Introduction
In the United States, approximately 4.1 million individuals have used heroin at least once in their lives, and about 359,000 of these individuals will go on to develop opioid use disorder (OUD). Most new users are males and are older than 17 years of age. Nonmedical use of prescription opioids has also risen dramatically from 11.8 million users in 2002 to 13.7 million users in 2003.1 Just the misuse of oxycodone has doubled within the past five years. A staggering 250% increase in oxycodone-related hospital ER admissions was documented in 2010.2 It is estimated that about 20% of individuals in the United States have used prescription opioids for a nonmedical reason at least once in their lifetime. The highest prevalence was among individuals 18 to 25 years of age, and as of 2010, 2 million of these individuals are dependent on prescription opioids. Treatment admissions for those with prescription OUD increased by 80% between 2004 and 2010.3 Among those patients who try heroin, 23% go on to develop OUD.Reference McCabe, West and Morales4 Deaths related to opioid overdose now exceed those caused by heroin and cocaine combined.Reference Bart5 Therefore, a greater understanding of the pharmacotherapies to treat OUD such as methadone and buprenorphine would allow the primary care physician to play an essential role in the treatment of this condition. Although counseling plays an integral role in enhancing treatment of OUD, it is not discussed in this article.
Neurobiology of OUD
OUD is a central nervous system disorder characterized by neurochemical changes that lead to compulsive opioid-taking behaviors despite severe consequences. As a result, the production of endogenous opioids such as β-endorphins, enkephalins, endomorphines, and dynorphyns are suppressed, which leads those patients with OUD to become dependent on exogenous opioids.Reference Kaye, Gervitz and Bosscher6 Opioid receptors are G-coupled receptors, and stimulation of the opioid receptors results in physiological and psychological effects, including euphoria, sedation, analgesia, constipation, and respiratory depression.Reference Farrell, Wodak and Gowing7 Of all of the opioid receptors, including μ, κ, Δ, and opioid receptor-like receptors, activation of the μ opioid receptors is responsible for the reinforcing effects of opioids, although activation of Δ opioid receptors may also add to opioid reinforcement. μ opioid receptors are present throughout the central nervous system, but they are most abundant in the ventral tegmental area (VTA), nucleus accumbens (NA), amygdala, and hippocampus.Reference Sigmon, Bisaga and Nunes8 Opioids exert their effects in the VTA and NA from either inhibition of GABAergic accumbal neurons or inhibition of excitatory glutamate terminals within the NA. Activation of μ opioid receptors in the VTA inhibits γ-amino butyric acid (GABA) release, which leads to increased extracellular dopamine levels in the NA.Reference Lobmaier, Gossop and Waal9 Over time, increased consumption of exogenous opioids results in brain adaptations such as tolerance and eventual dependence. Therefore, developing OUD is a complex interplay between genetics, environmental effects, and the pharmacological properties of opioids. Human family and twin studies have identified elevated genetic risk for opioid use disorder in first-degree relatives of those who have OUD.Reference Subramaniam and Stitzer10 The rewarding characteristics of opioids are related to their pharmacokinetic and pharmacodynamic properties. The rapidity with which an opioid enters the brain is directly correlated with the intensity of its reinforcing effects. This acceleration in drug availability is apparent in the transition from oral to intranasal, then to smoking, and ultimately, the intravenous route of introducing opioids into the central nervous system.11 Upon binding to the μ opioid receptor, the drug may be a full agonist (fully activating the receptor, such as heroin and methadone), a partial agonist (activating the receptor to a lesser degree than the full agonist), or an antagonist (not activating the receptor, but blocking opioids from entering the receptor). Drugs acting as a full agonist at the μ opioid receptor are more likely to be abused than those with activity at the other opioid receptors (eg, κ and Δ receptors). All of the most highly abused opioids, including morphine, heroin, hydrocodone, oxycodone, hydromorphone, and methadone, are μ opioid receptor agonists.Reference Clausen, Ancheiser and Waal12
