are very effective, not all patients benefit from them, and the rate of discontinuation is high (77). Extended-release formulations facilitate adherence, and while such formulations exist for buprenorphine and naltrexone, there are none for methadone, and longer-duration formulations (>1 month) could further improve retention.

There is also a need for medications with clinical outcomes other than abstinence, which is a very high bar to achieve. It is akin to requiring resolution of depression symptoms for approval of an antidepressant instead of the current approvals based on a decrease in symptom severity. Trials of medications that could have been potentially beneficial to patients with OUD may have failed because of their inability to help achieve continued abstinence, which is the main outcome required by the FDA for approval. Thus, research is ongoing to determine benefits to OUD patients from improvements in alternative outcomes, such as decreased craving, improved sleep, decreased OUD severity, or decreased drug use, that could serve as main outcomes for FDA approvals (78). Also ongoing is research to develop biomarkers that are acceptable to the FDA for medication development, including patient-reported outcomes.

Research on new medications includes drugs with different pharmacological properties at MORs (i.e., different intracellular signaling paths or pharmacokinetics) and drugs with targets other than MORs that involve novel molecules as well as repurposed ones. Repurposing of medications such as suvorexant (a dual orexin receptor antagonist approved for insomnia) or liraglutide (a glucagon-like peptide-1 receptor agonist approved for diabetes), if effective for OUD, would be faster to bring into the clinic. Novel drugs that target general addiction endophenotypes, such as drugs to inhibit enhanced stress reactivity (e.g., KOR antagonists and corticotropin-releasing factor receptor antagonists), decrease cue reactivity (e.g., dopamine D₃ receptor partial agonist/antagonists), modulate reward circuitry (e.g., neurokinin 1 and orexin 1 receptor antagonists), among others, are mostly in preclinical stages (79, 80). Research on psychedelics, including psylocibin and ketamine, for OUD is in its early stages, but encouraging preliminary results have been published for nicotine dependence and alcohol use disorders (81). Most of the available clinical data are based on the use of psychedelics to enhance behavioral treatments.

Immunotherapies based on monoclonal antibodies or vaccines targeting different opioid drugs such as heroin, oxycodone, and fentanyl have shown encouraging preclinical findings and are being evaluated clinically. The rationale for this approach is for antibodies to trap the drugs in plasma, restricting their brain access. A phase 1 trial for an oxycodone vaccine is under way, but ultimately vaccines will have to be polyvalent against the various opioids present in illicit drugs to be effective in real-world settings. Notably, previous clinical trials to test vaccines for cocaine and nicotine failed because of insufficient antibody titers. Passive immunization with polyvalent monoclonal antibodies would be advantageous over vaccines in that they lead to higher titers, but they require repeated dosing. Synthesis of longer-duration monoclonal antibodies may help circumvent some of these limitations.

Neuromodulation with invasive and noninvasive strategies offers promising interventions, whether such treatments are administered on their own or as an adjunct to MOUD. Noninvasive approaches include transcranial magnetic stimulation (TMS), direct current stimulation (tDCS), low-intensity focused ultrasound (LIFU), and peripheral nerve stimulation. Neuromodulation aims to restore the balance of neuronal networks disrupted in addiction, and the insula, anterior cingulate cortex, and dorsolateral prefrontal cortex have been the main targets tested (82). Auricular peripheral stimulation of several cranial and occipital nerves was approved for the treatment of opioid withdrawal (83).

Ultrasound used for ablation or neuromodulation is being studied for the treatment of neuropsychiatric disorders. High-intensity ultrasound is used to precisely destroy targeted brain regions without the need for surgery and was approved for Parkinson’s disease (84). To our knowledge, there are no ongoing ultrasound-based ablative trials for OUD. The use of LIFU, which is nonablative, has also been proposed for therapeutic purposes. LIFU, unlike TMS and tDCS, can penetrate deep into the brain to target very specific subcortical regions noninvasively. A clinical trial is currently evaluating LIFU to the nucleus accumbens in OUD.

Deep brain stimulation (DBS) is an invasive approach that requires insertion of electrodes within the brain. DBS of the nucleus accumbens is currently being investigated for OUD (85, 86).

The need for new overdose therapeutics has been driven by the difficulties in reversing fentanyl- and polysubstance-associated overdoses. Fentanyl overdose requires faster interventions, higher naloxone doses, and in some instances, repeated dosing. Development of fast-acting, high-affinity, and longer-acting MOR antagonists could offer advantages over naloxone. Fentanyl overdoses associated with other drugs are even more challenging. Since there is a multiplicity of drug combinations, for most of which there are no antidotes, interventions that stimulate respiration could be beneficial in general, regardless of the drug combination, as adjunctive interventions to naloxone.

Clinical Management of OUD

Although in general there is a need to guide the type of MOUD for a given patient, this need is most urgent for the treatment of individuals with fentanyl OUD. Currently, there are no reported clinical trials comparing MOUD treatments in individuals with fentanyl OUD, which may be more challenging than for other OUDs (87, 88). Specifically, research is needed that compares the effectiveness of buprenorphine, methadone, and extended-release naltrexone, different induction protocols, and different dosages (75).

Strategies are needed to improve retention in MOUD treatment, including for fentanyl OUD. For example, a retrospective analysis (89) showed that coadministration of buprenorphine and antidepressants was associated with lower risk of discontinuation, but clinical trials have not properly evaluated the effectiveness of this or other medication combinations.

Another lingering question relates to the optimal duration of MOUD treatment. Although 6 months has been suggested by some, MOUD discontinuation after 6 months is associated with poor outcomes (90), whereas longer time in treatment is associated with lower rates of relapse and mortality (26, 34, 35, 91, 92). Studies to help determine optimal length of MOUD treatment based on patient characteristics would be valuable in guiding treatment duration.

Although the effectiveness of MOUD is well documented, a major challenge has been to increase the proportion of individuals with OUD who seek treatment, which is currently less than 20%. Thus, research on strategies to help overcome obstacles that interfere with the willingness to seek treatment (e.g., stigma against individuals with OUD and against MOUD treatments) and that expands on ways of engaging patients in MOUD is crucial.

The increasing dangerousness of illicit drugs puts individuals without an OUD diagnosis who misuse opioids at risk of overdose as well. However, there are no guidelines on how to treat such individuals, which includes those with subthreshold OUD or mild OUD (pre-addiction). The National Institute on Drug Abuse’s Clinical Trials Network is examining the appropriate use of buprenorphine for this patient population, but additional strategies, including research on the value of naltrexone-XR, are needed. This situation also highlights the need for screening for substance use as regular practice for clinicians in general and for psychiatrists in particular, as individuals with psychiatric disorders have higher risk for substance misuse. Similarly, patients suffering from chronic pain may be at risk of seeking illicitly manufactured opioids.

Finally, as our understanding of the neurobiological and social contributors to high-risk drug use expands, it should be used to inform prevention efforts across the lifespan (33). Prevention should also include research on novel harm-reduction interventions, such as overdose prevention centers and drug checking to prevent people from overdosing (93).

In summary, the increasing dominance of more potent opioids and drug mixtures in the illicit drug market has resulted in an unprecedented number of fatalities. Individuals with OUD have the highest risk of dying from opioid overdose and frequently struggle with comorbid psychiatric disorders. Treatment of OUD with MOUD alongside interventions for comorbid conditions will improve treatment retention, prevent overdoses, and facilitate recovery, and screening for opioid misuse will help prevent OUD and help with early OUD treatment initiation.