Research has shown that genetic factors play a strong role in whether a person develops a substance use disorder, accounting for 40% to 60% of the risk [3,4,5]. In fact, family transmission of substance use disorder, particularly alcohol use disorder, has been well established. Individuals who have relatives with substance use disorder are at three- to five-times greater risk of developing substance use disorder than the general population. The presence of substance use disorder in one or both biologic parents is more important than the presence of substance use disorder in one or both adoptive parents. The genetic risk increases with the number of relatives with substance use disorder and the closeness of the genetic relationship [5]. However, most children of parents with substance use disorder do not develop disorders, and some children from families where substance use is not a problem develop disorders when they get older.

One model focuses on children who have temperaments that make it difficult for them to regulate their emotions and control their impulses. Clearly, these children are difficult to parent, and if one or both of their parents have a substance use disorder, it is likely that they will be poorly socialized and have trouble getting along in school [6,7]. Poor academic performance and rejection by more mainstream peers at school may make it more likely for these children to join peer groups where drinking and other risky behaviors are encouraged. Parents with substance use disorders will likely not monitor their children closely and will lose control over them at an early age. These children will begin using substances early, often before 15 years of age [8]. If such a child is genetically predisposed to substance use disorders, these environmental factors may further increase the tendency [9].

Another model of risk factors leading to substance use disorder focuses on substance use to regulate inner distress [10]. Some children have temperaments that make them highly reactive to stress and disruption. Regardless of the child's family environment, he or she maintains higher levels of inner distress (anxious and depressed feelings) than other children. When they first drink or use a substance, the inner distress dissipates for a while. This leads to more substance use and may lead to substance use disorder. More research is required before the role of stress as a risk factor in alcohol use disorders is understood.

Adverse childhood experiences, particularly sexual abuse, family rejection, and parental neglect, are independent risk factors for substance use disorders [11]. Adverse childhood experiences are linked with depression in adulthood, which itself is a risk factor for substance use disorder. This correlation can be modulated by resilience, which can also be a result of adverse childhood experiences.

As noted, the DSM-5-TR defines substance use disorder as a problematic pattern of substance use, leading to clinically significant impairment or distress. While criteria are outlined for specific substances in the DSM-5-TR, the components are generally the same regardless of substance used. The diagnosis of substance use disorder is made by meeting two or more criteria in a one-year period [1]:

There is considerable evidence that substance use is sensitive to the application of contingencies. Contingencies occur on a spectrum from contrived to naturalistic. Contingency management and vouchers are examples of contrived interventions, while 12-step programs are examples of naturalistic interventions [21]. Contrived contingencies may be effective in initially engaging patients in abstinence, but relapse to drug use may occur following removal of the reinforcer. In contrast, naturalistic contingencies are more likely to maintain the initial gains made by the patient and to facilitate the sustained change of behavior over time [22].

The goal of contingency management interventions is to increase the opportunity cost of substance use by arranging an environment where drug use results in the forfeiture of a predetermined item or privilege, referred to as an alternate reinforcer [23]. Treatment with a contingency management component was first used with cocaine-abusing methadone patients, a highly suitable population for two reasons: cocaine abuse is prevalent among patients with opioid use disorder receiving methadone maintenance, and methadone patients are required to report to the clinic daily to receive their medication under staff supervision. Daily clinic appointments are often considered a significant constraint on employment, travel, and other activities. Patients who are able to abstain from drugs of abuse, as measured by a urine drug screen, may be allowed several days of take-home methadone doses, which can act as a behavioral contingent [24]. Several studies have shown that this contingent condition has led to greater treatment retention and reductions in cocaine use than those found in comparison treatment conditions, although this effect dissipates with longer-term follow-up [22,25,26,27].

