What’s in a Name? Opiate versus Opioid
It may seem trivial to distinguish between an opiate and an opioid, the terms being frequently used interchangeably by the medical community. However, there are significant differences between the classes that have some practical impact (results of urine drug testing, for instance, can be more easily interpreted using knowledge of the differences). Put simply, although all opiates are also opioids, not all opioids are opiates. An opioid is any natural or synthetic chemical that has opium-like effects like those of morphine. All opioids bind to opioid receptors in the central nervous system (CNS). Opiates, on the other hand, are a specific type of opioid derived directly from the opium poppy and include opium, codeine, morphine, and thebaine. Ingestion of an opiate will produce an opiate-positive result using immunoassay urine drug screens. Other nonopiate opioids have been either modified from an opiate (semisynthetic) or created de novo (synthetic). Semisynthetic opioids demonstrate variable sensitivity in toxicology testing, whereas fully synthetic opioids, including fentanyl and methadone, will not be positive with an opiate screen and require additional tests. The term “narcotic”—derived from the Greek “narkotikon” meaning “to numb”—is a generally outdated and nonspecific term referring to illicit drugs, often opioids, that induce sleep, numbness, or stupor.
Opioid Use Disorder
According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM)-5, and similar to other substance use disorders, an opioid use disorder (OUD) is diagnosed when—due to using an opioid—at least two of the 11 criteria are present within the past year. Unlike many other substance use disorders, however, DSM-5 takes special consideration when an opioid is being prescribed for a medical condition (e.g., to suppress cough or relieve pain), given the expected neuroadaptation (i.e., tolerance and withdrawal) that develops after prolonged prescription opioid therapy. In this case, DSM-5 excludes tolerance and withdrawal from the criterion list, requiring at least two of nine (rather than of 11) criteria to support a diagnosis of an OUD. Without being able to rely on the signals of tolerance or withdrawal for diagnosis, clinicians must concentrate on the following three symptom clusters for diagnostic clarity: (1) loss of control (i.e., the substance is taken in larger amounts or over a longer period than was intended, or there are unsuccessful efforts to control use), (2) salience to the behavioral repertoire (i.e., a great deal of time is spent using or recovering from use, important activities are given up because of use, or use is continued despite great physical, psychological, occupational, or interpersonal consequence or risk), and (3) craving (strong desire to use opioid). Severity is determined by symptom count with the presence of 2–3 symptoms required for mild disorder, 4–5 for moderate, and 6+ for severe OUD. It is worth noting that this exclusion, based upon who is providing the opioid and for what, was added not due to strength of research evidence but by expert workgroup consensus. The clinical and research fields continue to struggle to distinguish those for whom long term opioid therapy for chronic pain is no longer benefiting and yet tapering or discontinuing opioids is difficult from those with an OUD.
Opioid Intoxication
Opioid intoxication is potentially life threatening—especially among individuals with limited tolerance to opioids. Diagnosis requires both a history of recent opioid ingestion as well as concomitant signs including euphoria, pupillary constriction (unless severe overdose with anoxia and pupillary dilation), slowed respiratory rate, drowsiness, slurred speech, and inattention.
Opioid Withdrawal
Uncomplicated acute opioid withdrawal, although described as extremely unpleasant, is generally not life threatening. Symptoms include dysphoric mood, nausea or vomiting, muscle aches, lacrimation or rhinorrhea, pupillary dilation, piloerection or sweating, diarrhea, yawning, fever, and insomnia, and typically appear within minutes or days following cessation of an opioid or administration of an opioid antagonist (e.g., naltrexone) or partial agonist (e.g., buprenorphine). In addition to acute withdrawal, there is growing awareness that many individuals exposed to long-term opioid use experience protracted withdrawal symptoms beyond the expected time frame of acute opioid withdrawal symptoms (4–10 days, up to 21 days for methadone). Symptoms such as anxiety, depression, sleep disturbance, irritability, cognitive impairment (including impaired attention and executive control), and fatigue can last for weeks or months beyond acute withdrawal. The challenge of the treatment provider is to determine to what extent such protracted symptoms are substance-induced and likely to subside, and which indicate a possible co-occurring disorder (SAMHSA, 2022).
Other Opioid-Induced Disorders
DSM-5 includes the following opioid-induced disorders: depressive disorder, anxiety disorder, sleep disorder, and sexual dysfunction. Opioids may also be associated with delirium due to opioid intoxication or withdrawal. Opioid-induced psychiatric disorders are diagnosed when symptoms consistent with the disorder predominate in the clinical picture.
Unspecified Opioid-Related Disorders
Occasionally an individual will have significant distress or impairment in social, occupational, or other important areas due to opioid use but not meet criteria for an OUD. In this case, a diagnosis of unspecified opioid-related disorder may be given.
General Considerations
A. Epidemiology
1. Prevalence of opioid use
Although trends in illegal drug use are expected to be dynamic, rarely have such dramatic shifts occurred as has been witnessed in opioid use in the first decades of the twenty-first century (Compton & Jones, 2019; Jalal et al., 2018). The turn of the century was dominated by an increase in prescribed opioids for the management of chronic pain, which led to a concomitant rise in prescription opioid misuse and addiction (Okie, 2010). In response to this, state legislatures and licensing boards implemented measures to curb the flood of opioid prescriptions being used. Today, all 50 U.S. states and the District of Columbia have ability to track opioid prescriptions through state prescription drug monitoring programs (PDMPs) to prevent multiple prescribers with overlapping prescriptions. Some states have implemented policies requiring providers to check a state PDMP prior to prescribing controlled substances, to ensure that PDMPs are used. The Centers for Disease Control (CDC) recommends checking the state PDMP prior to every opioid prescription and at least once every 3 months when prescribing opioids for chronic pain (Dowell, Ragan, Jones, Baldwin, & Chou, 2022). Additionally, many state licensing boards now require education on the treatment of pain and/or addiction and clinical guidelines have been released by various agencies to set standards for the use of opioid in the management of chronic pain (Dowell et al., 2022; Sandbrink et al., 2023). Perhaps because of such efforts, after a steady increase in overall national opioid prescription dispensing rates peaking in 2012 at 81.3 prescriptions per 100 persons, the overall national opioid dispensing rate fell to its lowest in 15 years in 2020 to about 43.3 prescriptions per 100 persons. While this is a national trend, certain regions of the country continue to have higher prescribing rates than others.
Unfortunately, simultaneous to this downward trend in prescription opioid prescribing in the United States, opioid use transferred and expanded to include nonprescribed or illegal opioid use with devastating results. As the supply of prescription opioids shrank over the second decade of the century, heroin use initially increased (Jones, Logan, Gladden, & Bohm, 2015) and then shifted from a largely heroin-based market to a fentanyl-based market. Fentanyl is roughly 50 times as potent as heroin, with analogues having even greater potency. This shift to fentanyl and synthetic derivatives is the major contributor to the current rise in fatal and nonfatal opioid deaths (Hedegaard, Minino, Spencer, & Warner, 2021) which, in 2021, topped 100,000 deaths (Spencer, Minino, & Warner, 2022) and contributed to an unprecedented downturn in life-expectancy among the U.S. population (Dowell et al., 2017).
According to the 2021 National Survey of Drug Use and Health (SAMHSA, 2022), 9.2 million people ages 12 and older had past year opioid misuse (either using a prescription opioid or heroin). Most of these report using prescription opioids alone (88.1%; although there is growing concern about illegal, counterfeit “pressed pills” that mimic scheduled opioids but are not) or in combination with heroin (6.2%). Heroin-only use is relatively rare (5.7% of those who misuse opioids). It is not possible to compare the 2021 national rates of opioid use to prior years given changes to survey data collection brought on by the COVID-19 pandemic.
2. Prevalence of OUD
It is difficult to accurately gauge the prevalence of OUD among those who use and misuse opioids. Population-level surveys often miss people at high risk either due to underreporting, declining participation, or not including people experiencing homelessness, incarceration, or hospitalization. And administrative claims data may miss a diagnosis due to underreporting in the claim or be less representative of populations with less insurance and more mistrust of the healthcare system. So, while recent population survey data indicate over 2 million people in the United States have an OUD, the rates are likely as much as three to four times higher (Keyes et al., 2022). Trends also suggest that, while rates of OUD are remaining stable or even declining since 2016, the mortality associated with opioid use and OUD has increased exponentially in recent years and admission for OUD treatment is increasing (Arfken, Owens, & Greenwald, 2020).
3. Prevalence of opioid overdose
In recent years, the number of opioid overdose deaths, both intentional and unintentional, has seen an exponential rise, primarily attributed to the proliferation of fentanyl and other high potency synthetic opioids in illicit drug supplies. Since the beginning of the 21st century, the United States has witnessed the tragic loss of nearly 600,000 lives due to opioid-related overdoses, with over 100,000 deaths occurring in the year leading up to April 2021. These distressing trends can be delineated into three distinct waves, each characterized by specific contributing factors (CDC, 2022b).
