Classification
Medications derived from Papaver somniferum , the opium poppy, have played a central role in medical practice for well over 3500 years. Sumerian clay tablets, which include our oldest known medical texts, called the opium poppy “Hul Gil,” the “Joy Plant.” In the Greco-Roman era, poppies were cultivated for their pain-relieving, antidiarrheal, and sedative properties. Today, medications in this class are divided into two groups. Opiates are naturally occurring compounds derived from the active alkaloids of the opium poppy. This group includes morphine, codeine, and thebaine. Opioids, defined as compounds that bind to opioid receptors, are typically manufactured medications that are classified as either fully synthetic or semisynthetic. Medications in the synthetic opioid group include alfentanil (Alfenta, Rapifen), fentanyl, meperidine (Demerol), methadone (Dolophine), pentazocine (Talwin), propoxyphene (Darvon), and sufentanil (Sufenta). Included in the semisynthetic opioid group are buprenorphine (Bunavail, Buprenex, Probuphine, Suboxone, Subutex, and Zubsolv), hydrocodone (Hycodan), oxycodone (Percodan), and oxymorphone (Numorphan), all of which are derived from thebaine. Other semisynthetic compounds derived from the opium poppy are hydromorphone (Dilaudid) and heroin, which is metabolized to morphine. Both of these drugs are highly abusable. The human body also produces a number of endogenous opioids, such as endorphins, enkephalins, and dynorphins. Other opioids that exist in nature, but are not related to opiates, include salvinorin A (from Salvia divinorum ) and mitragynine (from Mitragyna speciosa ).
Etiology
There is no clearly defined etiology for opiate use disorder. Risk is determined by multiple factors including genetics, psychiatric comorbidity, and social and environmental factors, including drug exposure. Twin studies suggest that genetics alone accounts for 45%–50% of the risk for opioid dependence. Recent work has identified two sites on chromosome 17 that are associated with an increased risk for drug dependence; one of these sites is connected to severe symptoms of opioid dependence, but not to dependence on other drugs. Further work is needed to identify the specific genes that are associated with the unique risk for opioid dependence.
Epidemiology
Patterns of Use
For most of the 21st century, heroin was the primary opiate abused in the United States. There were major epidemics after World War I, World War II, and the Vietnam War. Among the general population, it is estimated that 10%–30% of individuals who are exposed to licit and illicit opioids may develop symptoms of an opioid use disorder. These numbers may be significantly higher in individuals with co-occurring psychiatric disorders, particularly those exposed to sexual abuse or combat trauma. Although regular estimates of drug use in adults and adolescents have been available from the Monitoring the Future study and the National Survey on Drug Use and Health, information on drug use disorders has rarely been collected. There was a 16-year gap between publication of the 1990–1992 National Comorbidity Survey data and the 2000 National Survey on Drug Use and Health, which collected 12-month prevalence data on drug use disorders. Depending on the survey and the criteria used, estimates for the lifetime prevalence of any drug use disorders have ranged from 0.4% to 7.5%.
For many years, it was assumed that the lifetime risk for heroin use disorder was relatively low and ranged from 0.4% to 0.7%. In 2006, the National Survey on Drug Use and Health reported that 3.79 million individuals used heroin at least once in their lifetime and 323,000 were classified with either dependence or abuse of heroin. In addition, it was estimated that there were 250,000 individuals in methadone maintenance treatment. From 1984 to 1994, new users of heroin each year ranged between 28,000 and 80,000. From 1995 to 2001, the number averaged over 100,000; in 2006, it dropped slightly to 91,000. Heroin use began to increase gradually after 2006 and the number of new users reached 268,000 in 2014, representing almost a 100% increase in that time frame (Fig 4; NSDUH 2015, Figure 13). Even more concerning, the number of overdose deaths related to heroin increased by almost 300% during the same period.
