The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) defines opioid use disorder as a problematic pattern of opioid use, leading to clinically significant impairment or distress. The diagnosis of OUD is made by meeting two or more criteria in a one-year period [2,7]:

Pseudoaddiction describes drug-seeking behaviors iatrogenically produced in pain patients by inadequate pain treatment. This is manifested as preoccupation with and pursuit of opioid medication driven by a desire for pain relief, not the drug's mood-altering effects. Pseudoaddiction develops in three phases. Initially, the patient receives an inadequate level of analgesia, which leads to the patient's escalation of analgesic demands and behavioral changes. This may be exaggerated to convince others of the pain severity and need for more medication, which results in a crisis of mistrust between the patient and the healthcare team. Pseudoaddiction is preventable when the patient's report of pain is accepted as valid [1,3,4,5].

The isolation of morphine from opium was achieved in 1806 and was named for Morpheus, the Greek god of dreams [9]. The discovery of other alkaloids in opium followed: codeine in 1832 and papaverine in 1848. By the mid-nineteenth century, pure alkaloids were used in medical practice in place of crude opium preparations [9].

Data from the DAWN network indicates that opioid abuse is a growing problem in the United States. In 2011, the overall admission rate for misuse or abuse of opioid analgesics (excluding adverse reactions) was 134.8 per 100,000, an increase of 153% compared with 2004. In the 13 states involved in the DAWN network, the top four opioid analgesics involved in drug-related ED visits for 2011 were various formulations of oxycodone (175,229), hydrocodone (97,183), methadone (75,693), and morphine (38,416). Between 2004 and 2011, ED admissions increased 74% for methadone, 220% for oxycodone, 96% for hydrocodone, and 144% for morphine. Heroin-related ED episodes increased from 213,118 in 2009 to 258,482 in 2011 [16]. There was no meaningful change in ED admission rates involving opioid analgesics between 2009 and 2011 [15]. However, more than 81,000 drug overdose deaths occurred in the United States in the 12 months ending in May 2020, the highest number of overdose deaths ever recorded in a 12-month period, and the rise was mainly attributed to synthetic opioids [17]. From 2013 to 2019, the age-adjusted rate of deaths involving synthetic opioids other than methadone increased 1,040% [18].

Identified risk factors for fatal heroin overdose include male gender, single status, unemployment, history of heroin dependence, no current treatment for heroin dependence, intravenous (IV) use, and concomitant use of alcohol or benzodiazepines. An unexplained and consistent finding is that victims of fatal heroin overdose are generally older, experienced users. Also, at autopsy, a large proportion of overdose fatalities have relatively low blood morphine concentrations [34]. (Heroin is rapidly metabolized into morphine once administered.) Demographic patterns among overdose fatalities suggest that polydrug use and loss of tolerance are key factors, which partially explains low blood opioid concentrations. However, this does not explain the strong association of fatal overdose with age [34].

The numerous synthetic derivatives of morphine and thebaine are made by relatively simple modifications of the molecule. Examples of this include the transformation of morphine to diacetylmorphine by acetylation at the 3 and 6 positions. The main goals of opioid structural modification are to increase the affinity for various species of opioid receptors, alter the activity of the drug from agonist to antagonist, change the lipid solubility, and alter the resistance to metabolic breakdown [9].

The endogenous opioid system is complex and subtle, with diverse functions. The system plays a sensory role, which is prominent in inhibiting response to painful stimuli; a modulatory role in gastrointestinal, endocrine, and autonomic functions; an emotional role evidenced by the powerful rewarding and addicting properties of opioids; and a cognitive role involving modulation of learning and memory [9].

Morphine-like opioids depress respiration in part through a direct effect on the brainstem respiratory centers. Therapeutic doses of morphine depress all phases of respiratory activity and possibly induce irregular and periodic breathing. Clinically significant respiratory depression seldom occurs at standard therapeutic doses. The primary mechanism of respiratory depression involves a diminished responsiveness of the brainstem respiratory centers to carbon dioxide [9].