Repeated opioid administration induces tolerance and results in withdrawal syndrome upon abrupt cessation. The unpleasant effects of opioid withdrawals produce negative reinforcements, whereby the opioids continue to be used to avoid the onset of withdrawals. Furthermore, short-acting opioids cause stress dysregulation, which may worsen the withdrawal syndrome and can continue long after cessation of opioid use; thus, they can be a contributing factor to the development of relapse.Reference Stancliff, Herman and Fong13 Imaging studies in patients with OUD have shown that there is a progressive reduction in dopamine D2 receptors, and this reduction correlates with the duration of opioid use. Pharmacotherapy may not correct alterations in dopamine receptor availability; however, it does appear to normalize stress dysfunction in patients with OUD.Reference Zijlstraf, Booij and van den Brink14
Treatment of OUD
The first step in treating patients with OUD includes inpatient and outpatient detoxification, which involves management of opioid withdrawal symptoms following abrupt cessation of the use of μ-opioid agonists.Reference Van den Brink and Haasen15 Detoxification is only the beginning of treatment and should be followed by long-term treatment, which may include maintenance therapy with μ-opioid agonists, partial μ-opioid agonists, or μ-opioid receptor antagonists.Reference Wadorf16 The aims of detoxification are the management of withdrawal symptoms while the patient is in the opioid-free state. Detoxification only addresses the acute physiological effects of opioid withdrawals, not the emotional, cognitive, behavioral, and social elements of recovery. Therefore, detoxification should be considered the precursor to comprehensive treatment. This treatment can be delivered in an inpatient or outpatient setting.Reference Mayet, Farrell and Ferri17 The decision as to whether to perform detoxification on an outpatient versus an inpatient setting depends on the person's comorbid medical and psychiatric problems, the availability of social support, and the presence of polysubstance abuse. It is important to distinguish between withdrawals from short-acting opioids such as heroin than from long-acting opioids such as methadone. One method of detoxification is to stabilize those who are dependent on heroin with methadone, then gradually decrease the methadone 20% per week for inpatients and 3% per week for outpatients. Methadone detoxification is controversial, given the effectiveness of methadone maintenance. Nonetheless, methadone has been described as the most effective pharmacotherapeutic agent used in detoxification.Reference Bao, Liu and Epstein18 Centrally acting α-2 adrenergic agonists, such as clonidine, reduce neuronal firing from the locus coeruleus. Clonidine is administered 0.1 mg every 4–6 hr, and has been found to reduce or eliminate some of the acute withdrawal symptoms such as rhinorrhea, restlessness, muscle cramps, and some GI symptoms. However, clonidine only reduces some withdrawal symptoms, and patients often require adjunctive medications such as sedative-hypnotics.Reference Gossop19 Buprenorphine, a partial μ-opioid receptor agonist, is another option for detoxification. Its effectiveness is dependent on certain factors, including the type of opioid used, amount of opioid consumed, duration of use, and psychosocial factors, such as sober support.Reference Seifert, Metzner and Paetzold20 Buprenorphine was found to be of comparable effectiveness to methadone in detoxification. Other studies have found that buprenorphine is superior to clonidine in reducing symptoms of withdrawals.Reference Fingerhood, Thompson and Jasinski21 Although detoxification can be provided in inpatient or outpatient settings, when detoxification takes place in an outpatient setting, success rates are low and many patients fail to complete treatment.Reference Linteris22
FDA-Approved Pharmacotherapies in Treating OUD
Full μ-opioid receptor agonists
There are several approaches to treat patients with OUD that are approved by the FDA: agonists (have affinity and efficacy at the μ-opioid receptor), partial agonists (have affinity but only partial efficacy at the μ-opioid receptor), or antagonists (have affinity but no efficacy at the μ-opioid receptor). Agonists and partial agonists can be used in detoxification or maintenance therapy with good treatment retention.Reference Colson, Standiford and Silverman23 Agonist maintenance is appropriate for those patients with a history of treatment failures, more severe progression of opioid use, and a long history of multiple drug overdoses.Reference Fiellin and O'Connor24 The research by Drs. Marie Nyswander and Vincent Dole at the Rockefeller Institute found that methadone is the first line of maintenance treatment. Their work led to the use of once-daily dosing of methadone to prevent symptoms of opioid withdrawals and cravings. Methadone maintenance to treat OUD was established in the 1970s with the Federal Methadone Regulation and the Narcotic Addict Treatment Act of 1974. As of 2008, 260,000 patients were enrolled in methadone maintenance treatment programs.25 