Coping and social skill training (CSST) evolved from social learning theory and is used to improve the inadequate coping skills found in many persons with substance use disorders, including deficits in regulation of emotion and in effectively coping with social situations. CSST addresses four primary areas [33]:

The most common side effects of naltrexone are light-headedness, diarrhea, dizziness, and nausea. Pain or tenderness at the injection site is a side effect unique to the extended-release injectable formulation [41]. Most side effects tend to disappear quickly in most patients. Naltrexone is not recommended for patients with acute hepatitis or liver failure, for adolescents, or for pregnant or breastfeeding women [41,50]. Weight loss and increased interest in sex have been reported by some patients. In general, patients maintained on opioid antagonists should be treated with nonopioid cough, antidiarrheal, headache, and pain medications. The patient's family or physician should call the treating physician if questions arise about opioid blockade or analgesia. It is important to realize that naltrexone is not disulfiram; drinking while maintained on naltrexone does not produce side effects or symptoms.

In July 2004, after many years of safe use in Europe and around the world, the FDA approved the use of acamprosate for the maintenance of alcohol abstinence [49]. As in the case of naltrexone, acamprosate reduces the reinforcing (pleasurable) effects of alcohol to reduce craving. Oral dosing is two 333-mg delayed-release tablets three times daily [39,41]. Common side effects include diarrhea, anxiety, insomnia, nausea, dizziness, and weakness. Some research indicates that acamprosate may worsen depression and/or suicidal ideation; so, patients with a history of major depression should be monitored closely or prescribed a different medication [39]. Acamprosate is contraindicated in patients with severe renal impairment [39,41]. Due to risk of diminished renal function in patients 65 years of age and older, baseline and frequent renal function tests should be performed in this population. Dose reductions also may be necessary [41].

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 patients who have overdosed. 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 2014, the FDA approved naloxone as an autoinjector dosage form for home use by family members or caregivers [66]. The autoinjector delivers 0.4 mg naloxone intramuscularly or subcutaneously. The autoinjector comes with visual and voice instruction, including directions to seek emergency medical care after use [66]. In 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 central nervous system depression. It is available in a ready-to-use 2-mg, 4-mg, or 8-mg single-dose sprayer [67,68,69]. In 2023, the FDA approved 4-mg nasal spray naloxone for over-the-counter use [173].

The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification [71]. 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 [72]. Methadone is the most frequently used opioid agonist due to the convenience of its once-a-day dosing [71]. 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 [72].

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 [71].

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 [71,75]. 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 [75]. 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 [65]. Methadone is contraindicated for the following patients [73]:

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 [71,76]. 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 [71].

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. The primary advantage of buprenorphine over methadone is its superior safety profile [77].

Another effective non-nicotine therapy for smoking cessation is varenicline tartrate, a partial agonist selective for nicotine acetylcholine receptor subtypes. Released in 2006, varenicline is available in monthly dose packs (0.5 mg and 1 mg tablets) and is approved for a 12-week course of treatment [82]. Patients able to quit smoking may continue the therapy for an additional 12 weeks for increased likelihood of long-term cessation and even up to a year in certain cases, to prevent relapse; however, medication should be stopped and patients should be reassessed if the intervention has not led to smoking cessation within the initial 12 week timeframe [39,87,88]. Clinical trials reveal that varenicline may be favorable to bupropion for abstinence (44% versus 30%); the medication has also been shown to help at least 20% of patients remain smoke-free for up to one year [89,90]. Recognizing that cessation success rates increase when pharmacologic and behavioral therapies are combined, the manufacturer urges patients to combine use of varenicline with a behavioral support plan. Co-administration of varenicline and transdermal nicotine may exacerbate incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue. One study found varenicline alone to be more effective than other treatment options, while a meta-analysis study found that combination therapy (varenicline and NRT) was more effective than varenicline alone [91,92]. In 2021, the manufacturer of Chantix, a brand of varenicline, halted production of varenicline due to unacceptably high levels of nitrosamines; however, this issue was considered resolved by May 2022 [93]. In addition, all lots of 0.5-mg and 1-mg tablets of Chantix were subject to a voluntary recall. However, the FDA does not recommend that patients halt use of varenicline, and generic formulations and other brands remained available.