The first wave originated with the surge in opioid prescriptions during the late 1990s and early 2000s. This era saw a significant increase in the prescribing and availability of opioids, setting the stage for widespread misuse and addiction.
The second wave emerged around 2010, marked by a notable rise in heroin-related incidents. As opioid prescriptions became more closely regulated, individuals turned to heroin as a cheaper and more accessible alternative, fueling a new way of addiction and overdose deaths.
The third wave commenced in 2013, as the problem escalated with the influx of synthetic opioids, particularly illicitly manufactured fentanyl. These potent synthetic opioids began appearing in drug supplies, leading to a drastic spike in overdose fatalities and an already alarming death toll.
Of those who die by opioid overdose, the majority are classified as unintentional, with 5–7% recorded as intentional. Because it is difficult to accurately assess intent, the actual numbers are likely higher. Many people who develop a substance use disorder also have another mental illness including mood disorders, PTSD, anxiety disorders, or chronic pain which are independently associated with increased suicide risk. Among people with an OUD or those who use or are prescribed opioids, routine evaluation of co-occurring disorders and suicide risk is warranted.
4. Co-occurring psychiatric diagnoses
Similar to other substance use disorders, OUD co-occurs with other psychiatric illnesses at higher rates than seen in the general population (Jones & McCance-Katz, 2019). Common co-occurring disorders include mood, anxiety, psychotic, cognitive, eating, sleep, and personality disorders as well as attention-deficit/hyperactivity disorder (ADHD), chronic pain, and posttraumatic stress disorder (PTSD). PTSD, in particular, appears to have a complex relationship to OUDs. Trauma exposure is necessary for a diagnosis of PTSD and is simultaneously associated with the development of chronic pain, an independent risk factor for developing OUD (Bilevicius, Sommer, Asmundson, & El-Gabalawy, 2018). A 2012 study of returning veterans from the Middle East wars found those veterans with co-occurring mental health diagnoses were more likely than those without such diagnoses to receive a prescription for an opioid analgesic. Of the psychiatric diagnoses examined, PTSD conferred the highest probability of receiving an opioid prescription. Furthermore, veterans with PTSD were more likely than those without mental health diagnoses to receive high doses of opioids and concurrent sedative-hypnotics, obtain early refills, and suffer adverse opioid-related outcomes (Seal et al., 2012). Among those in treatment for OUDs, PTSD is associated with more severe addiction, higher rates of depression, attempted suicide, and psychosocial problems (Meshberg-Cohen, Ross MacLean, Schnakenberg Martin, Sofuoglu, & Petrakis, 2021). Several clinical practice guidelines for PTSD now recommend trauma-focused psychotherapy treatment as the first-line treatment for PTSD. If medication is preferred to treatment PTSD, specific guidance for treating individuals with PTSD and co-occurring OUDs have been written and disseminated by SAMHSA to promote optimal care for patients with both disorders and to highlight the importance of proactively screening and treating both disorders in a clinical setting (SAMHSA, 2012).
B. Etiology
Current formulations of addiction predominantly cut across substance type, emphasizing common factors contributing to addiction. From conception, genetic and environmental factors interact and influence the risk of both using drugs and, subsequently, developing addiction. Recognized risk factors for drug-seeking include young age, male sex, history of trauma, co-occurring psychiatric disorders, and psychological factors such as high sensation-seeking. Once exposed, it is difficult to predict who will or will not progress to addiction. Acute effects of the drug (pleasant or aversive), drug metabolism, and developmental stage of the individual at time of use (young age being a strong predictor) are among the influencing factors for regular drug use and later addiction. Quantity, frequency, and route of administration (IV or inhalation confer highest risk) of opioid use may also influence the development of addiction. With chronic exposure, neuroadaptation occurs to produce withdrawal symptoms when the opioid is discontinued. This negative reinforcement fuels the person to continue taking and seeking opioids to avoid the discomfort of withdrawal. Craving, or intense desire to seek and use drugs, may also emerge with chronic use, and serves to maintain the cycle of addiction. Substance use disorders remain among the most highly heritable medical disorders, with roughly half of the variation in disease liability attributable to heritable influences. Two large-scale studies of male twins examining opioid addiction reported between 23% and 54% of the variation in opioid addiction was attributable to genetic factors (Kendler, Karkowski, Neale, & Prescott, 2000; Tsuang et al., 1998). Lastly, a personal past history of a substance use disorder is among the strongest predictors of future risk and all persons being considered for a trial of opioid therapy for longer than a few days should be asked about a history of substance use disorder.
C. Genetics
Genetic factors contribute to the development of addiction, and vulnerability may be nonspecific. Using approaches such as twin, family and adoption studies suggest there are significant genetic underpinning for drug addiction in general and heritability of OUD has been estimated to be at about 50% (reviewed in Berrettini, 2017). Studies, including linkage studies, genetic association studies, and genome-wide association studies, have begun to identify and locate associated genes in OUD. Important areas of genetic vulnerability for OUD include (1) genetic variations that code for proteins in the pathway where opioids have their direct action, particularly those that lead to individual differences in biochemical and behavioral responses; (2) genes encoding proteins involved in metabolism; (3) genes encoding proteins involved in treatment agents; and (4) nonspecifically in genes that affect traits such as impulsivity and stress response (which is beyond the scope of this chapter; for more comprehensive review, see Wang, Chen, Lee, and Cheng, 2019).
Some promising findings include variance in alleles in the µ-opioid receptor gene (OPRM1), which regulates OPRM1 expression, in potassium-ion-channel genes (KCNC1 and KCNG2) and in a glutamate receptor auxiliary protein (CNIH3). Regarding metabolism, methadone dose may be regulated by variants in cytochrome P450 2B6 (CYP2B6), a methadone-metabolizing enzyme, and by a variance in OPRM1. Interestingly, δ-opioid-receptor gene single-nucleotide polymorphisms may also be important in the pharmacogenetic response to methadone compared to buprenorphine (Berrettini, 2017).
Most recently, a meta-analysis for OUD found genetic variation in 19 genes that was associated with OUD risk; OPRM1 and FURIN were two genes identified in the analysis of OUD alone. Further, the study found genetic links to other such as chronic pain, the inability to work because of a sickness or a disability, and other psychiatric disorders such as anxiety, depression, and PTSD (Deak et al., 2022).
Clinical Findings
A. Signs & Symptoms
1. Opioid intoxication and overdose
Opioid intoxication and overdose are potential medical emergencies due to diminished respiratory drive and reduced level of consciousness. Miosis (pinpoint pupils), slowed respiratory rate (hypoxemia/hypercarbia), slurred speech, pruritus, constipation, sedation, and psychomotor slowing are all signs and symptoms of intoxication.
2. Opioid withdrawal
Symptoms of opioid withdrawal emerge after stopping or dramatically reducing opioid use following a period of prolonged use and can be conceptualized as rebound hyperactivity in the biologic systems suppressed by the agonists. Symptoms of withdrawal can be seen after as little as 2–3 weeks of daily opioid use (Jaffe JH, 1975) and, in mild form, often manifest as flulike symptoms (anorexia, fatigue, rhinorrhea, lacrimation, insomnia, irritability, anxiety, yawning, piloerection). In more severe or advanced withdrawal, nausea, diarrhea, vomiting, abdominal pain and cramping, hot or cold flashes, musculoskeletal pain and spasms, increased blood pressure and elevated temperature, and mydriasis are seen. The Clinical Opioid Withdrawal Scale (COWS), a validated and easily accessible 11-item clinician-administered instrument designed to assess a patient’s level of opioid withdrawal, is often used to determine the presence of and extent of opioid withdrawal (Wesson & Ling, 2003). This scale is particularly useful in guiding the initiation of buprenorphine, which traditionally has required someone with physiologic dependence and recent use to be in moderate withdrawal before the initial dose.
The time course of a patient’s withdrawal after last use of an opioid depends largely on the half-life of the opioid being used and on the individual factors affecting absorption and elimination (Table 18–1). Regardless of which opioid is used, the acute symptoms of withdrawal are often followed by a more protracted abstinence syndrome, with disturbances of mood and sleep that can persist for months (Martin & Jasinski, 1969). It is hypothesized that these negative emotional symptoms accompanying abstinence (profound dysphoria, irritability, anxiety, heightened emotional pain, sleep disturbances, and intense desire/urges to obtain and use opioids) is the key motivational component of addiction, rather than merely the desire to relieve symptoms of withdrawal (Shurman, Koob, & Gutstein, 2010) and is a promising target for drug development (Koob, 2021).
