Fentanyl and Other Opioid Use Disorders: Treatment and Research Needs
Publication: American Journal of Psychiatry
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).
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).
| Research Gap | Goal |
|---|---|
| Need for extended-release MOUD treatments; greatest need is for methadone, for which no extended-release formulations are available | Increase treatment retention, prevent diversion |
| Development of clinically meaningful alternative end points for clinical trials in OUD, including patient-reported outcomes | Facilitate FDA approval of medications |
| Medications with targets other than MORs (e.g., other opioid receptors, dopamine D3 receptors, mGlu receptors, CRF receptors) | Expand treatment options for OUD |
| Repurposing of medications (e.g., orexin receptor antagonists such as suvorexant; glucagon-like peptide agonists) | Accelerate availability of expanded treatment options |
| Research on psychedelics, such as psylocibin, ketamine, ibogaine | Expand treatment options for OUD and other substance use disorders |
| Immunotherapies: vaccines and monoclonal antibodies | Counter effects of ingested or injected opioids by trapping them with antibodies |
| Neuromodulation (transcranial magnetic stimulation, direct current stimulation, low-intensity focused ultrasound, deep brain stimulation, peripheral nerve stimulation) | Restore the balance of neuronal networks disrupted in OUD |
| Fast, high-affinity opioid antagonists with longer duration | Reversal of overdoses from fentanyl and other high-potency opioids |
| Respiratory stimulant drugs | Increase breathing to help reverse polysubstance-related overdoses |
a
CRF=corticotropin-releasing factor; mGlu=metabotropic glutamate receptor; MOR=mu-opioid receptor; MOUD=medication for opioid use disorder; OUD=opioid use disorder.
| Research Gap | Goal |
|---|---|
| Optimal strategies to treat individuals with fentanyl OUD | Determine comparative effectiveness of methadone, sublingual buprenorphine, buprenorphine-XR, and naltrexone-XR |
| Induction protocols for treatment of fentanyl OUD and comparisons of doses | Determine doses needed to initiate and retain in treatment individuals with fentanyl OUD |
| Improve entry into and retention in MOUD treatment | Expand the number of individuals with OUD who seek and receive MOUD treatment and increase treatment retention |
| Treatment of mild or subthreshold OUD | Determine the role of naltrexone-XR or buprenorphine in overdoses in high-risk opioid misusers |
| Treatment of adolescents with OUD | Determine the efficacy of the various MOUD treatments and best strategies to increase retention and recovery |
| Determine patient-specific optimal medication, dosages, and length of treatment | Personalize interventions to increase retention and recovery |
| Treatment of patients with OUD and comorbid psychiatric disorders or with comorbid pain | Improve outcomes in patients with dual diagnoses |
| Prevention strategies that evaluate digital approaches and harm reduction (e.g., overdose prevention centers, drug checking) | Expand on universal and targeted prevention efforts to protect individuals early on from drug exposures and prevent overdose deaths among those misusing opioids |
a
MOUD=medication for opioid use disorder; OUD=opioid use disorder; XR=extended release.
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.
References
1.
Crowley NA, Kash TL: Kappa opioid receptor signaling in the brain: circuitry and implications for treatment. Prog Neuropsychopharmacol Biol Psychiatry 2015; 62:51–60
2.
Darcq E, Kieffer BL: Opioid receptors: drivers to addiction? Nat Rev Neurosci 2018; 19:499–514
3.
Shokri-Kojori E, Naganawa M, Ramchandani VA, et al: Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine. Hum Brain Mapp 2022; 43:1419–1430
4.
Contet C, Kieffer BL, Befort K: Mu opioid receptor: a gateway to drug addiction. Curr Opin Neurobiol 2004; 14:370–378
5.
Laurent V, Morse AK, Balleine BW: The role of opioid processes in reward and decision-making. Br J Pharmacol 2015; 172:449–459
6.
Chavkin C, Koob GF: Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacology 2016; 41:373–374
7.
Blanco C, Wall MM, Okuda M, et al: Pain as a predictor of opioid use disorder in a nationally representative sample. Am J Psychiatry 2016; 173:1189–1195
8.
Koob GF, Le Moal M: Addiction and the brain antireward system. Annu Rev Psychol 2008; 59:29–53
9.
Tao R, Auerbach SB: mu-Opioids disinhibit and kappa-opioids inhibit serotonin efflux in the dorsal raphe nucleus. Brain Res 2005; 1049:70–79
10.
Crowley NA, Bloodgood DW, Hardaway JA, et al: Dynorphin controls the gain of an amygdalar anxiety circuit. Cell Rep 2016; 14:2774–2783
11.
Lutfy K, Cowan A: Buprenorphine: a unique drug with complex pharmacology. Curr Neuropharmacol 2004; 2:395–402
12.