The Substance Abuse and Mental Health Services Administration (SAMHSA) has identified three evidence-based practices that engage and improve outcomes for individuals with concurrent substance use and concurrent substance use disorders [95]:

In the United States, 7.7 million adults have co-occurring mental and substance use disorders. Of the 20.3 million adults with substance use disorders, 37.9% also had mental illnesses. Among the 42.1 million adults with mental illness, 18.2% also had substance use disorders [96]. No specific combinations of mental and substance use disorders are defined uniquely as co-occurring disorders, but the most common mental disorders seen in substance use disorder treatment include [96]:

Treatment should initially focus on stabilization of the patient's substance use disorder, with an initial goal of two to four weeks abstinence before addressing comorbidities. Patients who persistently display symptoms of a psychiatric disorder during abstinence should be considered as having an independent disorder and should receive prompt psychiatric treatment [104].

Key ethical issues to consider when caring for patients with substance use disorders include informed consent, confidentiality, autonomy, competence, access to services, and explicit and implicit bias.

Long-term opioid use often begins with treatment of acute pain. When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of immediate-release opioids in a quantity no greater than that needed for the expected duration of severe pain. In most cases, three days or less will be sufficient; more than seven days will rarely be needed [125,127]. However, it may be necessary to prescribe for longer periods in patients with acute severe pain. Approximately half of all states have passed legislation limiting initial opioid prescriptions for acute pain to a seven-day supply or less, and many insurers, pharmacy benefit managers, and pharmacies have enacted similar policies [127].

The inadequate management of pain is the result of several factors related to both patients and clinicians. In a survey of oncologists, patient reluctance to take opioids or to report pain were two of the most important barriers to effective pain relief [139]. This reluctance is related to a variety of attitudes and beliefs [135,139]:

The Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R) is a patient-administered, 24-item screen with questions addressing history of alcohol/substance use, psychologic status, mood, cravings, and stress. Like the ORT, the SOAPP-R helps assess risk level of aberrant drug-related behaviors and the appropriate extent of monitoring [146,147].

The original CAGE (Cut down, Annoyed, Guilty, and Eye-opener) Questionnaire consisted of four questions designed to help clinicians determine the likelihood that a patient was misusing or abusing alcohol. These same four questions were modified to create the CAGE-AID (adapted to include drugs), revised to assess the likelihood of current substance abuse [148].

Although identification of an opioid use disorder can alter the expected benefits and risks of opioid therapy for pain, patients with co-occurring pain and substance use disorder require ongoing pain management that maximizes benefits relative to risks. Clinicians should use nonpharmacologic and nonopioid pharmacologic pain treatments as appropriate to provide optimal pain management [150]. For patients with pain who have an active opioid use disorder but are not in treatment, clinicians should consider buprenorphine or methadone treatment for opioid use disorder, which can also help with concurrent management of pain [150]. For patients who are treated with buprenorphine for opioid use disorder and experience acute pain, clinicians can consider temporarily increasing the buprenorphine dosing frequency (e.g., to twice a day) to help manage pain, given the duration of effects of buprenorphine is shorter for pain than for suppression of withdrawal [150,151]. For severe acute pain (e.g., from trauma or unplanned major surgery) in patients receiving buprenorphine for opioid use disorder, clinicians can consider additional as-needed doses of buprenorphine. In supervised settings, adding a short-acting full agonist opioid to the patient's regular dosage of buprenorphine can be considered without discontinuing the patient's regular buprenorphine dosage; however, if a decision is made to discontinue buprenorphine to allow for more mu-opioid receptor availability, patients should be monitored closely because high doses of a full agonist opioid might be required, potentially leading to oversedation and respiratory depression as buprenorphine's partial agonist effect lessens. For patients receiving naltrexone for opioid use disorder, short-term use of higher-potency nonopioid analgesics (e.g., NSAIDs) can be considered to manage severe acute pain. Patients receiving methadone for opioid use disorder who require additional opioids as treatment for severe acute pain management should be carefully monitored, and when feasible should optimally be treated by a clinician experienced in the treatment of pain in consultation with their opioid treatment program [150]. The ASAM National Practice Guideline for the Treatment of Opioid Use Disorder (2020 Focused Update) provides additional recommendations for the management of patients receiving medications for opioid use disorder who have planned surgeries for which nonopioid therapies are not anticipated to provide sufficient pain relief [150].