Table 18–1 Properties of Various Opioids
| Opioid | Mechanism of Action | Available Formulations | Pregnancy Category/DEA-Schedule | Expected Positive Urine Screen | Dose Equivalent to Oral Morphine 30 mg | Detection Time in Urinea | Half-life | Onset & Peak of Withdrawal Symptoms After Last Dose | Metabolism |
|---|---|---|---|---|---|---|---|---|---|
Opiates-natural (from opium) | |||||||||
Codeine | μ-Opioid receptor agonist | Oral | CII | Opiates immunoassay—positive; GC/MS or LC/MS/MS—codeine, possibly morphine & hydrocodone | 200 mg | 1–3 days | 2.5–4 h | 12 h/48–72 h | CYP2D6, morphine is active metabolite |
Morphine | μ-Opioid receptor agonist; κ-opioid receptor agonist | Oral, parenteral (SC, IM, IV), intrathecal, rectal | CII | Opiates immunoassay—positive; GC/MS or LC/MS/MS—morphine, possibly hydromorphone on GC/MS | N/A | 1–3 days | 2–4 h | 6 h/36–72 h | CYP2D6; phase II glucuronidation |
Semisynthetic Opioids (derived from opium) | |||||||||
Buprenorphine | Partial µ-opioid receptor agonist; κ-opioid receptor antagonist; δ-opioid receptor antagonist | Transmucosal (sublingual), parenteral (IM, IV), transdermal | CIII—requires special DEA license when prescribing for opioid addiction | Buprenorphine immunoassay—positive; GC/MS or LC/MS/M—buprenorphine, norbuprenorphine | N/A | 3–7 days | 20–44 h | 24–48 h/72–96 h | CYP3A4 |
Heroin | μ-Opioid receptor agonist | N/A | CI | Opiates immunoassay—positive; GC/MS or LC/MS/M—6-acetyl morphine (<24 h), morphine | N/A | 1–3 days | 60–90 min | 3–4 h/36–72 h | Rapid deacetylation to 6-MAM, morphine |
Hydrocodone | μ-Opioid receptor agonist | Oral | CII | Opiates immunoassay—positive; GC/MS or LC/MS/MS-hydrocodone, possibly hydromorphone | 30 mg | 1–3 days | 4–5 h | 6 h/48–72 h | CYP2D6; CYP3A4 |
Hydromorphone | µ-Opioid receptor agonist | Oral, parenteral (SC, IM, IV), Rectal | CII | Opiates immunoassay—positive; GC/MS or LC/MS/MS-hydromorphone | 7.5 mg | 1–3 days | 2.5 h | 6 h/48–72 h | Phase II glucuronidation |
Oxycodone | μ-Opioid receptor agonist; κ2b-opioid receptor agonist | Oral | CII | Oxycodone immunoassay—positive; opiates immunoassay—possibly positive, particularly at high doses; GC/MS or LC/MS/MS—oxycodone, possibly oxymorphone | 20 mg | 1–3 days | 3.5–4 h | 6 h/48–72 h | CYP3A4; CYP2D6 |
Oxymorphone | μ-Opioid receptor agonist | Oral, parenteral (SC, IM, IV) | CII | Opiates or oxycodone immunoassay—positive; GC/MS or LC/MS/MS—oxymorphone | 10 mg | 1–3 days | 7–11 h | 6 h/48–72 h | Phase II glucuronidation |
Synthetic Opioids (human-made) | |||||||||
Fentanyl | μ-Opioid receptor agonist | Transdermal, transmucosal (intranasal, buccal, sublingual) | CII | GC/MS or LC/MS/MS—fentanyl, norfentanyl | 12.5 mcg/h | 1–3 days | 4 h | 6–36 h/24–48 h | CYP3A4 |
Methadone | μ-Opioid receptor agonist; NMDA-receptor antagonist | Oral | CII—requires administration in federally regulated methadone clinic if prescribed for opioid addiction | Methadone immunoassay—positive; GC/MS or LC/MS/MS—methadone | Complex; a slow conversion to/initiation of methadone is required | 1–7 days | 8–59 h | 24–48 h/72–96 h | CYP3A4; CYP2B6; CYP2C19; CYP2C9 (minor); CYP2D6 (minor); chronic dosing may induce its own metabolism |
Tramadol | μ-Opioid receptor agonist; norepinephrine and serotonin reuptake inhibition | Oral | CIV | GC/MS or LC/MS/MS—tramadol | 225 mg | 1–3 days | 6–8 h | 12–20 h/3–7 days | CYP2B6; CYP2D6; CYP3A4 |
aDetection times are approximate and depend on individual metabolism and the dose of the drug.
3. Opioid addiction and sequelae
Unlike with alcohol, where there are measures of frequency and quantity of use that allow us to estimate risk, any nonprescribed opioid use in the past year warrants an assessment of DSM-5 criteria for an OUD. The classic “3 Cs” of addiction include (1) loss of control, (2) craving, and (3) continued use despite negative consequences, which roughly corresponds to the DSM-5 syndrome. As noted earlier, DSM-5 OUD includes some combination of a general loss of control over opioid use (using more than intended, difficulty cutting down or limiting use), repeated negative consequences of use (including interpersonal/social, psychiatric, and medical consequences, loss of activities once enjoyed, excessive time spent on addiction-related activities, repeated use in high-risk situations), the presence of cravings, and physiologic dependence (tolerance or withdrawal). Symptoms of tolerance and withdrawal are often present with prolonged opioid use, but neither are necessary to make a diagnosis of an OUD, nor are they sufficient in the case of medically prescribed opioid use.
If looking for a reliable test of the consumption and consequences of drug use disorders, the Drug Abuse Screening Test (DAST) can be used. The DAST has 28 items, each weighted equally, in a true–false format, and can aid in identifying the presence of a drug use disorder.
Physical and laboratory signs (see later discussion) may accompany ongoing opioid use, addiction, and medical sequelae. Addiction to opioids increases the likelihood of drug injection. Injecting opioids bypasses first-pass metabolism, increasing bioavailability and, therefore, allowing more efficient use of the drug. In addition, drug injection produces a rapid and intense effect known as a “rush.” Frequently, the median cubital vein of the nondominant arm is used for injecting; however, because of venous scarring or the stigma of drug injection, veins in the hand, foot, or other less obvious areas may preferred. There are several cutaneous signs that may signal addiction and intravenous drug use. These include needle puncture marks, track marks (hyperpigmented linear scars located along veins), hand edema (from injecting into fingers and hands), thrombophlebitis, abscesses, truncal piloerection (sign of opioid withdrawal), and jaundice (due to viral hepatitis often acquired through nonsterile injection of opioids).
4. Screening and identification of addiction in setting of prescription opioids
Current guidelines recommend nonopioid therapies be used for subacute and chronic pain (Dowell et al., 2022) and that opioids only be considered if expected benefits in pain and function are anticipated to outweigh potential harms. There is, at this time, no validated, reliable screening tool to predict which patients will experience harm and which will benefit from opioid therapy—though ample evidence exists that risk of serious harm increases as the dosage of opioids rises, without a clearly defined threshold below which no risk is present (Chou et al., 2020; Sandbrink et al., 2023). Once the decision has been made to initiate opioids for chronic pain, however, clinicians have a responsibility to engage in thorough discussions with patients, addressing realistic benefits and well-known risks associated with opioid use, including OUD, overdose, and death.
Diagnosing an OUD in the context of long-term opioid therapy for chronic pain can be difficult. As noted previously, DSM-5 OUD excludes the criteria of tolerance and withdrawal in the context of prescribed opioids. Yet other criteria may be equally problematic. For example, is someone having a hard time tapering opioids because of an inability to cut back on use or loss of control, or because of poorly controlled pain? Is a patient’s depression worsening because of an opioid addiction or, again, because of underlying pain? One of the criteria is spending a great deal of time in activities necessary to obtain, use, or recover from the effects of opioids—but what does this mean for patients who are using opioids as prescribed around the clock long term, even for decades?
Therefore, shifting the central question from “Does my patient have an addiction?” to “Do the risks of continued opioid prescribing outweigh the benefits or could equal or greater benefit be achieved at a lower dose?” can be an extremely helpful first step in determining whether a trial of opioids for chronic pain should be continued or not. It is recommended to monitor all patients on long-term opioid therapy through routine drug testing, most commonly urine. Moderate quality evidence suggests that increased drug screens and more follow-up after new prescriptions is associated with fewer suicide attempts (Sandbrink et al., 2023). Other risk-mitigation strategies include routinely reviewing the state PDMP and provision of naloxone to reverse opioid overdose.