Heroin, or diacetylmorphine, is a highly potent, semisynthetic analgesic produced by the anhydrous acetylation of morphine. Heroin is generally believed to have no significant opioid receptor activity; however, heroin is rapidly metabolized to 6-monoacetylmorphine (6-MAM) and then to morphine. While diacetylmorphine and 6-monoacetylmorphine readily cross the blood-brain barrier, morphine itself is much slower to do so; thus, heroin can be considered a prodrug that facilitates the brain entry of morphine [51]. The drug rapidly enters the brain after IV administration, where it binds to mu, kappa, and other stereospecific opioid-receptor binding sites in the locus coeruleus [8]. The onset of euphorigenic action is approximately 30 minutes after intranasal ingestion, 15 minutes after subcutaneous injection, and almost instantaneously after IV injection, with a duration of about three to four hours [8]. As with many other opioids, heroin reduces the anticipatory anxiety associated with emotional or physical pain and alters the perception of pain [8].

Since 1995, oxycodone has been marketed in the United States as OxyContin, a Schedule II controlled-release oral tablet formulation. Oxycodone is also available in immediate-release tablets in combination with aspirin or acetaminophen under various trade names, including Percodan and Percocet, which contain 2.5–10 mg of oxycodone [55]. The oxycodone content of OxyContin ranges from 10 mg to 80 mg. When taken orally, OxyContin tablets release oxycodone over a 12-hour period. However, when the controlled-release mechanism is destroyed by crushing the tablet, the oxycodone can be snorted, ingested, or injected. It is this delivery of a large amount of the active drug in a relatively brief time period (compared to the intact tablet and the low-dose immediate-release form) that underlies addicts' interest in OxyContin [1].

Drugs with an abuse liability have habit-forming actions that can be localized in a variety of brain regions. Drugs of abuse mimic or enhance the actions of endogenous chemical messengers in the brain [85]. The mesolimbic dopamine system is the likely substrate upon which opioids act to produce their reinforcing effects. Both the positive (rewarding) and negative (aversive) reinforcement of opioid mu- and kappa-receptor agonists are mediated by the mesolimbic dopamine system [81].

Opioid use affects multiple endocrine functions and is associated with hypogonadism, adrenal dysfunction, reduced bone mineral density, and growth hormone abnormalities [91].

Sequelae of nonfatal overdose include [34]:

Most research regarding acute withdrawal from an opioid has been conducted with heroin users. Withdrawal symptoms are the result of mu-agonist withdrawal in the case of heroin and begin approximately eight hours after the last dose. The symptoms begin slowly, peak at 48 to 72 hours, and then gradually taper during the next four to seven days [104]. As noted, typical symptoms of withdrawal include agitation, anxiety, piloerection, tachycardia, mild hypertension, and pupillary mydriasis. Approximately 8 to 12 hours after the last dose, increases in vital signs, pulse, blood pressure, and respiratory vital rate are observed. At the peak, pronounced anxiety, tremors, shakes, smooth and skeletal muscle cramps, and joint and deep bone pain begin to manifest [8].

There is broad consensus that patients with acute and chronic pain have often received inadequate pain control out of a fear of creating dependence. This is typified by the results of a survey in which 35% of Canadian family physicians reported they would never prescribe opioids for moderate-to-severe chronic pain and 37% identified dependence as a major barrier to prescribing opioids [112]. Prescriber knowledge deficit has been identified as a key obstacle to appropriate opioid prescribing and, along with gaps in policy, treatment, attitudes, and research, contributes to widespread inadequate treatment of pain [113]. A 2013 survey measured primary care physician understanding of opioids and addiction. Of the 200 participants, [114]:

These statistics reflect knowledge and attitude gaps among physicians that lead to undertreatment of pain and unnecessary suffering among patients experiencing pain [112]. In response to this, the Joint Commission and other organizations have enacted accreditation standards that consider pain to be the fifth vital sign, assessed whenever other vital signs are measured [1].

However, with the growing concern about the undertreatment of pain and the underuse of opioids in pain treatment, there is also a renewed concern about prescription opioid dependence and overdose deaths [1]. The disparate concerns regarding undertreatment of pain and facilitation of dependence is underscored by the fact that, until recently, pain management and addiction specialists rarely communicated. Pain management physicians rightly concern themselves with alleviation of pain and have traditionally underestimated dependence among their patients, with such patients often simply dismissed from further care. Addiction specialists, on the other hand, seldom encounter pain patients whose quality of life is vastly improved by opioids, but instead see failed patients from pain treatment programs [1]. Additionally, there is a shortage of pain specialist physicians in the United States that is expected to worsen. This has resulted in most of the medical care for patients with chronic pain being delivered by primary care physicians, despite, as stated, significant and widespread knowledge deficits among these practitioners in the medical skills necessary for providing optimal pain management, managing drug abuse and addiction, and utilizing risk evaluation and mitigation strategies when prescribing opioids [115].