Methadone is a μ-opioid receptor agonist, and it is also an antagonist at the N-methyl-D-aspartate (NMDA) receptor. It is available in tablet or liquid form and comes as a racemic mixture. The R isomer (R-methadone) is believed to be responsible for its analgesic properties, and the S isomer (S-methadone) is the NMDA receptor antagonist, which may be responsible for QTc prolongation (usually seen in doses exceeding 100 mg per day). NMDA antagonism leads to reverse opioid tolerance, which explains why some patients remain on the same methadone dose without an increase over a long period of time.Reference Kreek, Borg and Zhou26 The bioavailability of methadone after oral ingestion is variable, ranging from 70–80% with peak plasma concentration reached within a period of 2 hr. Methadone is metabolized mainly by the cytochrome P450 CYP3A4 and secondarily by CYP2D6. The use of certain medications can induce (eg, rifampin, phenytoin) or inhibit (eg, ketaconazole, fluvoxamine) plasma methadone levels.Reference McCance-Katz, Sullivan and Nallami27 Methadone is safe and effective, with a half-life that is variable ranging from 8 to 59 hr. However, like other μ-opioid agonists, methadone has the potential for inducing respiratory depression when given in doses that exceed an individual's tolerance or when methadone is used in combination with other sedating substances, such as sedatives and alcohol.Reference Martin, Campbell and Killip28 Therefore, it is contraindicated in patients with respiratory depression, acute bronchial asthma, or hypercarbia. Methadone relieves opioid withdrawal symptoms, and when it reaches steady-state, the euphoric effects of superimposed opioids are blocked. Mean 1-year retention for patients receiving methadone maintenance is about 60%. Methadone maintenance usually lasts at least 12 months and can continue for years. The length of treatment depends on the patient's needs. The typical dose is 20–30 mg and should not exceed 30 mg on the first day of induction. The usual maintenance dose ranges from 80–120 mg per day, with dosing adjustments made based on the patient's cravings and withdrawal symptoms.Reference Stotts, Dodrill and Kosten29 Main side effects of methadone maintenance include sedation, diaphoresis, constipation, insomnia, nausea, seizures, weight gain, and sexual dysfunction. As a Schedule II narcotic, methadone has abuse potential similar to other opioids, which can lead to increased overdoses and deaths.Reference Koob and Volkow30
Partial μ-opioid receptor agonists
Many patients with OUD are reluctant to seek treatment at a methadone clinic because of the side effects and the social stigma associated with methadone, as well as the requirement of daily dosing. Therefore, office-based treatment of OUD evolved after the passage of the Drug Addiction Treatment Act (DATA) of 2000, which allows physicians to use Schedule III–IV drugs such as buprenorphine (a Schedule III drug) to treat patients with OUD in an office-based setting. This allows the patient to be treated with more privacy and frees the patient from daily dosing.Reference Ducharme, Fraser and Gill31 In October 2002, sublingual buprenorphine and buprenorphine/naloxone tablets were approved by the FDA, allowing qualified U.S. physicians to prescribe them to treat patients with OUD in an office-based setting.Reference Parran, Aldeman and Merkin32 In order to treat patients with OUD with buprenorphine and buprenorphine/naloxone, physicians with a valid medical license must qualify for a waiver under the DATA 2000 by meeting one or more of the following criteria33:
1. Subspecialty board certification in addiction psychiatry
2. Addiction certification from the American Society of Addiction Medicine
3. Subspecialty board certification in addiction medicine from the American Osteopathic Association
4. Completion of at least 8 hours of training with respect to the treatment and management of patients with OUD
5. Participation as an investigator in clinical trials leading to the approval of Schedule III, IV, or one narcotic drug for maintenance or detoxification
Unlike methadone, which is a full μ-opioid receptor agonist, buprenorphine is a partial agonist at the μ-opioid receptor and an antagonist at the κ receptor. As a partial agonist, the maximum effect of buprenorphine is less than the maximum effect of methadone. This “ceiling effect” is due to the partial agonistic action on the μ-opioid receptor, and possibly due to agonistic action on the opioid receptor-like (ORL1) receptor.Reference Bell, Trinh and Butler34 A “ceiling effect” is where the analgesic effect plateaus, and no additional benefit is seen by increasing the dose. For buprenorphine, this “ceiling effect” is reached at a dose of about 16–20 mg.Reference Helms and Trescot35 In addition, because of its partial agonism, patients are