When implementing a chronic pain treatment plan that involves the use of opioids, the patient should be frequently reassessed for changes in pain origin, health, and function [132]. This can include input from family members and/or the state PDMP. During the initiation phase and during any changes to the dosage or agent used, patient contact should be increased. At every visit, chronic opioid response may be monitored according to the "5 A's" [132,152]:

In 2019, 16% of persons who died of an opioid overdose also tested positive for benzodiazepines, a class of sedative medication commonly prescribed for anxiety, insomnia, panic attack, and muscle spasm [159]. Benzodiazepines work by raising the level of GABA in the brain. Common formulations include diazepam, alprazolam, and clonazepam. Combining benzodiazepines with opioids is unsafe because both classes of drug cause central nervous system depression and sedation and can decrease respiratory drive—the usual cause of overdose fatality. Both classes have the potential for drug dependence and addiction.

The CDC recommends that healthcare providers use particular caution prescribing benzodiazepines concurrently with opioids [125,127]. If a benzodiazepine is to be discontinued, the clinician should taper the medication gradually, because abrupt withdrawal can lead to rebound anxiety and complications such as hallucinations, seizures, delirium tremens, and, in rare instances, death. A commonly used tapering schedule is a reduction of the benzodiazepine dose by 25% every one to two weeks [125,127].

There are no universal recommendations for the proper disposal of unused opioids, and patients are rarely advised of what to do with unused or expired medications [161]. According to the FDA, most medications that are no longer necessary or have expired should be removed from their containers, mixed with undesirable substances (e.g., cat litter, used coffee grounds), and put into an impermeable, nondescript container (e.g., disposable container with a lid or a sealed bag) before throwing in the trash [162]. Any personal information should be obscured or destroyed. The FDA recommends that certain medications, including oxycodone/acetaminophen (Percocet), oxycodone (OxyContin tablets), and transdermal fentanyl (Duragesic Transdermal System), be flushed down the toilet instead of thrown in the trash [162,163]. The FDA provides a free toolkit of materials (e.g., social media images, fact sheets, posters) to raise awareness of the serious dangers of keeping unused opioid pain medicines in the home and with information about safe disposal of these medicines. The Remove the Risk Outreach toolkit is updated regularly and can be found at https://www.fda.gov/drugs/ensuring-safe-use-medicine/safe-opioid-disposal-remove-risk-outreach-toolkit [163]. Patients should be advised to flush prescription drugs down the toilet only if the label or accompanying patient information specifically instructs doing so.

Research has more closely defined the location of prescribed opioid diversion into illicit use in the supply chain from the manufacturer to the distributor, retailer, and the end user (the pain patient). This information carries with it substantial public policy and regulatory implications. The 2021 National Survey on Drug Use and Health asked non-medical users of prescription opioids how they obtained their most recently used drugs [2]. Among persons 12 years of age or older, 39.3% obtained their prescription opioids through a prescription from one doctor (vs. 34.7% in 2019), 33.9% got them from a friend or relative for free, 7.9% bought from a drug dealer or other stranger, and 7.3% bought them from a friend or relative [2]. Less frequent sources included stealing from a friend or relative (3.7%); multiple doctors (3.2%); and theft from a doctor's office, clinic, hospital, or pharmacy (0.7%) (vs. 0.2% in 2009–2010) [2].

In addition to aberrant urine screens, there are certain behaviors that are suggestive of an emerging opioid use disorder. The most suggestive behaviors are [160,166,167]:

Behaviors with a lower level of evidence for their association with opioid misuse include [160,166,167]:

The DEA is responsible for formulating federal standards for the handling of controlled substances. In 2011, the DEA began requiring every state to implement electronic databases that track prescribing habits, referred to as PDMPs. Specific policies regarding controlled substances are administered at the state level [171].