It is important to note that prescription opioid abuse has been tempered by improvements in opioid prescribing, community intervention, and improved awareness. Following a peak in opioid prescribing in 2011, numbers have consistently fallen. However, opioid use disorder rates and overdose fatalities continue to rise. This reinforces the need for appropriate opioid prescribing practices, patient assessment and referral, and optimal opioid use disorder treatment in patients with suspected addiction.

Abuse liability is related to the ease of extraction and modification to produce the desired psychologic effect. Medication tends to be more readily abusable if it has a rapid onset and short duration of action, is highly potent, and is smokable or easily ingested. Examples of opioids with high abuse liability include hydromorphone (Dilaudid) tablets, which can be easily dissolved in water and injected, and OxyContin tablets, which can be crushed to disable the controlled-release properties and then snorted or dissolved in solution and injected. A specific black box warning on the labeling of a medication can alert potential substance abusers of the abuse liability. Also, brand name drugs, which carry a higher street value, are more likely to be abused and diverted than generic equivalents [1].

In studies of trends in medical use and abuse of opioid analgesics, a corresponding increase in the rate of abuse with prescription rates has been apparent [116,117,118]. Thus, the increased medical use of opioid analgesics for the treatment of pain has contributed to an increase in opioid analgesic abuse and overdose fatalities. The abuse of hydrocodone and oxycodone products, which increased disproportionately to their availability between 2000 and 2011, is an extreme example of this trend [1]. Results of epidemiologic studies indicate a high prevalence of lifetime abuse of other substances and of substance-related disorders in patients with OxyContin dependence, suggesting that substance abuse predated the use of OxyContin [119].

Legitimate pain clinics offer large amounts of drugs with a high potential for abuse, often with little evaluation and follow-up [117]. In some states (e.g., Florida, Texas), increasingly liberal prescribing practices were linked to rising overdose death rates. Since 2011, misuse of prescription opioids has decreased; however, abuse of synthetic opioids (including illicitly manufactured fentanyl) has increased precipitously.

The dependence of a patient to a drug initially prescribed for a medical condition is referred to as iatrogenic dependence. Opioid prescriptions fall into two major subgroups: treatment of acute pain with short-term opioids and treatment of chronic pain with long-term opioids. In contrast to the rare association of dependence with short-term use, long-term administration of opioids is estimated to result in opioid abuse or dependence in 2.8% to 18.9% of patients, which typically parallels the rate of abuse or dependence among opioid users in the general population [29].

In response to acute overdose, the short-acting opioid antagonist naloxone is considered the criterion standard. Naloxone is effective in reversing respiratory depression and coma in overdose patients. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This prompted discussion of making naloxone available to the general public for administration outside the healthcare setting to treat acute opioid overdose, and in April 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [121]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directs to seek emergency medical care after use [121]. In November 2015, the FDA approved intranasal naloxone after a fast-track designation and priority review. Intranasal naloxone is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or CNS depression. It is available in a ready-to-use 8-mg, 4-mg, or 2-mg single-dose sprayer [122,123,124,125]. In 2023, the FDA approved the first over-the-counter naloxone nasal spray [126]. It is available as a 3-, 4-, or 8-mg single dose, administered in one nostril [55].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [56]. The most frequently employed method of opioid withdrawal is a slow, supervised detoxification during which an opioid agonist, usually methadone, is substituted for the abused opioid [80]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [56]. Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacologic detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine [80]. Naltrexone is used following medically supervised withdrawal to help prevent relapse to opioid misuse [134].