When, in the context of long-term opioid therapy, the risks appear to outweigh the benefits, it is important to apply a rational, patient-centered approach to treatment. Misapplication of the 2016 CDC Opioid Prescribing Guidelines (Dowell, Haegerich, & Chou, 2016) inadvertently led to some systems adopting stringent and harmful policies including rapid opioid tapers and abrupt discontinuation without collaboration with patients. Such actions are not recommended as they have contributed to significant harm including worsening pain outcomes, serious opioid withdrawal, increased suicidal ideation and behavior, overdose and death (Dowell et al., 2022). Rather, when risks outweigh benefits, several treatment options exist: (1) switch to a medication for OUD, if diagnosis is present (i.e., methadone through an opioid treatment program (OTP), buprenorphine, or IM naltrexone); (2) initiate a patient-centered opioid taper—either to discontinuation or to lowest effective dose—while optimizing nonopioid pain care treatments; (3) offer a switch to a partial agonist opioid therapy (e.g., buprenorphine) to provide immediate safety benefit and potential improvement in function and pain relief (Becker, Frank, & Edens, 2020; Edens, 2020).
B. Psychological Assessment and Measurement-based Care
1. Initial assessment
Once an OUD has been identified and diagnosed, it’s important to follow up with a thorough substance use evaluation identifying: (1) acute or urgent safety risks including withdrawal, overdose, and suicidal thinking; (2) age of initiation of any use, regular use, and problematic use; (3) patterns of use, including quantity of frequency of use, and questions of when, where, how (route of administration), and with whom the patient uses; and (4) treatment history, including periods of abstinence and details surrounding prior or current relapse.
Neuropsychological tests can be useful in determining the extent of lasting brain dysfunction, require patient participation, and are preferably conducted at least 3 weeks after the most recent substance use. Although these tests may be useful, many factors influence them, including medication, co-occurring medical conditions or psychiatric disorder, and compliance with testing.
2. Monitoring progress
While psychological assessment has long played a central role in the field of psychology, providing valuable insights into individuals’ psychological functioning, in more recent years, measurement-based care has emerged as an evidence-based practice, representing a specialized form of applied psychological assessment (Resnick, Oehlert, Hoff, & Kearney, 2020). Measurement-based care involves the systematic use of standardized instruments, questionnaires, or scales that capture patients’ self-reported experiences and perceptions related to their mental health and well-being. These measures are administered at regular intervals throughout the course of treating, allowing clinicians to gather objective data on patients’ progress and outcomes.
The Brief Addiction Monitor, revised (BAM-R) is an assessment tool designed to provide a comprehensive snapshot of an individual’s substance use and related behaviors. The BAM-R consists of several key components including substance use patterns, consequences and problems related to substance use, motivation to change, social support, and recovery environment. It is a 17-item scale that offers a valuable tool for health professionals and to quickly assess and monitor an individual’s progress, tailor treatment plans, and identify areas that require intervention or additional support (Cacciola et al., 2013).
C. Laboratory Findings
In patients presenting with evidence or history of opioid addiction, the following laboratory tests are often performed:
Urine drug of abuse screens. The panel of drugs tested in routine urine toxicology can vary depending on the laboratory used. It is important, therefore, to be familiar with local procedures. The most commonly tested classes of drug in a urine drug screen include amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opiates, and phencyclidine (PCP). The “NIDA 5,” a frequently used U.S. federal drug panel determined by the National Institute of Drug Abuse (NIDA), includes amphetamines, cocaine, marijuana, opiates, and PCP. Notably, many, if not most, routine urine tests do not include and will not detect synthetic opioids including fentanyl, methadone, and buprenorphine, which will require a special lab order. Oxycodone also usually requires a separate test, although, at high doses, it may result in an opiate positive finding. If needed, therefore, these tests should be ordered separately if not included in the local panel. Increasingly, local facilities are adding oxycodone and fentanyl onto routine opioid screens, given the rising prevalence.
Complete blood count and differential. Leukocytosis is common (in detoxification), and white blood cell counts greater than 14,000/mm3 are not unusual. In the context of human immunodeficiency virus (HIV) infection, however, white blood cell counts may be low.
Liver panel
Electrolytes
Thyroid
Syphilis serology
HIV
Hepatitis panel
Urinalysis
Pregnancy test in women
Electrocardiogram. If considering methadone, which can prolong the QTc interval, a baseline ECG is essential.
Chest X-ray
Tuberculin skin test
Though not routinely ordered, obtaining hormonal (e.g., testosterone) levels may be useful in patients complaining of erectile dysfunction, a common complaint with long-term opioid use.
D. Neuroimaging
Brain imaging techniques—both structural and functional—have allowed for a significant understanding of complex behavioral disorders including addiction. Acute and chronic effects of opioids include neurovascular disorders, leukoencephalopathy, and atrophy (Cadet, Bisagno, & Milroy, 2014), perhaps in part because µ-opioid agonists are vasoconstrictors on vascular smooth muscle and are thought to induce vasospasms and subsequent ischemia. Autopsy results of those who die from heroin overdose show a high percentage of cerebral edema; a smaller percentage have ischemia in the globus pallidus. These abnormalities are thought to be related to cerebral hypoxia. Some of these findings may be due to the impurities and not directly related to opioid use, as injection opioid use is associated with a higher incidence of acute cerebral ischemia than other routes of administration. There is evidence from neuroimaging of brain morphology alterations in substance use disorders in general, suggestive of adaptation which in the future may lead to better understanding of the disorder. Further, addiction has been conceptualized as dysregulation of reward processes mediated by the limbic system. Functional imaging techniques have confirmed heightened neural activation in OUD (Pando-Naude et al., 2021). Much of this work is not specific to opioid addiction and is beyond the scope of this chapter (Moningka et al., 2019).
E. Course of Illness
The course of OUD is variable and influenced by factors such as types of opioids used, route of administration, length of time misusing, and setting of use. To illustrate the power of environment and setting, Lee Robins’ famous 1974 study of 900 returning Vietnam veterans found that, although 35% had tried heroin in Vietnam and 20% were addicted to it, only 1% reported addiction 1 year later and 2% reported 2 years later. Moreover, although half of the veterans who had been addicted to heroin in Vietnam used heroin on their return to the United States, only one-eighth of the men became readdicted to heroin. Thus, the great majority of U.S. service members who used heroin or developed heroin addiction while stationed in Vietnam during the Vietnam War were able to quit completely or use intermittently and sparingly after return to the United States, where heroin was less available and less pure (Robins, Davis, & Nurco, 1974; Robins, Helzer, Hesselbrock, & Wish, 2010). Among those who continued a pattern of addiction upon return, however, the course was characterized by significant social problems including arrests and unemployment, not unlike another important naturalistic study of people who used heroin. In that study, 581 incarcerated males who were addicted to heroin were compulsorily enrolled between 1962 and 1964 in the California Civil Addict Program, a mandated drug treatment program for heroin-addicted criminal offenders. At 33-year follow-up, close to half of the initial study participants were dead, 20% tested positive for heroin (with 10% refusing urine drug screening and 14% incarcerated), and 40% reported past-year heroin use (Hser, Hoffman, Grella, & Anglin, 2001). From these two landmark studies, therefore, we can confidently conclude that the course of OUD is variable, yet potentially severe and even deadly. Frustratingly for clinicians, what we are less certain of is how to predict who will have a relatively benign or malignant course.
Two large U.S. population studies, the National Survey of Drug Use and Health (NSDUH) and the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), have also provided valuable insights into the course of OUD. Both studies confirm that many individuals with OUD first use opioids for nonmedical reasons in their teenage or young adult years, most often obtaining it from friends or family. These studies also highlight the high prevalence of co-occurring mental health conditions as well as the significant treatment gap that exists between people who need treatment and people who can access it (Saha et al., 2016; Saini, Johnson, & Qato, 2022). Optimistically, however, longitudinal data from NSDUH and NESARC have provided evidence that recovery and remission from OUD are achievable with treatment, the mainstay of which is medications that have been shown to reduce opioid use, prevent relapse, and improve overall outcomes for individuals with OUD. An important caveat to these national epidemiologic studies is the exclusion of the incarcerated persons, where substance use disorders are disproportionately high and theoretically contain the more severe cases, with more psychosocial barriers to treatment and recovery.
Differential Diagnosis
Other substance use disorders should be included in the differential diagnosis when seeing a patient with suspected opioid addiction. In the intoxicated patient, one should consider alcohol, benzodiazepines, and PCP intoxication as well as other medical causes of altered mental status such as traumatic brain injury, anticholinergic overdose, or hypoglycemia. History of opioid ingestion and urine drug testing are the most useful in determining the etiology of intoxication. Patients in opioid withdrawal typically have good insight into their condition, and the diagnosis is determined by history. However, other intoxication and withdrawal syndromes may mimic opioid withdrawal.