Erbs E, Faget L, Scherrer G, et al: A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks. Brain Struct Funct 2015; 220:677–702
13.
Le Merrer J, Becker JA, Befort K, et al: Reward processing by the opioid system in the brain. Physiol Rev 2009; 89:1379–1412
14.
Pradhan AA, Befort K, Nozaki C, et al: The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci 2011; 32:581–590
15.
Dripps IJ, Jutkiewicz EM: Delta opioid receptors and modulation of mood and emotion. Handb Exp Pharmacol 2018; 247:179–197
16.
Saigusa T, Aono Y, Waddington JL: Mechanisms underlying delta- and mu-opioid receptor agonist–induced increases in extracellular dopamine level in the nucleus accumbens of freely moving rats. J Oral Sci 2017; 59:195–200
17.
Laurent V, Bertran-Gonzalez J, Chieng BC, et al: δ-opioid and dopaminergic processes in accumbens shell modulate the cholinergic control of predictive learning and choice. J Neurosci 2014; 34:1358–1369
18.
Volkow ND, Michaelides M, Baler R: The neuroscience of drug reward and addiction. Physiol Rev 2019; 99:2115–2140
19.
Pergolizzi JV, Jr., Raffa RB, Rosenblatt MH: Opioid withdrawal symptoms, a consequence of chronic opioid use and opioid use disorder: current understanding and approaches to management. J Clin Pharm Ther 2020; 45:892–903
20.
Volkow ND, Koob GF, McLellan AT: Neurobiologic advances from the brain disease model of addiction. N Engl J Med 2016; 374:363–371
21.
Koob GF, Volkow ND: Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 2016; 3:760–773
22.
Volkow ND, Blanco C: Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment, and prevention. World Psychiatry (in press)
23.
Goldstein RZ, Volkow ND: Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 2011; 12:652–669
24.
Perry JL, Joseph JE, Jiang Y, et al: Prefrontal cortex and drug abuse vulnerability: translation to prevention and treatment interventions. Brain Res Rev 2011; 65:124–149
25.
Zhang R, Volkow ND: Brain default-mode network dysfunction in addiction. Neuroimage 2019; 200:313–331
26.
Timko C, Schultz NR, Cucciare MA, et al: Retention in medication-assisted treatment for opiate dependence: a systematic review. J Addict Dis 2016; 35:22–35
27.
Degenhardt L, Randall D, Hall W, et al: Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved. Drug Alcohol Depend 2009; 105:9–15
28.
Gibson A, Degenhardt L, Mattick RP, et al: Exposure to opioid maintenance treatment reduces long-term mortality. Addiction 2008; 103:462–468
29.
Schwartz RP, Gryczynski J, O’Grady KE, et al: Opioid agonist treatments and heroin overdose deaths in Baltimore, Maryland, 1995–2009. Am J Public Health 2013; 103:917–922
30.
Connock M, Juarez-Garcia A, Jowett S, et al: Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation. Health Technol Assess 2007; 11:1–171
31.
Lynch FL, McCarty D, Mertens J, et al: Costs of care for persons with opioid dependence in commercial integrated health systems. Addict Sci Clin Pract 2014; 9:16
32.
Substance Abuse and Mental Health Services Administration (SAMHSA): Treatment Improvement Protocol (TIP) 63: Medications for Opioid Use Disorder. Washington, DC, US Department of Health and Human Services, SAMHSA, 2018
33.
Blanco C, Volkow ND: Management of opioid use disorder in the USA: present status and future directions. Lancet 2019; 393:1760–1772
34.
Krupitsky E, Nunes EV, Ling W, et al: Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-controlled, multicentre randomised trial. Lancet 2011; 377:1506–1513
35.
Lee JD, Friedmann PD, Kinlock TW, et al: Extended-release naltrexone to prevent opioid relapse in criminal justice offenders. N Engl J Med 2016; 374:1232–1242
36.
Mattick RP, Breen C, Kimber J, et al: Methadone maintenance therapy versus no opioid replacement therapy for opioid dependence. Cochrane Database Syst Rev 2009; 2009:CD002209
37.
Mattick RP, Breen C, Kimber J, et al: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2004:CD002207
38.
Schuckit MA: Treatment of opioid-use disorders. N Engl J Med 2016; 375:357–368
39.
Nielsen S, Larance B, Degenhardt L, et al: Opioid agonist treatment for pharmaceutical opioid dependent people. Cochrane Database Syst Rev 2016:CD011117
40.
Sees KL, Delucchi KL, Masson C, et al: Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA 2000; 283:1303–1310
41.
Amato L, Davoli M, Perucci CA, et al: An overview of systematic reviews of the effectiveness of opiate maintenance therapies: available evidence to inform clinical practice and research. J Subst Abuse Treat 2005; 28:321–329
42.