A major shortcoming of UROD is the lack of evidence that an opioid antagonist can accelerate the restoration of neurobiologic homeostasis following opioid withdrawal [143]. Although significant drawbacks and questionable long-term efficacy exist with UROD, popular demand has proven difficult to restrain, in part due to the marketing of the procedure as a painless cure for opioid dependence. Marketing and the media have also blurred the fact that the original purpose of the procedure was to induce patients as rapidly as possible onto naltrexone and not to magically and permanently terminate years of opioid dependence [142]. There are a number of drawbacks to UROD relative to other detoxification methods. For example, one study found that, when used alone, naloxone has a high relapse rate in the long term [145]. The study included 64 opioid-dependent men 18 years of age and older (mean age: 31.1 years) at the time of UROD. One month after UROD, 48 patients (75%) reported relapse and 16 patients (25%) reported abstinence. There was no significant difference between the two groups regarding marital status, level of education, and family history of opioid dependence. Four patients from the nonrelapsed group reported on episode of opiate use [145]. Another study was conducted to assess UROD efficacy with naltrexone and estimate the relapse rate in a two-year follow-up period [146]. A total of 424 opioid-addicted self-reporting patients were enrolled in the study and entered the UROD program; 400 patients completed the program. Of the total patients, 303 (75.75%) were successful and 97 (24.25%) relapsed. No patients in the relapse group continued naltrexone maintenance at six-month follow-up. The relapse rate was 14% at the first month visit and 24% at the six-month visit and thereafter. All relapsed patients had discontinued use of naltrexone before relapse occurred [146]. A Canadian review of the evidence for UROD found no significant differences between UROD and control groups in commencement or duration of withdrawal treatment [147].

The first demonstrated efficacy of methadone treatment for opioid dependence was published in 1965. Methadone is now the most inexpensive and empirically validated agent available for use in opioid replacement therapy. Studies have shown one-year treatment retention rates of 80%, with significant reductions in illicit opioid use [56]. Individual and group counseling are the main ancillary therapies and consist primarily of cognitive-behavioral and supportive-expressive approaches. There is some evidence that augmentation of methadone with intensive psychosocial therapy significantly improves outcomes [56]. Efforts to provide methadone in an office-based setting have been successful, although federal regulation has limited the flexibility of providers [84,107].

Treatment is initiated with a dose of 25–30 mg and is gradually titrated in 5- to 10-mg increments per day to a desired range of 60–120 mg. Low-dose treatment is associated with less positive outcomes than doses of 60–120 mg/day or greater [55,60]. One published review of efficacy literature concluded that high doses of methadone (>50 mg daily) are more effective than low doses (<50 mg daily) in reducing illicit opioid use. This may be due to the increased availability of highly pure heroin [60]. Additionally, high doses of methadone are more effective than low doses of buprenorphine (<8 mg daily). High dosages of methadone are comparable to high dosages of buprenorphine (>8 mg daily) on measures of treatment retention and reduction of illicit opioid use [77]. Methadone is contraindicated for the following patients [55,107]:

Buprenorphine offers several advantages over methadone, including lower cost, milder withdrawal symptoms following abrupt cessation, lower risk of overdose, and longer duration of action, allowing alternate-day dosing [56,156]. Identifying subpopulations of opioid addicts who differentially respond to buprenorphine versus methadone has not been clearly established. However, patients with less chronic and less severe heroin dependence benefit more fully from buprenorphine than from a pure opioid agonist like methadone [56].

Higher doses of buprenorphine (12 mg or greater) are more effective than lower doses in reducing illicit opioid use, with some studies reporting similar efficacy to methadone on major treatment-outcome measures. One systematic review was conducted to evaluate buprenorphine maintenance compared to placebo and methadone maintenance in the management of opioid dependence [157]. Outcomes considered were treatment retention, suppression of illicit drug use, and reduction in criminal activity and mortality. A total of 31 trials involving 5,430 participants with moderate- to high-quality evidence were included in the review. According to the data reviewed, buprenorphine retained participants better than placebo at low doses (2–6 mg), at medium doses (7–15 mg), and at high doses (≥16 mg). Only high-dose (≥16 mg) buprenorphine was more effective than placebo at suppressing illicit opioid use (as measured by urinanalysis). Buprenorphine in flexible doses (i.e., adjusted to participant need) was less effective than methadone in retaining participants, and for those retained in treatment, no difference was observed in suppression of illicit opioid use. In low fixed-dose studies, methadone (≤40 mg) was more likely to retain participants than low-dose (2–6 mg) buprenorphine. However, there was no difference between medium-dose (7–15 mg) buprenorphine and medium-dose (40–85 mg) methadone in retention or in suppression of illicit opioid use. Similarly, there was no difference between high-dose (≥16 mg) buprenorphine and high-dose (≥85 mg) methadone in retention or suppression of self-reported heroin use [157]. In a study of 34,000 Massachusetts Medicaid beneficiaries, the incidence of relapse was greater with buprenorphine than with methadone [156]. The primary advantage of buprenorphine over methadone is its superior safety profile [30].