Incidence of Substance Use Disorders
The most recent national survey, the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions, was designed to collect data on drug use disorders and, for the first time in a national survey, to collect separate data on both illicit drugs and prescribed medications. The National Epidemiologic Survey on Alcohol and Related Conditions surveyed 43,093 adults (18 years of age or older) in the United States, and captured data at the time when the United States’ epidemic of prescription opioid abuse was at its peak. The National Comorbidity Survey and the Environmental Catchment Area Survey combined data on heroin and other opiates into a broad drug abuse category that also included other illicit drugs, thus making it impossible to get specific data on opiates, or to separate out information on heroin from data on prescribed opiates. The National Epidemiologic Survey on Alcohol and Related Conditions reported the prevalence of 12-month and lifetime drug abuse as 1.4% and 7.7%, respectively, and the rates of drug dependence as 0.6% and 2.6%, respectively. Rates of abuse and dependence were significantly higher in men than in women and in Native Americans than in whites, blacks, and Hispanics. The lifetime prevalence of nonmedical prescription opioid drug use was 4.7%. The lifetime prevalence of nonmedical opioid drug use disorders was 1.4%, indicating that approximately 30% of users were at risk for developing an opioid drug use disorder. Men were significantly more likely to progress from use to abuse to dependence than were women, as were Native Americans as compared with whites. The mean age at onset of opioid abuse or dependence was 22.8 years, and the mean age at first treatment was 26.2 years, a lag of 3.4 years. Approximately two-thirds of individuals with opioid use disorders never received treatment. This prevalence of nonmedical opioid use disorders is two to three times higher than prior estimates of the prevalence of heroin use disorders.
Abuse of Opioid Analgesics
The abuse of opioid analgesics was traditionally thought to be a relatively small part of the drug problem in the United States. Although there were few data on the risk for dependence among individuals treated for chronic pain, the risk was assumed to be minimal. During the 1960s, the introduction of pentazocine (Talwin) triggered a period of abuse after opiate addicts discovered that the injected combination of Talwin and amphetamines (“T’s and Blues”) produced a potent euphoric effect. After this problem was identified, the US Food and Drug Administration (FDA) required that the medication be reformulated as a combination tablet of Talwin and naltrexone (TalwinNX). This formulation produced an antagonist reaction in addicted individuals if the tablets were crushed and injected, essentially eliminating significant misuse of this medication. The abuse of other opioid analgesics remained a minimal problem until the introduction of OxyContin in 1996. From 1970 to 1995, the National Survey on Drug Use and Health reported that the annual number of new nonmedical users of pain relievers ranged from 700,000 to 1,000,000. In the 5 years following 1996, this number almost tripled to 2,500,000. These numbers reflected a new epidemic of misuse of pain relievers in the United States ( Fig. 25.1 ). The number of nonmedical users of pain relievers began to decline after 2006. In 2014 it was estimated at 10.34 million noninstitutionalized persons 12 years of age or older (see Fig. 25.4 ).
As noted previously, prior to 2000, the National Survey on Drug Use and Health reported only drug use data, not data on drug use disorders. In 2005, the National Survey on Drug Use and Health reported that 4.9% of 12- to 17-year-olds had used prescription pain relievers nonmedically in the past year. This was more than 24 times the reported use of heroin in this group (0.2% versus 4.9%). In this cohort, past-year dependence or abuse was 1.1% (275,000 individuals) for pain relievers versus 0.0% (fewer than 9000 individuals) for heroin dependence or abuse. In 2006, the National Survey on Drug Use and Health reported that 33,422,000 Americans 12 years of age or older admitted to the nonmedical use of pain relievers at least once in their lives and that 12,649,000 had done so in the last year. The survey classified 1,635,000 individuals 12 years of age or older with dependence or abuse of pain relievers, as compared with 323,000 individuals classified with dependence or abuse of heroin. The 2006 National Survey on Drug Use and Health estimated that 7,800,000 adults in the United States (3.2% of the total population) were in need of treatment for some type of illicit drug problem; less than 20% of that group received any treatment in 2006. By 2015, there were more than 2.1 million new illicit users of pain relievers, making the misuse of pain relievers the second most common new drug of misuse, ahead of marijuana (2.6 million). In comparison, there were only 135,000 new initiates to heroin misuse in 2015 ( Fig.25.2 ). These data make it clear that the misuse of pharmaceutical analgesics has replaced heroin as the dominant opioid misuse problem in the United States.