Diagnosing OUDs becomes most challenging in patients with chronic pain conditions who are prescribed opioids. Given that tolerance and withdrawal commonly develop upon repeated exposure to opioids, these symptoms cannot be included in the diagnosis of a DSM-5 OUD—yet, in clinical practice, it is not uncommon to see these symptoms incorrectly equated with prescription opioid misuse. As previously mentioned, it is important to weigh the overall risks and benefits of continued opioid therapy for the management of chronic pain conditions, recognize that daily exposure to opioids is a risk factor for developing OUD and monitor all patients on long-term opioid therapy accordingly, and to transition to medications for OUD if two of the nine remaining DSM-5 OUD criteria (excluding tolerance and withdrawal) are present.
Treatment
A. Psychotherapeutic Interventions
The most robust evidence for treatment of OUDs is medication. However, there are times when nonmedication behavioral or talk therapies may be helpful to address ambivalence, improve treatment adherence, or target co-occurring mental health conditions. Contingency management (CM) is a behavioral approach involving giving patients tangible rewards to reinforce positive behaviors. Studies conducted in OTPs and outpatient substance use treatment programs have demonstrated that incentive-based interventions are highly effective in promoting abstinence from opioids, other substances of abuse (e.g., stimulants), medication adherence, and treatment engagement and retention (Kidorf, King, Gandotra, Kolodner, & Brooner, 2012; Prendergast, Podus, Finney, Greenwell, & Roll, 2006). Though monetary rewards are most often thought of and appear most effective when considering treatment with CM, a common example of CM is rewarding patients with take-home methadone doses after so many days of negative urine drug panel testing in an OTP setting. A 2021 systematic review and meta-analysis that included 74 randomized clinical trials and more than 10,000 adults receiving medications for OUD (MOUD) further supported contingency management’s overall medium to large effect size in addressing co-use of stimulants, abstinence from opioids, adherence to treatment, and other health behaviors such as smoking cessation (Bolivar et al., 2021). The authors urged policy makers—and the Centers for Medicare and Medicaid Services specifically—to allow funds to include CM in the treatment of people with substance use disorders.
Defined broadly, cognitive–behavioral therapy for substance use disorder (CBT-SUD) may include any behavioral or cognitive–behavioral intervention designed to help patients overcome addiction through promoting treatment engagement, retention, or reducing substance use. As such, CBT may describe heterogeneous treatments involving positive or negative reinforcements, motivational and cognitive elements, and skills building (McHugh, Hearon, & Otto, 2010). More narrowly, CBT-SUD incorporates several key ingredients: functional analysis of the patient’s substance use, training in recognizing and coping with cues, cravings, thoughts about using substances, planning for emergencies and identified high-risk situations, development of drug refusal skills, and practice of skills within sessions (McHugh et al., 2010). CBT is a mainstay of psychotherapy in addiction treatment programs. Compared to MOUD, however, its effect is limited in opioid addiction and is typically considered adjunctive to pharmacotherapy rather than a stand-alone treatment. A randomized controlled trial involving patients prescribed buprenorphine for OUD in a primary care setting showed no additional benefit of CBT as compared to physician management with buprenorphine alone. Patients with significant comorbidities including cocaine, alcohol, or benzodiazepine dependence and untreated major depression or psychosis were excluded from the study (Fiellin et al., 2013).
Motivational enhancement therapy (MET) is a specific application of motivational interviewing (MI), a style of counseling that addresses patient ambivalence and enhances a patient’s intrinsic motivation to facilitate change. It is explicitly nonconfrontational. MET is provided in four sessions typically over 12 weeks. Research has shown MET to be most effective for patients with alcohol, nicotine, and cannabis use disorders. One large study showed MI promoted treatment retention in individuals receiving methadone for OUD (Saunders, Wilkinson, & Phillips, 1995). Another study successfully incorporated brief motivational interventions into opioid programming to reduce cocaine and heroin use (Bernstein et al., 2005). The few numbers of studies and lack of reviews indicate the insufficient evidence to recommend MI or MET for people seeking treatment for opioid use (DiClemente, Corno, Graydon, Wiprovnick, & Knoblach, 2017).
Acceptance and commitment therapy (ACT) is a mindfulness-based therapy that encourages patients to observe their thoughts without judgment, accept even sometimes painful feelings and sensations that arise, and identify and commit to value-based behaviors. Although a form of CBT, it also differs in its emphases on noticing and accepting thoughts and feelings rather than working to change them. Research is limited, although there are some data showing augmentation of opioid negative urines in individuals treated with methadone and aid in discontinuing methadone if that is a goal (Stotts et al., 2012). There has been more recent interest in using ACT for people with OUDs and co-occurring psychiatric conditions, such as chronic pain (Smallwood, Potter, & Robin, 2016) or depression (Saedy, Kooshki, Jamali Firouzabadi, Emamipour, & Rezaei Ardani, 2015).
Twelve-step facilitation (TSF) is a brief (12–15 sessions) manualized therapy designed to introduce central tenets of Alcoholics Anonymous (AA), including acceptance that willpower is not enough to achieve sobriety, that group process must supplant self-centeredness, and that spiritual renewal is a key to long-term recovery. The TSF counselor assesses the client’s alcohol or drug use, advocates abstinence, explains the basic 12-step concepts, and actively supports and facilitates initial involvement and ongoing participation in AA. TSF was originally developed for Project MATCH, an 8-year, national clinical trial of alcohol use disorder treatment matching funded by the NIAAA, and appears comparable in efficacy to cognitive–behavioral and motivational enhancement therapies for people who use drugs (Nowinski, 1995). TSF has also been studied among individuals with opioid addiction, including those taking methadone in an OTP setting, and has been found comparable to other therapies in promoting remission (Ball, 2007). It has also been found to improve cocaine use outcomes in an OTP setting (Carroll, Nich, Shi, Eagan, & Ball, 2012).
B. Psychopharmacologic Interventions
1. Intoxication and overdose
Because opioids reduce respiratory drive and diminish level of consciousness, opioid intoxication and overdose are medical emergencies requiring close monitoring and intervention. Emergency management includes assessment of airway access, providing ventilation if needed, an assessment of cardiac function, IV fluids, and administration of naloxone. Naloxone, a μ-opioid antagonist that is administered intravenously or subcutaneously, is first-line treatment of acute overdose, as it rapidly reverses the respiratory depression and sedation caused by opioid intoxication. Opioids with a high receptor affinity (e.g., buprenorphine) require greater naloxone concentrations and/or continuous infusion to antagonize opioid effects than opioids with lower affinity (Dahan, Aarts, & Smith, 2010). Continued monitoring of the patient is essential, as the half-life of naloxone is short compared to longer-acting opioids (e.g., buprenorphine and methadone) and, therefore, repeated dosing may be required to prevent return of sedation and respiratory compromise. Given the current abundance of fentanyl and other high-potency synthetic opioids being sold in illicit markets, the risk of opioid overdose is very high for all people using nonprescribed opioids—with risk further increased in young people, people recently leaving prison or other settings in which abstinence is required, people who mix sedatives (e.g., benzodiazepines) with opioids, people who mix stimulants with opioids, and people with other significant medical comorbidities such as obstructive sleep apnea (SAMHSA, 2018).
In 1996, recognizing the growing problem of opioid overdose and the time-sensitive nature of naloxone administration, the first community-based programs began offering naloxone and other opioid overdose prevention services to persons who use drugs, their families, friends, and service providers (e.g., homeless shelters and substance use treatment programs). These services include education regarding overdose risk factors, recognition of signs of opioid overdose, appropriate responses to an overdose, and administration of naloxone. Since that time, hundreds of local, state, and federal agencies, including the U.S. Veteran Healthcare Administration (Oliva, Richardson, Harvey, & Bellino, 2021), have developed overdose prevention and naloxone distribution programs. Just as one would keep a fire extinguisher readily available for use in a time of emergency, naloxone should be stored in a pocket, purse, or cabinet for rapid access in an emergency. Originally approved as a prescription in 2015 by the U.S. Food and Drug Administration (FDA), over the counter naloxone nasal spray was approved in 2023.
2. Opioid withdrawal
Symptoms of acute opioid withdrawal can be managed medically to reduce suffering and significant associated morbidity. Though rarely life threatening, opioid withdrawal is associated with intense discomfort, strong cravings to use opioids, and low completion rates—which is a set up for risk of subsequent overdose and high mortality. Without coupling to ongoing medication treatment for OUD, medical-managed opioid withdrawal in patients with OUD is generally insufficient, ineffective, and associated with very high rates of relapse (Kakko, Svanborg, Kreek, & Heilig, 2003; Weiss et al., 2011) and death. Therefore, it is essential to clarify the goals of opioid withdrawal before and during the process, including initiation of MOUD with linkage to ongoing treatment. Generally, goals of opioid withdrawal include: (1) relief of suffering during the transition from physical dependence to nondependence, (2) initiation of MOUD, (3) identification and management of co-occurring medical and psychiatric problems, and (4) engagement in ongoing SUD treatment (Capata, 2021). Given the relapsing and remitting nature of addiction and the high rate of death associated with a return to use after reduced tolerance, medically managed opioid withdrawal in people with OUD should not be initiated without a predetermined plan for ongoing medication and treatment. Pregnant women with on OUD are recommended to start opioid agonist medications, rather than undergo a medically supervised withdrawal that is associated with high relapse rates and death (“Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy,” 2017). Occasionally, a taper or discontinuation of prescribed opioids for patients with chronic pain without evidence of addiction may be considered. When doing so, it is recommended that the person agrees with the taper and that it proceeds cautiously to avoid transition to nonprescribed opioid use and emergence of an OUD. Rapid opioid tapers without collaboration with patients have contributed to significant patient harm and is not recommended (Dowell et al., 2022).