Faggiano F, Vigna‐Taglianti F, Versino E, et al: Methadone maintenance at different dosages for opioid dependence. Cochrane Database Syst Rev 2003:CD002208
43.
Pasman E, Kollin R, Broman M, et al: Cumulative barriers to retention in methadone treatment among adults from rural and small urban communities. Addict Sci Clin Pract 2022; 17:35
44.
McCarty D, Bougatsos C, Chan B, et al: Office-based methadone treatment for opioid use disorder and pharmacy dispensing: a scoping review. Am J Psychiatry 2021; 178:804–817
45.
Lofwall MR, Walsh SL: A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med 2014; 8:315–326
46.
Olofsen E, Algera MH, Moss L, et al: Modeling buprenorphine reduction of fentanyl-induced respiratory depression. JCI Insight 2022; 7:e156973
47.
Allen SM, Nichols TA, Fawcett J, et al: Outcomes associated with once-daily versus multiple-daily dosing of buprenorphine/naloxone for opioid use disorder. Am J Addict 2022; 31:173–179
48.
Falcon E, Browne CA, Leon RM, et al: Antidepressant-like effects of buprenorphine are mediated by kappa opioid receptors. Neuropsychopharmacology 2016; 41:2344–2351
49.
Khanna IK, Pillarisetti S: Buprenorphine: an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res 2015; 8:859–870
50.
Greenwald M, Johanson CE, Bueller J, et al: Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices. Biol Psychiatry 2007; 61:101–110
51.
Laffont CM, Ngaimisi E, Gopalakrishnan M, et al: Buprenorphine exposure levels to optimize treatment outcomes in opioid use disorder. Front Pharmacol 2022; 13:1052113
52.
Tkacz J, Severt J, Cacciola J, et al: Compliance with buprenorphine medication-assisted treatment and relapse to opioid use. Am J Addict 2012; 21:55–62
53.
Haight BR, Learned SM, Laffont CM, et al: Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2019; 393:778–790
54.
Comer SD, Sullivan MA, Yu E, et al: Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry 2006; 63:210–218
55.
Weerts EM, Kim YK, Wand GS, et al: Differences in delta- and mu-opioid receptor blockade measured by positron emission tomography in naltrexone-treated recently abstinent alcohol-dependent subjects. Neuropsychopharmacology 2008; 33:653–665
56.
Committee Opinion No 711: Opioid use and opioid use disorder in pregnancy. Obstet Gynecol 2017; 130:e81–e94
57.
Fajemirokun-Odudeyi O, Sinha C, Tutty S, et al: Pregnancy outcome in women who use opiates. Eur J Obstet Gynecol Reprod Biol 2006; 126:170–175
58.
Borodovsky JT, Levy S, Fishman M, et al: Buprenorphine treatment for adolescents and young adults with opioid use disorders: a narrative review. J Addict Med 2018; 12:170–183
59.
Certification of Opioid Treatment Programs, 42 Code of Federal Regulations (CFR) 8. Washington, DC, US Government Publishing Office, 2017
60.
Feder KA, Krawczyk N, Saloner B: Medication-Assisted treatment for adolescents in specialty treatment for opioid use disorder. J Adolesc Health 2017; 60:747–750
61.
Matson SC, Hobson G, Abdel-Rasoul M, et al: A retrospective study of retention of opioid-dependent adolescents and young adults in an outpatient buprenorphine/naloxone clinic. J Addict Med 2014; 8:176–182
62.
Fishman MJ, Winstanley EL, Curran E, et al: Treatment of opioid dependence in adolescents and young adults with extended release naltrexone: preliminary case-series and feasibility. Addiction 2010; 105:1669–1676
63.
Ling W, Amass L, Shoptaw S, et al: A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction 2005; 100:1090–1100
64.
Weiss RD, Potter JS, Fiellin DA, et al: Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry 2011; 68:1238–1246
65.
Moore BA, Fiellin DA, Cutter CJ, et al: Cognitive behavioral therapy improves treatment outcomes for prescription opioid users in primary care buprenorphine treatment. J Subst Abuse Treat 2016; 71:54–57
66.
Schwartz RP, Alexandre PK, Kelly SM, et al: Interim versus standard methadone treatment: a benefit-cost analysis. J Subst Abuse Treat 2014; 46:306–314
67.
Sigmon SC, Schwartz RP, Higgins ST: Buprenorphine for persons on waiting lists for treatment for opioid dependence. N Engl J Med 2017; 376:1000–1001
68.
National Academies of Sciences, Engineering, and Medicine: Medications for Opioid Use Disorder Save Lives. Washington, DC, National Academies Press, 2019
69.
Sofuoglu M, Devito EE, Carroll KM: Pharmacological and behavioral treatment of opioid use disorder. Psychiatr Res Clin Pract 2019; 1:4–15
70.