Risks Associated With the Use of Opioid Analgesics
For many years, pain management specialists had voiced concern about the undertreatment of pain. The pharmaceutical industry also identified a need for less abusable and more potent opioids for pain management. In the 1980s, the Bard Corporation developed a sustained-release technology suitable for morphine. This led to the marketing of sustained-release morphine in England under the brand name of MST Continus; in 1984, the same medication was introduced in the United States by Purdue Pharma as MS-Contin. This formulation proved effective in preventing significant abuse, and the medication gained wide acceptance in the American market. The expanding use of opioids for the treatment of severe pain led to an interest in a medication with greater potency, longer duration of action, and low abuse potential. Oxycodone provided the desired potency, but it could not be successfully formulated with the sustained-release technology that had been effective with morphine. This problem was resolved in 1996 when Purdue introduced OxyContin, a time-release formulation of oxycodone with an acrylic coating that was designed to dissolve slowly and provide 12 h of pain control, permitting individuals with pain to sleep through the night. This formulation permitted delivery of doses ranging from 10 to 160 mg—doses far in excess of the 30-mg maximum dose previously available in oxycodone tablets. This was a major advance in the management of severe pain. Based on the experience with MS-Contin, both Purdue and the FDA assumed that this formulation would have low abuse potential, and Purdue was permitted to market the medication as a potent, long-acting narcotic with a lower abuse potential than other opioid analgesics. Consequently, Purdue marketed OxyContin as a first-line agent for the treatment of nonmalignant pain. At that time, there was a general presumption that iatrogenic addiction secondary to the treatment of legitimate pain was a rare event. This assumption was based on a series of articles published between 1977 and 1982, all of which reported a minimal risk of iatrogenic addiction in the treatment of acute pain. This view was reinforced by Portenoy and Foley, who found evidence of abuse problems in only 2 of 38 individuals chronically treated with opiates for nonmalignant pain. They concluded that opioid maintenance therapy was safe, except in individuals with a history of drug abuse. In 2000, Joranson et al. reviewed emergency room data from the Drug Abuse Warning Network and found no evidence of an increase in analgesic abuse, despite significant increases in the prescription of opioid analgesics.
In the late 1990s, clinicians in rural Virginia and northern Maine reported that young people were crushing OxyContin tablets and snorting or injecting the drug. This method of ingestion produced a highly euphoric and reinforcing experience; abusers were exposed to very high doses of oxycodone, and many quickly became addicted. There was also a corresponding spike in overdose deaths. Despite growing evidence of addiction and overdose deaths, Purdue executives remained convinced of the efficacy and safety of their medication. By 2000, sales of OxyContin reached over $1 billion/year and the company was marketing it as a first-line agent for a wide variety of pain syndromes, with recommendations that it be used before lower scheduled narcotics, or even before Ultram (tramadol), a nonnarcotic. In 2001, the FDA required a new label for OxyContin that dropped claims about a reduced risk of abuse. By this time it had become apparent that overdose deaths and reports of addictive behavior did not just involve individuals who were illicitly using the drug, but that some people being treated for legitimate pain problems were becoming addicted and finding it impossible to stop their use of the drug. In retrospect, clinicians realized that the bulk of the medical literature claiming a minimal risk of iatrogenic addiction primarily reported on experience using opioids to treat acute pain and that there were few data on the risk of addiction in individuals treated for chronic pain. Similarly, there were no data on the addiction risks associated with the use of long-acting high-potency agents such as OxyContin for either acute or chronic pain. All of the published research on the abuse risk of chronic opioid treatment preceded the marketing of those medications.
As physicians became aware of the problems associated with OxyContin, many shifted to oral methadone as a safer alternative for the management of chronic pain. From 1998 to 2006, the number of methadone prescriptions for pain in the United States increased from 0.5 million to over 4 million. Unfortunately, there was a linear relationship between opioid-related overdose deaths and the increase in prescription of pain relievers ( Fig. 25.3 ).
Starting in the late 2000s, national surveys began to identify an increase in the number of individuals reporting the use of heroin ( Fig. 25.4 ). By 2014, even though the rate of nonmedical use of prescription opioids had been steadily declining, the rate of heroin use had spiked considerably. Indeed, in 2014, there were 910,000 individuals who had used heroin during the previous year, which is almost double from a decade prior. Consequently, there has been a dramatic increase in the number of heroin-related overdoses during that same time period. In 2014, there was a 300% increase in the number heroin-related overdoses compared to 2010 ( Fig.25.5 ). The number of treatment admissions for opioid use disorder remained fairly steady from 2011 to 2014 at slightly below 500,000 admissions per year, although the number related to the misuse of opioid analgesics dropped to 132,000, whereas the number related to heroin increased to over 357,000.