Medically managed opioid withdrawal may take place in any setting—including outpatient, partial-hospital, or inpatient settings. The initial evaluation of opioid withdrawal and OUD should include route of opioid use, last opioid use, type and quantity of opioid, use of other substances, and interest in various medication options (Torres-Lockhart, Lu, Weimer, Stein, & Cunningham, 2022). There are three dominant approaches to managing opioid withdrawal medically: (1) opioid agonist medications, including methadone, buprenorphine, and, in Canada only and approved as a third-line treatment, slow-release oral morphine, (2) nonopioid medications for opioid withdrawal, or (3) in patients prescribed long term opioids for the management of pain who do not have evidence of OUD, a gradual reduction of prescribed opioids or transition to buprenorphine. Especially with the rise of fentanyl and other high potency synthetic opioids, two approaches may be used together (e.g., nonopioid medications during the initiation of opioid withdrawal followed by initiation of an opioid agonist). Many individuals with opioid withdrawal symptoms and an OUD diagnosis have previous treatment experience and preferences. If patients express a preference for MOUD treatment and there are no contraindications, it is possible to manage opioid withdrawal using the same medication. This approach simplifies the transition to long-term treatment. Conversely, people who prefer MOUD treatment with opioid antagonists, such as extended-release (XR) injectable naltrexone, should generally be provided nonopioid medications targeting opioid withdrawal symptoms to prevent delays in initiating XR naltrexone treatment (Torres-Lockhart et al., 2022).
The long-acting opioid agonists, methadone and buprenorphine, are considered first-line treatment for opioid withdrawal. Factors such as patient preferences, prior OUD treatment, and medication availability should guide the choice of which medication to use. In the United States, prescribing regulations for methadone and buprenorphine are governed by laws passed by Congress. Either can be administered for opioid withdrawal in emergency departments and other nonopioid detoxification settings. In the inpatient setting, methadone and buprenorphine can be administered as long as needed for treatment of a concomitant medical problem. However, in outpatient settings, only buprenorphine can be prescribed. Methadone is dispensed to treat OUD through a highly regulated, SAMHSA-certified, facility known as an OTP.
Methadone is a long-acting high-affinity µ- and δ-opioid receptor agonist. The starting dose of methadone should consider the potential risks of respiratory depression and sedation and is typically 20–30 mg. Methadone should be initiated at the initial signs of withdrawal and additional doses of 5–10 mg can be given every 4–6 hours, with a recommended maximum of 30 mg on day 1. In patients with significant physiologic dependence, 30 mg should be adequate for even the most severe withdrawal. Because deaths in opioid-intolerant individuals have occurred at a dose of 40 mg, lower doses are initially given in the range of 10–20 mg to individuals with an unclear degree of physiologic dependence. After 1–2 hours of observation, withdrawal symptoms may be reassessed and, if needed, additional medication up to 30 mg provided. Further dosing should be held if intoxication or sedation is observed. Once the dose requirement for methadone has been established, methadone may be given daily and, if it’s going to be used for ongoing OUD treatment, increased each 3–5 days to a dose that suppresses cravings and nonprescribed opioid use. If methadone is being used to treat withdrawal with a goal to stop opioid agonists, it should be tapered over 3–5 days in 5- to 10-mg increments. The half-life of methadone is subject to individual variability, averaging 24 hours but ranging between 4 and 130 hours (Eap, Buclin, & Baumann, 2002) resulting in cumulation of blood levels and associated death from respiratory depression if methadone doses are too rapidly increased early in treatment.
Buprenorphine is a partial agonist at the µ-opioid and antagonist at the δ- and κ-opioid receptors and is frequently used to manage opioid withdrawal with less restrictive regulations. Unlike methadone, buprenorphine may be prescribed out of a physician’s office. The availability of this medication has greatly increased access to care for persons with OUD. For almost two decades, however, prescribing buprenorphine required physicians to complete additional training and apply for a special waiver to prescribe. In late 2022, the MAT Act (Mainstreaming Addiction Treatment) was signed into law eliminating this requirement. All practitioners with a current Drug Enforcement Agency (DEA) registration that includes schedule III authority are now allowed to prescribe buprenorphine for OUD in their practice if permitted by state law. As part of the same legislation, the MAT Act requires new or renewing DEA registrants to attest to either (1) a total of eight hours of training on opioid or other substance use disorder, (2) board certification in addiction medicine or addiction psychiatry, or (3) graduation within 5 years from health profession schools that included at least 8 hours of SUD curriculum (SAMHSA, 2023b).
Before initiating buprenorphine, people should discontinue all nonprescribed opioids and be exhibiting symptoms of mild to moderate withdrawal. Buprenorphine is a partial agonist with a very high affinity for the µ-opioid receptor. If the person has physiologic dependence but is not yet in withdrawal, buprenorphine will displace the full µ-opioid agonist and lead to precipitated opioid withdrawal, an often dramatic and uncomfortable outcome. Most people who use drugs are keenly aware of their personal withdrawal time course, and it is good practice to obtain their prior experiences. This information, along with an objective assessment of the COWS (a minimum score of 7–13 is generally recommended), can aid in timing the initial dose. Once moderate opioid withdrawal symptoms have emerged, an initial dose of buprenorphine 4 mg/naloxone 1 mg (2/0.5 mg if physical dependence is low or significant medical concerns that might warrant lower initial dose) is recommended. In the sublingual buprenorphine/naloxone formulation, naloxone is biologically inactive. Its purpose is solely to prevent diversion and injection of buprenorphine—when buprenorphine/naloxone is injected, naloxone becomes active and can precipitate withdrawal. After 2–4 hours, in the absence of sedation, a second dose of 4/1 mg (or 2/0.5 mg if that was initially used) may be provided if withdrawal symptoms remain. Buprenorphine 8 mg is generally the recommended target dose for day 1, with 12 mg being a maximum. If withdrawal symptoms are expected to continue beyond the maximum dose on day 1, nonopioid medications targeting specific symptoms should be provided. Over the next 2 days, the dose should be increased to 12/3–16/4 mg/day, with a daily maximum generally not exceeding 24 mg a day. Many clinicians are noting that, with the prevalence of fentanyl and other high potency synthetic opioids in the current market, people are coming to treatment settings with higher degrees of tolerance and physiologic dependence than seen with other, earlier full agonist opioids (e.g., heroin, nonprescribed oxycodone, etc.). There is little research to guide clinicians in how to manage the changing landscape—and alternative buprenorphine initiation protocols are emerging (Blevins, 2023). Nonetheless, the standard buprenorphine initiation protocol described above remains the most well studied and clinical experience supports this method of initiation in people who use fentanyl and other high potency synthetic opioids.
Once initiated, the goal of treatment is to continue one of the three FDA-approved treatments for OUD. If a taper to discontinuation is desired, however, a buprenorphine taper is best performed over a long period of time in conjunction with ongoing treatment. Occasionally, patients have compelling reasons to need a moderate or even a short taper, for example, because of impending incarceration where MOUD may not be continued. In these cases, a taper over 3–14 days may be initiated. Nonopioid medications (see below paragraph on these medications) may be used concurrently for symptoms that persist and to minimize discomfort. Medically managed opioid withdrawal without linkage to MOUD is generally ineffective, with high relapse rates and associated death. Every effort should be made to engage patients in ongoing treatment for opioid addiction, with medications being most effective and first line (2004).
Though largely beyond the scope of this chapter, it’s important for healthcare providers to be aware of alternative medication treatment options available outside the United States. Widely used in Europe and now recommended as a third-line treatment for OUD in Canada, slow-release oral morphine, prescribed by specialists in primary care and administered daily by community pharmacies, is showing promise for those who have not tolerated or responded to methadone or buprenorphine yet remain at high risk of poor outcomes, including overdose and death (Bruneau et al., 2018). Other countries are using injectable hydromorphone or even injectable, inhaled, or smoked diacetylmorphine to treat OUD (Humphreys et al., 2022). There is increasing interest in alternative opioid agonist medications in the United States as well, though none are currently legally available.