The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor [77].

Twelve-step programs for opioid use disorder include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA is widely considered the most successful treatment for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety [167]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [167]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [168].

Twelve-step programs for opioid use disorder include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA is widely considered the most successful treatment for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety [167]. The 12-step model emphasizes acceptance of dependence as a chronic, progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [167]. Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse [168].

The understanding of drug dependence as a chronic and relapsing disorder has helped professionals gain a better comprehension of the vital role played by 12-step programs. Every patient attempting to recover from a substance use disorder will encounter a time when he or she faces urges to use without the resources or assistance of healthcare professionals. Twelve-step programs are not considered treatment, nor are they intended as substitutes for treatment. Instead, they are organizations that provide ongoing and indefinite support in the achievement and maintenance of abstinence and in personal growth and character development [168].

Major depression prevalence among opioid-dependent patients is estimated to be 20% to 30% lifetime and 10% to 20% at enrollment in treatment. Depression is also associated with the use of prescription opioids for chronic pain and worse treatment outcomes. Approximately 50% of patients with chronic pain have a comorbid psychiatric condition, and 35% of patients with chronic back and neck pain have a comorbid depression or anxiety disorder [33,152,186,187]. The prevalence of depression is lower in out-of-treatment patients than in those seeking treatment and is associated with increased retention in methadone treatment. Thus, depression has a mixed effect on prognosis. It appears to be a motivating factor in treatment-seeking while at the same time interfering with treatment effectiveness [33,152,186,187]. In addition, opioid-dependent patients with Axis I psychiatric comorbidity often require significantly higher methadone doses [56].

SSRIs are generally safe and well-tolerated, but clinical trials with these agents in methadone patients have been negative [152]. Therefore, SSRIs may be considered first-line treatment based on their safety profile, but if the patient does not respond, then TCAs or newer generation agents should be considered. SSRIs in combination with cognitive-behavioral therapy have been found to be highly effective for treating clients with comorbid depression [183]. More stimulating antidepressants, such as venlafaxine and bupropion, may be suitable in patients with prominent low energy or past or current symptoms consistent with attention deficit hyperactivity disorder (ADHD) [152]. The utility of nonpharmacologic treatments should be emphasized. Psychosocial therapies are as effective as pharmacotherapy in the treatment of mild-to-moderate depressive and anxiety symptoms. Treatment of personality disorders is nonpharmacologic [190]. If depression persists, psychosocial modalities, such as cognitive therapy, supportive therapy, or contingency management, have some evidence to support their efficacy in opioid-dependent patients [152,183].

Opioids are considered the first choice if pharmacotherapy is necessary [206]. Opioid treatment of NOWS reduces the time to regain birth weight, reduces the duration of supportive care, and increases the length of hospital stay. There is no evidence of effect on treatment failure [207]. Treatment with long-acting opioids has been shown to be superior to phenobarbital and diazepam in infants with NOWS [207]. Phenobarbital is generally considered a second-line agent and is effective for the treatment of withdrawal and polydrug exposure. Clonidine is also a safe second-line option for treatment of NOWS symptoms that are refractory to opioid therapy [206,209]. Buprenorphine and methadone have both been shown to be safe and effective treatments for opioid use disorder during pregnancy [210]. A meta-analysis showed that methadone was associated with higher treatment retention and buprenorphine resulted in a 10% lower incidence of NOWS, decreased neonatal treatment time of 8.46 days, and less morphine (3.6 mg) needed [211]. Infants whose mothers receive these medications may still experience NOWS; however, it is less severe than in the absence of treatment [211].

The relapse rate among patients receiving treatment for opioid dependence and other substance abuse is high (25% to 97%), comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma [219]. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification [87].

Duration of agonist replacement therapy is usually recommended as a minimum of one year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids [30].

Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opioids, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opioids do so with the help of a 12-step support program, such as NA [30].