Neurobiology
The functions of all the compounds in this class (opiates, synthetic opioids, and endogenous opioids) are mediated through a variety of receptors in the central and peripheral nervous systems. The mu, delta, and kappa opioid receptors are well defined, and genes encoding for these receptors have been cloned. The mu receptor was named because of the affinity of morphine for this receptor. Full agonists at the mu receptor activate the receptor, are highly reinforcing, and include the most abused types of opioids. There are two primary subtypes of the mu receptor; subtype 1 (mu 1 ) apparently mediates analgesic effects, whereas subtype 2 (mu 2 ) is likely responsible for the symptoms associated with opioid overdose (including respiratory depression) and withdrawal. Agonists at the mu receptor include morphine, methadone, and beta-endorphin. These compounds also have agonist activity at the delta receptor (named because of their presence in the vas deferens). The primary agonists at the delta receptor are met-enkephalins and leu-enkephalins.
Another group of receptors were named kappa because of their affinity for the opioid agonist ketazocine. Kappa receptors bind endogenous dynorphin and are thought to mediate spinal cord analgesia. They are also involved in the psychotomimetic and dysphoric effects seen in overdoses of pentazocine and other kappa-active synthetic opiates. Opioid antagonists (naloxone and naltrexone) are synthetic derivatives of oxymorphone and act primarily at the two mu receptor sites, although they also have some antagonist activity at the kappa receptor ( Fig. 25.6 ).
There is another group of medications that have mixed agonist-antagonist properties. For example, pentazocine acts as a kappa agonist and as a weak mu antagonist. Butorphanol has mixed kappa and mu agonist properties and weak antagonist properties. Buprenorphine is classified as a partial opioid agonist at the mu and kappa receptors and an antagonist at the delta receptor. Although it binds tightly to the mu receptor, it only partially activates the receptor (see Fig. 25.4 ). There appears to be a plateau effect that limits activation to about 50% of receptor activity and prevents the respiratory depression seen with full mu receptor agonists; of interest, the analgesic effect of buprenorphine does not seem to be limited by the plateau effect. When a partial agonist is administered in the presence of a full agonist, the partial agonist either displaces the full agonist or prevents its binding to the receptor. As a result, the partial agonist acts as an antagonist to the full agonist.
More recently, a new receptor named the orphanin/nociceptin receptor or opioid receptor–like receptor has been identified. Orphanin/nociceptin is an endogenous opioid–like neuropeptide that acts as an agonist at the opioid receptor–like receptor. It has an inhibitory effect on synaptic transmission and appears to be involved in memory, learning, attention, and pain perception. Despite the structural similarity between the opioid receptor–like receptor and the three classical opioid receptors, most opioids lack affinity for the nociceptin system, and it is not affected by opioid antagonists. The function of the nociceptin/opioid receptor–like receptor system in pain control needs further clarification, and other functions are still a matter of speculation, although investigation suggests that it has a role as a downregulator of immune function. It is also known that activation of the opioid receptor–like receptor causes motor impairment, suggesting that development of opioid receptor–like receptor agonists would be difficult.
The abuse potential of opioids can be predicted by three sets of characteristics. Drugs with a shorter half-life have a greater abuse potential (heroin > methadone). Drugs with higher lipophilicity cross the blood-brain barrier more rapidly and are more likely to be abused (heroin > morphine > methadone). Finally, those drugs with a faster route of administration have a higher abuse potential (intravenous injection > subcutaneous injection > oral ingestion). Heroin (di-acetyl-morphine) has two acetyl groups that render it very lipophilic, enabling it to cross the blood-brain barrier more rapidly than morphine, thereby making it a preferred drug for injecting opioid abusers.