Albert S, Brason FW Ⅱ, Sanford CK, et al: Project Lazarus: community-based overdose prevention in rural North Carolina. Pain Med 2011; 12:S77–S85
71.
Walley AY, Xuan Z, Hackman HH, et al: Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ 2013; 346:f174
72.
Gowing L, Ali R, White JM: Opioid antagonists with minimal sedation for opioid withdrawal. Cochrane Database Syst Rev 2017; 5:CD002021
73.
D’Onofrio G, O’Connor PG, Pantalon MV, et al: Emergency department–initiated buprenorphine/naloxone treatment for opioid dependence: a randomized clinical trial. JAMA 2015; 313:1636–1644
74.
Dhanda A, Salsitz EA: The duration dilemma in opioid agonist therapy. J Opioid Manag 2021; 17:353–358
75.
Sullivan M, Bisaga A, Pavlicova M, et al: Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxification with naltrexone versus buprenorphine. Am J Psychiatry 2017; 174:459–467
76.
Merrall EL, Kariminia A, Binswanger IA, et al: Meta-analysis of drug-related deaths soon after release from prison. Addiction 2010; 105:1545–1554
77.
Hser YI, Saxon AJ, Huang D, et al: Treatment retention among patients randomized to buprenorphine/naloxone compared to methadone in a multi-site trial. Addiction 2014; 109:79–87
78.
Volkow ND, Woodcock J, Compton WM, et al: Medication development in opioid addiction: meaningful clinical end points. Sci Transl Med 2018; 10:eaan2595
79.
Schank JR, Ryabinin AE, Giardino WJ, et al: Stress-related neuropeptides and addictive behaviors: beyond the usual suspects. Neuron 2012; 76:192–208
80.
Rasmussen K, White DA, Acri JB: NIDA’s medication development priorities in response to the opioid crisis: ten most wanted. Neuropsychopharmacology 2019; 44:657–659
81.
van der Meer PB, Fuentes JJ, Kaptein AA, et al: Therapeutic effect of psilocybin in addiction: a systematic review. Front Psychiatry 2023; 14:1134454
82.
Steele VR, Maxwell AM: Treating cocaine and opioid use disorder with transcranial magnetic stimulation: a path forward. Pharmacol Biochem Behav 2021; 209:173240
83.
Everett NA, Turner AJ, Costa PA, et al: The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats. Neuropsychopharmacology 2021; 46:297–304
84.
Koga S, Ishaque M, Jeffrey Elias W, et al: Neuropathology of Parkinson’s disease after focused ultrasound thalamotomy. NPJ Parkinsons Dis 2022; 8:59
85.
Fattahi M, Eskandari K, Sayehmiri F, et al: Deep brain stimulation for opioid use disorder: a systematic review of preclinical and clinical evidence. Brain Res Bull 2022; 187:39–48
86.
Hassan O, Phan S, Wiecks N, et al: Outcomes of deep brain stimulation surgery for substance use disorder: a systematic review. Neurosurg Rev 2021; 44:1967–1976
87.
Varshneya NB, Thakrar AP, Hobelmann JG, et al: Evidence of buprenorphine-precipitated withdrawal in persons who use fentanyl. J Addict Med 2022; 16:e265–e268
88.
Wakeman SE, Chang Y, Regan S, et al: Impact of fentanyl use on buprenorphine treatment retention and opioid abstinence. J Addict Med 2019; 13:253–257
89.
Zhang K, Jones CM, Compton WM, et al: Association between receipt of antidepressants and retention in buprenorphine treatment for opioid use disorder: a population-based retrospective cohort study. J Clin Psychiatry 2022; 83:21m14001
90.
Morgan JR, Schackman BR, Leff JA, et al: Injectable naltrexone, oral naltrexone, and buprenorphine utilization and discontinuation among individuals treated for opioid use disorder in a United States commercially insured population. J Subst Abuse Treat 2018; 85:90–96
91.
Nosyk B, Sun H, Evans E, et al: Defining dosing pattern characteristics of successful tapers following methadone maintenance treatment: results from a population-based retrospective cohort study. Addiction 2012; 107:1621–1629
92.
Sordo L, Barrio G, Bravo MJ, et al: Mortality risk during and after opioid substitution treatment: systematic review and meta-analysis of cohort studies. BMJ 2017; 357:j1550
93.
Understanding the opioid overdose epidemic. Atlanta, Centers for Disease Control and Prevention, 2021. https://www.cdc.gov/opioids/basics/epidemic.html
Information & Authors
Information
Published In
History
Accepted: 7 April 2023
Published online: 1 June 2023
Published in print: June 01, 2023
Keywords
Authors
Competing Interests
The authors report no financial relationships with commercial interests.
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBLogin options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).