For people who prefer treatment with the opioid antagonist intramuscular XR naltrexone, symptomatic management of opioid withdrawal with nonopioid medications can be used to minimize discomfort and promote treatment retention. Alpha-2 adrenergic agonists, such as clonidine or lofexidine, are the primary medications used, targeting the autonomic hyperactivity and associated anxiety seen in opioid withdrawal. Lofexidine was FDA approved in 2018 and was the first nonopioid treatment for opioid withdrawal symptoms (Urits et al., 2020). While it has been shown to have weaker side effects (less sedation and hypotension) than clonidine, the high cost limits its use compared to clonidine. In addition to α-2 adrenergic agonists, symptomatic treatment of gastrointestinal symptoms is commonly treated with loperamide, a peripheral µ-opioid agonist with limited CNS activity to manage diarrhea. Dicyclomine, an anticholinergic medication that relaxes smooth muscle and inhibits cramping, is often used for abdominal cramping. Antihistamines (e.g., hydroxyzine or diphenhydramine) or sedating antidepressants (e.g., trazodone or doxepin) are used for insomnia and restlessness. Nonsteroidal anti-inflammatory drugs may be used for muscle aches. Promethazine or metoclopramide are often used for nausea and vomiting and muscle relaxants (e.g., methocarbamol) can help with muscle spasms. Initiation of XR naltrexone to treat OUD is recommended after full resolution of opioid withdrawal, which can take 7–10 days.
3. Medications for OUD
The goal of any medically-supervised opioid withdrawal in the context of an OUD is to initiate medication treatment and engage people in long-term treatment. Appropriately prescribed and dosed pharmacologic treatment has been shown to improve patient survival, decrease nonprescribed opioid use and associated criminal activity, improve birth outcomes among pregnant women, lower a person’s risk of contracting HIV or hepatitis C, and increase treatment retention (SAMHSA, 2023a). Because of this, the SAMHSA clinical guidelines on treatment of opioid addiction are unequivocal in writing, “absent a compelling need for the complete avoidance of all opioids, long-term maintenance treatment … is to be preferred in most instances to any form of detoxification or withdrawal treatment” (2004). There are three approaches to long-term pharmacologic management of opioid addiction which include prescribing an opioid (1) agonist, (2) partial agonist, or (3) antagonist medication.
i. Methadone has decades of demonstrated efficacy in reducing opioid consumption; criminal behavior; psychosocial and medical morbidity, including rates of HIV infection; and mortality (Heikkinen et al., 2022; Russolillo, Moniruzzaman, & Somers, 2018). Methadone administration for the treatment of opioid addiction is highly regulated in the United States with facilities required to obtain SAMHSA certification and referred to as OTPs. Pharmacologically, methadone is a long-acting medication (half-life ~24 hours) that fully agonizes the high-affinity µ- and δ-opioid receptors. Two enantiomeric forms exist: levo-methadone and dextro-methadone. levo-Methadone accounts for most the opioid agonist effects of the drug and has no effect on the electrocardiographic QT interval. dextro-Methadone, on the other hand, is an N-methyl-D-aspartate (NMDA) antagonist. In most countries, including the United States, the racemic mixture is the only formulation available (Soyka & Zingg, 2009). Given its long action and the slow accumulation in solid organs, caution is required in the early phases of induction or during dose increases to prevent overdose; initial daily dose should not exceed 30 mg. In addition, patients should be cautioned regarding cardiac effects, including the risk of QTc prolongation and potentially fatal arrhythmias. Baseline and follow-up ECGs are recommended, particular for those on doses greater than 100 mg daily. Common side effects of methadone are like other opioids and include constipation, sweating, nausea, lightheadedness, insomnia, and sedation. Because it is metabolized primarily through the CYP3A4 and CYP2B6 pathways, caution is advised when combined with potent CYP3A4 inducers (e.g., carbamazepine, rifampin) or inhibitors (e.g., protease inhibitors, ketoconazole, grapefruit juice). Chronic opioid use is generally well tolerated, though constipation, sweating, sleep abnormalities, hyperalgesia and changes in endocrine function may be ongoing (Arout, Edens, Petrakis, & Sofuoglu, 2015; Brennan, 2013).
ii. Buprenorphine is a partial agonist at the µ-opioid receptor. Because of the partial µ-opioid agonism, there is a ceiling to the effect on respiratory suppression that can provide some protection from respiratory depression and death in overdose. Most often, buprenorphine/naloxone, rather than buprenorphine alone, is prescribed as treatment for OUD. The purpose of the addition of naloxone—biologically inactive in sublingual form—is to reduce diversion and injection. Generally, buprenorphine monotherapy is reserved for pregnant women or those in a controlled environment such as a hospital. Both formulations are DEA schedule III and can be prescribed in an office-based setting. Just as with a medically supervised withdrawal, buprenorphine/naloxone is typically initiated once a patient is in mild to moderate withdrawal. It is administered in sublingual form (because of poor oral bioavailability) and should be held under the tongue until it dissolves completely. The half-life of buprenorphine is long, about 37 hours, allowing for once-daily or even as much as three-times-weekly dosing. The target dose for day 1 is 8 mg, with higher doses used on subsequent days until withdrawal symptoms and cravings are controlled. The typical daily maintenance dose is between 12 and 24 mg (average 16 mg) but may be up to 32 mg. Common potential adverse effects include constipation, nausea or vomiting, sedation, and worsening opioid withdrawal (if taken too close to last opioid ingestion). Buprenorphine, like methadone, is metabolized through CYP3A4 and should be used with caution when potent CYP3A4 inducers or inhibitors are co-prescribed (McCance-Katz, Sullivan, & Nallani, 2010).
iii. Naltrexone is the third FDA-approved medication for treating OUD. It is available in both oral and extended-release IM formulation. Naltrexone blocks the action of agonist or partial-agonist opioids and removes the rewarding effects of using opioids. Data on the effect of naltrexone on opioid cravings are mixed (Dijkstra, De Jong, Bluschke, Krabbe, & van der Staak, 2007; Krupitsky et al., 2011). A 2011 Cochrane review of 13 studies showed that oral naltrexone did not perform better than placebo or no pharmacological treatments and is not recommended for treatment of OUD. The extended-release injectable form of naltrexone, approved for treatment of OUD in 2010, however, has shown more promising results (Tanum et al., 2017). A 24-week randomized trial conducted in Russia—a country that does not provide alternative agonist therapies—showed significantly decreased cravings, greater treatment retention, and more opioid-free days compared to placebo (Krupitsky et al., 2011). A U.S. trial of 570 patients randomized to receive either IM naltrexone or buprenorphine-naloxone found that patients struggled to be initiated onto an opioid antagonist. For those who were successfully inducted, however, 24-week relapse rates, opioid negative urines, and days abstinent from opioids were similar between buprenorphine and IM naltrexone (Lee et al., 2018). Injectable naltrexone is now considered a second-line MOUD (Perry et al., 2022).
C. Harm Reduction
In response to what the CDC calls an opioid overdose epidemic, the federal and state governments have enacted prevention strategies to combat these disturbing trends. In addition to encouraging safe opioid prescribing practices, other strategies designed to reduce harm include prescribing naloxone to reverse opioid overdoses—like prescribing epinephrine in the unlikely but potentially deadly event of anaphylaxis, expanding access to sterile syringe programs, and providing fentanyl test strips to people who use drugs so they can test their own supply of opioid before using it. Though largely unavailable and still considered illegal in the United States, safe consumption sites are emerging in large cities such as New York and San Francisco as a way for people who use drugs to do so in a monitored setting with immediate access to opioid overdose treatment.
D. Other Interventions
Mutual (or peer) support programs including 12-step (e.g., Narcotics Anonymous [NA] and SMART Recovery can be helpful to many people with OUD entering treatment. Narcotics Anonymous is a self-help organization that follows the 12-step model of recovery as outlined by AA in 1939 (Company, 1939). NA is frequently attended by individuals with cocaine, heroin, other opioid, methamphetamine, alcohol, cannabis and other illicit drug use. Long-term members tend to rate themselves as spiritual, if not religious, and many have served as sponsors to other members. NA is free, anonymous, and readily available throughout the country in a variety of community settings (Galanter, Dermatis, Post, & Santucci, 2013). SMART (Self-Management and Recovery Training) Recovery is a global online and in-person mutual support organization offering an alternative to those for whom 12-step programs aren’t accessible or desired. SMART Recovery uses facilitated meetings and topics to cover their four-point program: (1) building and maintaining motivation to change; (2) coping with urges to use; (3) managing thoughts, feelings, and behaviors in an effective way; (4) living a balanced, positive, and healthy life (“Why SMART,” 2022).