Biological Effects of Use
The primary acute effects of opioids are euphoria, analgesia, decreased consciousness and respirations, vomiting, reduced gut motility, and constricted pupils. Codeine is also effective as a cough suppressant, and morphine is used to treat cardiac-related pulmonary edema. Analgesia and euphoria are produced directly through agonist effects at the mu receptor and indirectly through activation of the dopaminergic reward system in the nucleus accumbens. In overdose situations, consciousness is depressed to levels of nonresponsiveness, the pupils are pin point, and there is marked suppression of autonomic functions with decreased pulse, blood pressure, and respiration, leading to lethal respiratory depression. The skin becomes cyanotic, and skeletal muscles become flaccid. Pulmonary edema occurs in 50% of cases. Physical tolerance can develop within 1–2 weeks with repeated dosing, requiring increased doses to maintain the original opioid effect. Tolerance develops more rapidly with shorter-acting opiates and with binge patterns of use, but is very slow to develop in individuals maintained on methadone. Of interest, there is no downregulation of mu receptors in methadone recipients, supporting the observation that most neurophysiologic functions return to normal with methadone maintenance treatment. With chronic use, physical dependence develops and users manifest a characteristic withdrawal syndrome if the dose is reduced or stopped. In some animal models, physical dependence has developed in the absence of tolerance, suggesting that these are dissociable phenomena. Tolerance develops more quickly to opiate side effects than to the analgesic effect. Chronic opiate use leads to reduced dopaminergic tone and decreased binding capacity at the D 2 dopamine receptor. Once tolerance develops, opiates are required to maintain an altered homeostatic set-point within the hypothalamic-pituitary-adrenal axis and within the pathways that govern memory and hedonistic desires. Abnormalities in the hypothalamic-pituitary-adrenal axis may persist for over 1 year following opioid withdrawal treatment. A relative endorphin deficiency is also present during chronic opiate misuse and during the prolonged opiate withdrawal syndrome, but endorphin levels normalize during methadone maintenance treatment. Despite the development of tolerance, pupillary constriction, constipation, and sweating may persist indefinitely. Long-term users report lethargy, decreased libido, and diminished sexual function; men have below-normal testosterone levels, and women may develop amenorrhea and have difficulty conceiving.
In physically dependent individuals, there is a characteristic withdrawal syndrome when opioids are reduced or stopped abruptly. Symptoms begin within 6–12 h following the last dose of a short-acting opiate, such as heroin. Early stages are characterized by anxiety, nausea, muscle aches, and abdominal cramps. This progresses to yawning, rhinorrhea, lacrimation, sweating, piloerection (gooseflesh, “going cold turkey”), dilated pupils, diarrhea, insomnia, elevated temperature, heart rate, blood pressure, and respirations. In the most severe stage, the syndrome includes severe craving, abdominal cramps, diarrhea, and painful cramps and muscle spasms (“kicking the habit”). Many of the acute symptoms of opiate withdrawal are driven by an overactive catecholaminergic system located in the locus coeruleus and by dopaminergic neurons located in the ventral tegmental area. The syndrome is most severe in individuals dependent on short-acting opiates such as heroin, but it clears in 4–7 days. Withdrawal from long-acting opioids, such as methadone, is less severe but can last for 14 days or more. Withdrawal symptoms from the partial agonist buprenorphine are slightly less severe than those caused by methadone and last 5–7 days, making it the preferred opioid for use in medically supervised withdrawal ( Fig. 25.7 and Table 25.1 ). Following withdrawal, many addicts experience a prolonged state of dysphoria that may last for months. Indeed, the negative emotional states during withdrawal and periods of abstinence is a result of the adaptations in the fear circuitry, which includes the extended amygdala. The fear circuitry becomes overactive, and the addicted individual begins to seek drug use to find relief from these negative emotional states.
| Drug | Onset | Peak | Duration |
|---|---|---|---|
| Heroin | 6–12 h | ∼3 days | 4–7 days |
| Buprenorphine | 1–3 days | ∼4 days | 5–7 days |
| Methadone | 1–2 days | ∼7 days | 12–14 days |
Psychological Effects of Use
In nontolerant users, opioids produce sedation, analgesia, and, in some cases, euphoria and a profound sense of well-being. This is often described as being “high” or “on the nod.” Many users also report an antidepressant effect from opioids. As use becomes more frequent, users cycle between states of euphoria and normality ( Fig. 25.8 ).