less likely to abuse buprenorphine, and there is less respiratory depression associated with this drug. The recommended maximum sublingual dose is 24 mg or 32 mg, which is equivalent to 60–70 mg of methadone.Reference Ahmadi36 Buprenorphine undergoes extensive first-pass metabolism, and oral administration results in poor bioavailability. However, following sublingual administration, bioavailability is increased to 50%.Reference Schuh and Johanson37 Peak plasma levels are reached within 1–3 hr, and the elimination half-life is 37 hr. Buprenorphine is metabolized by the cytochrome P450 3A4 system. Phase III clinical trials indicate that buprenorphine maintenance has a safety profile comparable to methadone.Reference Fudala, Bridge and Herbert38 Nonetheless, deaths have been reported when buprenorphine is injected and used in combination with sedatives.Reference Kintz39 To reduce the harm associated with buprenorphine injection, it is available in formulations that combine buprenorphine with the μ-opioid receptor antagonist naloxone in a 4:1 ratio. Naloxone undergoes extensive first-pass metabolism and is not absorbed into the systemic circulation when taken orally or sublingually. However, injection allows naloxone to enter systemic circulation and compete with buprenorphine for receptor occupancy. Commercially, buprenorphine/naloxone comes in a 2/.5 mg or 8/2 mg combination as a tablet or film strip. Results from several clinical studies have confirmed the superiority of buprenorphine over placebo. It appears that decreased illicit opioid use and increased retention are observed in higher doses of buprenorphine (greater than 8 mg). In patients with higher dependence severity (eg, using a lot of opioids), they should be placed on full agonist maintenance (ie, methadone) over buprenorphine.Reference Mattick, Ali and White40 Buprenorphine is a high-affinity and moderate-efficacy μ-opioid receptor partial agonist, and it will displace other high-efficacy opiates, if present, and induce withdrawal symptoms. Thus, it is advised that the first dose of buprenorphine be given no sooner than 12 hr after the last use of a short-acting opioid and 24 hr after a long-acting opioid.Reference Moore, Fiellin and Barry41 Buprenorphine response is dose-related, with most patients stabilizing at doses between 12–16 mg daily. During maintenance treatment with buprenorphine, patients have reduced illicit opioid use, but following buprenorphine taper, more than 90% of patients return to illicit opioid use.Reference Weiss, Porter and Fiellin42 Another clinical trial found that buprenorphine (16–32 mg) is as effective as high-dose methadone (60–100 mg) in reducing opioid use in short-term maintenance of 17 weeks.Reference Comer, Sullivan and Vosburg43 A Cochrane review determined that both buprenorphine and methadone are effective in treating OUD.Reference Mattick, Kimber and Breen44 Recently, there has been growing interest in comparing buprenorphine versus methadone in special populations, such as pregnant females with OUD. In a recent, randomized, double-blind, double-dummy, flexible-dosing, parallel group controlled trial in neonates of pregnant females with OUD, patients either received 4–24 mg of sublingual buprenorphine or 20–100 mg of oral methadone. It was demonstrated that the length of hospitalization was shorter for buprenorphine-exposed than for methadone-exposed neonates. Total amount of opioid agonist medication administered to treat neonatal abstinence syndrome in methadone-exposed neonates was three times greater than for buprenorphine-exposed neonates.Reference Jones, Johnson and Jajinski45
μ-Opioid receptor antagonists
Naloxone
Naloxone is a short-acting, nonselective, opioid receptor antagonist with high affinity for the μ-opioid receptor. Because it has extensive first-pass metabolism through the liver, its oral availability is less than 1%.Reference Berkowitz46 However, when naloxone is administered intravenously, the half-life is 70 min. This μ-opioid receptor antagonist competes with agonists at the μ-opioid receptor and displaces these agonists, thus leading to the reversal of opioid intoxication, including respiratory depression, hypotension, and sedation. These properties make naloxone an ideal combination with buprenorphine to prevent μ-opioid receptor activation by buprenorphine if this combination drug is used intravenously.Reference Machikanti, Helm and Fellows47 In the scenario of opioid overdose, up to 2 mg of naloxone is given intravenously or intramuscularly, and the onset of action is within minutes. If no reversal symptoms are observed, then bolus injections of 0.4–2 mg may be repeated until the desired effects are achieved.Reference Fiellin, Moore and Sullivan48 The half-life of naloxone is shorter than long-acting opioids such as methadone; therefore, repeated intravenous or intramuscular injections of 0.4 mg are necessary to achieve sustained effects of reversing the symptoms of opioid overdose.Reference Handal, Schauben and Salamone49