Acupuncture, including body, auricular, and electro acupuncture, is sometimes used to treat opioid and other drug cravings as well as symptoms of opioid withdrawal. Two large rigorous trials in patients with alcohol- and cocaine-addiction showed no benefit of acupuncture on treatment retention or abstinence (Bullock et al., 2002; Margolin et al., 2002). Yet, other studies have showed significant reductions in craving in response to acupuncture (Chang & Sommers, 2014) and an exploratory review noted promising results when using different outcomes such as opioid withdrawal and cravings, rather than abstinence or treatment retention (White, 2013).
Family interventions may be needed because, frustratingly for loved ones, drug addiction is often complicated by a perceived lack of need for treatment by the addicted individual. The Community Reinforcement and Family Training (CRAFT) approach is a brief, typically 12- to 20-session, psychotherapy intervention designed to engage the addicted individual’s significant other—be it parents, partners, or children—with a goal to ultimately engage the addicted person and to improve overall family function. A 2010 systematic review found four high-quality randomized controlled trials with a total sample of 264 concerned significant others. CRAFT significantly outperformed both Al-Anon/Nar-Anon (three times more engagement) and the Johnson Institute intervention (two times more engagement) over a 6-month period, engaging over two-thirds of individuals with addiction in an average of four to six treatment sessions (Roozen, de Waart, & van der Kroft, 2010).
Co-occurring Disorders
The most common co-occurring medical disorders among individuals with OUD are infectious—both viral (e.g., HIV, hepatitis C and B virus) and bacterial (e.g., endocarditis), particularly among people who injection drugs. Patients should routinely be consented and screened for the presence of HIV and hepatitis. Hepatitis C (HCV) can now be treated and cured with oral direct-acting antivirals and the World Health Organization has called for the elimination of HCV as a public health threat by the year 2030. To achieve this goal, 90% of people with HCV should be diagnosed, and 80% treated, including people who use drugs (Falade-Nwulia et al., 2020). Substance use treatment clinic settings and addiction specialty prescribers should be trained and equipped to screen, diagnose, and treat HCV (Roder et al., 2021). The other common comorbidity is chronic pain, which can complicate the treatment of OUD (Volkow, Jones, Einstein, & Wargo, 2019). Current guidance recommends nonpharmacologic and non-opioid therapies for the management of chronic pain, even among people on MOUD. Many of these treatments are familiar to mental health providers, including cognitive and behavioral therapies (Barry et al., 2019), antidepressants, and antiepileptics—and providers who treat people with substance use disorders should develop comfort talking with patients about strategies for managing chronic pain.
Co-occurring mental health disorders are also common among individuals with OUD and confer risk for poorer psychosocial functioning, increased suicidal behavior, and worse treatment outcomes (Jones & McCance-Katz, 2019). The most frequent co-occurring mental health condition is another substance use disorder (including tobacco, alcohol, cannabis, stimulant, and benzodiazepine). Mood, anxiety, and trauma-related disorders also commonly co-occur with opioid addiction. According to NESARC, more than half of individuals meeting criteria for an OUD also met criteria for a mood disorder, an anxiety disorder, or both (Conway, Compton, Stinson, & Grant, 2006; Grella, Karno, Warda, Niv, & Moore, 2009). In addition, NESARC’s longitudinal design allowed for the recognition that mood and anxiety disorders were predictive of incident nonmedical prescription opioid use and of development of prescription opioid addiction, though the reverse was not true (i.e., lifetime prescription opioid addiction did not predict an incident mood or anxiety disorder (Martins et al., 2012). A history of conduct disorder in childhood or adolescence has been identified as a significant risk factor for substance-related disorders, including OUD (Carpentier, Knapen, van Gogh, Buitelaar, & De Jong, 2012). PTSD is also seen with increased frequency among people who use opioids; indeed, one study found PTSD to be present in one third of those with OUD—the most of any substance use disorder. Treatment of OUD produced similar addiction-related improvements among those with and without a co-occurring PTSD diagnosis. However, those with PTSD were lower functioning at baseline and continued to have poorer functioning at 2 years, perhaps suggesting that PTSD symptoms remained despite addiction treatment (Mills, Teesson, Ross, & Darke, 2007). There is also a high degree of comorbidity between PTSD, OUD and chronic pain complicating the treatment of all three (Lopez-Martinez, Reyes-Perez, Serrano-Ibanez, Esteve, & Ramirez-Maestre, 2019). Treatment targeting both opioid addiction and co-occurring substance, mood, anxiety, and stress-related disorders should be provided to individuals with comorbidities.
Complications
There are many serious medical and public health consequences of opioid addiction. Of particular concern is the high risk of lethal and nonlethal opioid overdose. Overdose risk has risen exponentially over the past several decades—with more than 100,000 overdose deaths in 2021. In addition, opioid use substantially increases the risk of infectious disease, with as many as 80–90% of people who inject opioids screening positive for hepatitis B or C. HIV risk, endocarditis, pulmonary embolism, thrombophlebitis, and other sequelae are all significantly elevated among those who inject drugs. Pregnant women with opioid addiction are at increased risk of poor outcomes including miscarriage, stillbirth, or preterm or low-birth-weight infants. Mothers prescribed methadone or buprenorphine throughout pregnancy have improved outcomes, and ongoing medication treatment is strongly recommended. Neonatal abstinence syndrome is an expected and treatable condition that follows prenatal exposure to opioid agonists (“Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy,” 2017). Other complications of chronic opioid use include constipation, pruritus, urinary retention, sedation, endocrine and immunologic dysfunction, and hyperalgesia (Benyamin et al., 2008).
Adverse Outcomes of Treatment
Because treatment retention and receipt of MOUD is a strong predictor of remission from OUD symptoms, it’s important to minimize side effects of medication treatments. Methadone, being a full opioid agonist, is potentially addictive and fatal in overdose. Though unquestionably safer, buprenorphine as a partial agonist, can still be associated with overdose—particularly when combined with other sedating medications. There is also concern that long-term opioid therapies may negatively affect cardiac and endocrine function and play a complicated role in the maintenance of chronic pain.
Drug Interactions
Methadone and buprenorphine are both metabolized via cytochrome P450 isoenzymes, particularly CYP3A4, and therefore are affected by drugs that either induce or inhibit these isoenzymes. CYP 3A4 inhibitors may lead to elevated plasma levels of buprenorphine and methadone and subsequent oversedation, reduced respiratory drive, and even death. Conversely, removal of inhibiting medications can increase buprenorphine and methadone metabolism, leading to withdrawal symptoms. Potent inhibitors of this isoenzyme include the azole antifungals (e.g., ketoconazole, itraconazole). Of importance given the overlap of HIV and OUDs, several protease inhibitors (e.g., ritonavir, nelfinavir) also inhibit CYP 3A4, and caution is advised when using them concomitantly with opioids. The addition of CYP3A4 inducers to a medication regimen may lead to withdrawal symptoms in methadone- or buprenorphine-maintained individuals, and discontinuation of inducers can lead to elevated opioid levels. CYP3A4 inducers include nonnucleoside reverse transcriptase inhibitors (e.g., nevirapine, efavirenz), antiepileptics (carbamazepine, phenytoin, oxcarbazepine, phenobarbital), antibiotics (rifampin, rifabutin, rifapentine) (Baciewicz, Chrisman, Finch, & Self, 2013), St. John’s wort, and even cocaine (McCance-Katz, Rainey, & Moody, 2010; McCance-Katz, Sullivan, et al., 2010). Drug interactions are not limited to the cytochrome P450 system and may be influenced by changes in absorption, protein binding, or renal clearance. In addition, interactions between sedating medications (such as benzodiazepines or alcohol) and methadone or buprenorphine are of particular concern and are frequently involved in lethal and nonlethal overdose.
Prognosis
Left untreated, the prognosis for people with OUD is very poor. People with severe OUD are at risk for injuries, infections, incarceration, overdose, and death—either from overdose or by suicide. The mortality rate is 10-fold for people with OUD compared to the average US population. In 2021, life expectancy declined in the US for the second year in a row—an unprecedented statistic attributed to increased overdose deaths, along with COVID-19 (CDC, 2022a). Psychotherapy alone has extremely poor outcomes, as do medically assisted opioid withdrawal programs without initiation of MOUD. With MOUD however, OUD is treatable, and prognosis and course are dramatically improved. MOUD has been shown to decrease opioid use, opioid-related deaths, transmission of infectious disease, and incarceration and is associated with improved social functioning and treatment retention (NASEM, 2019). Among pregnant women, MOUD improves not only the health of the mother but also outcomes for newborns (“Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy,” 2017). Sadly, only one in four people who need MOUD, receive it, despite often high levels of contact with the healthcare or prison systems, with adolescents and older adults showing the greatest treatment gap (Mauro, Gutkind, Annunziato, & Samples, 2022).