Regular use eventually leads to physical tolerance, a state where progressively higher doses are required to produce the desired experience of euphoria. Eventually the individual becomes physically dependent and starts to experience withdrawal symptoms whenever the euphoria wears off. Drug craving becomes progressively more severe, and higher doses are required to prevent the development of withdrawal. In this later stage of dependency, users rarely feel normal and typically cycle between states of low-level intoxication and withdrawal (see Fig. 25.8 ). Large doses of opiates are needed to eliminate withdrawal symptoms, and it may be difficult for the addicted individual to achieve any state approaching normality, let alone euphoria. At this stage, individuals addicted to opioids are chronically irritable and depressed. Individuals maintained on stable doses of long-acting opioids such as methadone, levo-alpha acetyl methadol, or buprenorphine become tolerant to any sedative effects, and they generally report the absence of craving, euphoria, or withdrawal symptoms. They often feel more alert and energized following their daily dose. However, many individuals on maintenance treatment fail to develop tolerance to the side effects of constipation and sweating.
Diagnosis
The 2013 the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) brought substantial changes to the diagnostic criteria for substance use disorders. The diagnoses of substance abuse and substance dependence were combined to create one diagnosis: substance use disorder. The decision to make this change was based on the weaknesses of the previous nosology, including the low reliability and validity of the substance abuse diagnosis, that the majority of substance abuse diagnoses were made with only one criterion (hazardous use criterion), and the incorrect assumption that substance abuse is a less severe or prodromal version of substance dependence. In addition, one of the criteria from substance abuse—recurrent legal problems stemming from substance use—was dropped because the criteria was met very infrequently and because patients rarely endorse legal problems alone in the absence of other criteria. Finally, the decision was made to add a criterion for cravings because of empirical support from behavioral, neuroimaging, pharmacology, and genetic studies, as well as greater coherence with ICD-10, which already includes craving as a criteria.
Clients may present with the typical symptoms of either opioid intoxication or withdrawal described in the sections that follow titled “Opioid Overdose” and “Opioid Withdrawal Syndromes.” A urine toxicology examination should be obtained on all clients to confirm current use and to screen for the misuse of other substances (see section “Psychiatric Comorbidity”). All clients require a medical evaluation to screen for HIV/AIDS, hepatitis, and other bloodborne infections. Chronic users are likely to present with track marks and other signs of injection drug misuse, although some individuals addicted to pain relievers may have no history of intravenous drug use and may present no abnormal findings on physical examination.
Some confusion continues to exist between the DSM-5 diagnosis of opioid use disorder and the common condition of physiological dependence. Physical dependence occurs whenever there is ongoing use of opiates for medical treatment. Physically dependent individuals may manifest both tolerance and withdrawal symptoms, but they show no symptoms of craving or loss of control, and the majority are able to taper off opiates with little or no difficulty. A few individuals, particularly those treated with high-potency opioids, may experience prolonged and severe withdrawal symptoms and will require a much more gradual medication taper. For some clients (between 3% and 30%), long-term treatment with opiates may trigger an iatrogenic addiction. They may experience euphoria when initially treated, and then go on to develop craving and loss of control of their medication use, eventually meeting full DSM-5 criteria for opioid use disorder. When evaluating these clients, it may be useful to look for the presence of the “4 Cs” commonly associated with addiction: C raving, C ompulsive use, loss of C ontrol, and C ontinued use despite apparent harm. Clinical experience suggests that individuals at highest risk for misusing pain medications are those with a prior history of alcohol use disorder or other substance misuse, family history of substance use disorders, and with co-occurring psychiatric disorders, including antisocial personality disorder.
Psychiatric Comorbidity
Dependence on alcohol and other classes of drugs is common in the majority of individuals with opioid disorder and has a significant impact on the outcome of treatment. There is also a high rate of comorbidity between all of the drug use disorders and other psychiatric disorders. With few exceptions, the National Epidemiologic Survey on Alcohol and Related Conditions data showed positive and significant correlations between drug use disorders, alcohol use disorders, nicotine dependence, and antisocial personality disorder. As Kessler noted in his reviews of the literature on the epidemiology of comorbidity of mental and substance use disorders, the available data have consistently shown that comorbid disorders are more chronic and have a significantly more persistent and severe course. Unfortunately, methodologic limitations in the original National Comorbidity Survey, the Environmental Catchment Area Survey, and the National Comorbidity Survey Replication make it difficult to get specific comorbidity estimates regarding opioid use, misuse, and dependence. Although the National Comorbidity Survey found an odds ratio of 2.4 for comorbidity between any lifetime alcohol or drug use disorder and any lifetime DSM-III revised mental disorder, there were no drug-specific data available in that study. Responses on opiates, cocaine, cannabis, and hallucinogens were combined under a single category of drug use disorders. Both the National Comorbidity Survey and the Environmental Catchment Area Survey relied on data collected prior to the recent epidemic of the misuse of pain relievers, and these surveys did not distinguish between heroin misuse and the misuse of prescribed medications.