Naltrexone
Naltrexone is an oral, long-acting, semisynthetic μ and κ opioid receptor antagonist with high affinity to the μ-opioid receptor. Following oral administration, it is rapidly absorbed but undergoes significant first-pass metabolism with a bioavailability of less than 50%. Peak plasma levels are reached within 4 hr, and it has a half-life of 9 hr.50 A daily dose of naltrexone (50 mg) will block the pharmacological effects of 25 mg of IV heroin up to 24 hours. Increasing the dose extends its duration of action to 48 hr with 100 mg and 72 hr with 150 mg. Neither tolerance nor dependence develops with naltrexone, and it is FDA-approved for relapse prevention of OUD. Its safety is well established, although there have been reports about potential hepatotoxicity and its use in the setting of acute hepatitis or end-stage liver disease. Therefore, it is prudent to evaluate liver function prior to administering naltrexone and refrain from using it if liver function tests are 3–5 times normal levels.Reference Pfohl, Allen and Atkinson51 The use of μ-opioid receptor antagonists is used to eliminate a conditioned response to use opioids following detoxification via negative reinforcement of environmental stimuli such as psychosocial stressors. If the antagonist prevents the patient with OUD from relieving this negative state through opioid use, then the behavior of relapsing back to opioids would eventually cease.Reference Schottenfeld, Chawarski and Mazlan52 Early studies found that naltrexone was well tolerated, with nausea being the main side effect. Patients taking naltrexone reported fewer days of heroin use and had fewer opiate-positive urine drug screen tests.Reference Volavka, Resnick and Kesterbaum53 However, poor patient adherence and high dropout rates have been major obstacles for oral naltrexone treatment. A Cochrane meta-analysis found that due to extensive drop-out rates, oral naltrexone maintenance with or without psychotherapy was no better than placebo treatment.Reference Minozzi, Amato and Vecchi54 Extended-release naltrexone (XR-NTX), which is delivered by a once monthly injection, may improve treatment outcomes that have suffered because of non-adherence to the daily oral naltrexone regiment. In 2010, the FDA approved XR-NTX for prevention of relapse to opioid dependence in detoxified patients. In a multicenter, phase III, randomized, double-blind, placebo-controlled, 24-week clinical trial, the efficacy of XR-NTX was evaluated. In this study, monthly intramuscular injections of XR-NTX 380 mg (n=126) or placebo (n=124) were combined with 12 biweekly sessions of drug counseling. With XR-NTX, 36% of patients maintained complete abstinence for weeks 5–24 versus 23% of placebo patients. XR-NTX–treated patients also had significantly more self-reported opioid-free days, median percentage days of opioid-free days, less cravings, longer median retention, and normalized mental health functional scores.Reference Krupitsky, Nunes and Ling55 Another study showed 53% retention at 6 months compared with 38% for placebo. Patients receiving XR-NTX also had significantly fewer days of illicit opioid use.Reference Gastfriend56
Conclusion
OUD remains among the most challenging medical conditions to treat, and it causes significant morbidity and mortality. The development of effective pharmacotherapies to treat OUD has helped to improve management of this condition. The aims of this article is to review FDA-approved agonists, partial agonists, and antagonists available to treat this pernicious disease. Methadone maintenance is the gold standard of treatment, as it is associated with reduction in opioid use, criminal behaviors, transmission of infectious diseases, and finally, opioid overdose. Buprenorphine has emerged as an effective alternative in treating OUD with a higher safety profile. Naltrexone therapy is associated with unacceptably low adherence and retention rates; although XR-NTX is promising in treating OUD, long-term data concerning efficacy and safety remain unknown. Hopefully, continued research and combined efforts by physicians, scientists, and government officials alike will lead to novel ideas in order to curtail the rising numbers of patients with OUD, and also grant the much-needed respite from the destructive costs of this debilitating condition.
Disclosures
Thomas Nguyen and Jennie Hahn have nothing to disclose. Stephen Strakowski has the following disclosures: Eli Lilly, research (institutional support); Janssen/J&J, research (institutional support); AstraZeneca, research (institutional support); Sumatomo, research (institutional support); Pfizer, research (institutional support).