Data specific to comorbidity in opiate use disorder are relatively limited. Clinical studies have reported that a range of 55%–74% of individuals with opioid use disorder in treatment have an affective disorder. Brooner et al. evaluated 716 individuals seeking methadone maintenance treatment and reported that 47% of the sample met criteria for other psychiatric disorders. The most common diagnoses were antisocial personality disorder (25.1%) and major depression (15.8%). Rosen and colleagues recently evaluated a group of 140 methadone maintenance participants over the age of 50. In this sample, 57.1% had at least one other psychiatric disorder in the previous year. The most prevalent disorders in this cohort were major depression (32.9%), posttraumatic stress disorder (27.8%), and generalized anxiety disorder (29.7%); women had higher levels of depression than men (43.8% vs. 27.2%) and had twice the prevalence rate of panic disorder and agoraphobia. As indicated above, depression and anxiety disorders are common in this population and are associated with increased severity of substance use disorders and poorer treatment outcome. Other substance use disorders are also common in individuals dependent on opiates. Brooner et al. evaluated 68 methadone maintenance participants enrolled in an HIV education program. In this group, lifetime rates for abuse or dependence were as follows: cocaine 55.9%, sedative/hypnotics 53%, marijuana 47.1%, and alcohol 47.1%. Forty-eight percent of the sample met criteria for a nonsubstance use psychiatric disorder, the most common being antisocial personality disorder (29%) and major depression (19%). Individuals with other psychiatric disorders also had a greater number of substance use disorders and a more severe clinical course.
The association between heroin misuse and antisocial personality disorder reflects an overlap of genetic and psychological factors. Individuals willing to initiate heroin use are often impulsive, and typically see themselves as nonconformists, or risk takers, and in defiance of social convention. Their use of heroin is not surprising given the illegality of heroin and the commonly acknowledged social deviation associated with intravenous drug use. The National Epidemiologic Survey on Alcohol and Related Conditions study showed strong associations between drug use disorders, other substance use disorders, and antisocial personality disorder. The authors suggested that this association is related to the unique genetic factors that underlie these groups of disorders.
As compared with earlier national epidemiologic surveys, the National Epidemiologic Survey on Alcohol and Related Conditions provided more specific information on opiate dependence and other co-occurring psychiatric and substance use disorders. Individuals identified in the National Epidemiologic Survey on Alcohol and Related Conditions who were dependent on one type of prescription medication were highly likely to have clinically significant drug use disorders for both illicit drugs and other classes of nonmedical prescription drugs. There was a high comorbidity for mood, anxiety, personality, and other substance use disorders, including nicotine and alcohol. The specific odds ratios for comorbidity between opioid use disorders and other conditions were other nonmedical prescription drug use disorder (80.1), other illicit drug use disorder (28.1), alcohol use disorder (11.4), nicotine dependence (6.7), any mood disorder (4.6), bipolar I disorder (4.9), any anxiety disorder (3.0), panic with agoraphobia (4.3), any personality disorder (4.9), and antisocial personality disorder (8.1). These conditions were all diagnosed according to the criteria of the DSM-IV, which required the criteria of clinical significance and ruled out conditions considered to be substance-induced.
Co-occurring Psychiatric Disorders and the New Opioid-Dependent Population
Recent studies suggest that some features of psychiatric comorbidity and opioid use disorder have changed during the last decade. The availability of cheap, high-quality heroin has meant that most initiates begin by snorting the drug; some become addicted yet never progress to intravenous use. Members of this group minimize the risk of nonintravenous drug use. They see snorting heroin as relatively socially acceptable and do not see themselves as socially deviant (and indeed are probably less antisocial than earlier generations of heroin users). Similarly, misusers of pain relievers are even less likely to see their behavior as dangerous or antisocial (they naively assume that legal drugs are both safe and less likely to lead to addiction). Data from the 2015 National Survey on Drug Use and Health showed that more than 53.7% of the misusers of pain relievers were given the drug for free or bought or took the drug from friends or relatives; less than 4.9% purchase from drug dealers ( Fig. 25.9 ).
This type of distribution system reinforces the perception that the illicit use of these drugs is normative. It is only after these individuals become physically dependent and have escalating habits that they are forced to seek out illicit suppliers. At some point they may recognize that heroin is cheaper than opioid pharmaceuticals and they may then switch to snorting and/or intravenous heroin use. As the severity of their opioid dependence progresses, they are also likely to manifest symptoms of a substance-induced personality disorder, with both dependent and antisocial features. Such substance-induced antisocial traits typically resolve when these individuals become engaged in addiction treatment, but they may reappear during periods of relapse.
Iatrogenic Addiction
There is a growing and less well-defined group of individuals who may present with iatrogenic opioid use disorder. Since the mid-1990s, careless and overenthusiastic prescribing of highly potent opioid analgesics has placed many individuals at increased risk for addiction. Of particular concern are veterans returning from combat in Iraq and Afghanistan who may have both combat stress and physical injuries requiring treatment with potent opioids. Comparison of individuals who misuse prescription opioids and individuals who misuse heroin shows higher levels of chronic pain, depression, and benzodiazepine use among those who misuse prescription opioids. They are also less likely to use illicit nonopioid drugs or to inject drugs. As compared with individuals with heroin use disorder, this group is more likely to have had psychiatric treatment, yet they have fewer family problems, are more socially stable, and have fewer illegal sources of income. They also tend to resist referrals for methadone maintenance and are likely better candidates for naltrexone treatment or office-based buprenorphine treatment.
The misuse of other substances is also less common in this population as compared with individuals who misuse heroin. Alcohol misuse has been a longstanding problem among individuals on methadone maintenance. Marijuana use is also very common, although clinicians have disagreed over the clinical significance of this behavior. During the 1980s, cocaine misuse became rampant among those who misuse opioids. Although this problem has declined in the general population, it remains epidemic in individuals with heroin use disorder. The concurrent misuse of all of these substances continues to be a problem among those on methadone maintenance; however, clinicians report less-frequent problems of this type in clients treated with buprenorphine in the office-based setting. Dobler-Mikola et al. reported on the first 6 months of methadone maintenance treatment for 103 participants and noted that 51% continued to use cocaine and 61% continued to use heroin. In contrast, Mintzer et al. reported that 54% of Suboxone recipients at 6 months had no urine tests that were positive for illicit substances. In a separate study, Fiellin et al. reported that the self-reported frequency of opiate use dropped from 5.3 days per week to 0.4 days per week during a 6-month buprenorphine maintenance trial; 50%–57% of the participants had at least one cocaine-positive urine test during the 6-month trial.
The demographics of this new population with opioid use disorder are more apparent in individuals being treated with buprenorphine. The Substance Abuse and Mental Health Services Administration was required by the legislation (Drug Addiction Treatment Act of 2000) that authorized the office-based use of buprenorphine to complete a national survey reviewing demographic data on buprenorphine recipients who were being treated in that setting. As compared with individuals on methadone, this study indicated that buprenorphine recipients were younger, included higher percentages of whites and women, and were far more likely to be employed and have higher levels of education ( Fig. 25.10 ).
Clinicians have generally reported that these clients are less deteriorated, appear much less socially deviant, and are more typical of the general population. On average, addicted individuals enter buprenorphine maintenance treatment 5 years earlier than methadone maintenance clients enter treatment. They are significantly less likely to have used needles and consequently have a much lower incidence of hepatitis C and HIV disease.
Clinical Management
Opiate Overdose
Opiate overdose is a life-threatening emergency. Patients typically present with depressed consciousness, depressed respirations, and miotic pupils. With meperidine (Demerol) overdoses, the pupils may not be miotic. Similarly, with severe hypoxia or in overdoses with multiple classes of drugs, the pupils may be dilated. It is also common to see hypotension and diminished heart rate and occasionally pulmonary edema. The patient should be checked for venous sclerosis (track marks), but these may be missing in younger individuals who may be taking prescription medications orally or may be inhaling or smoking heroin. A drug overdose should be suspected in any comatose individual, and serum toxicology and blood glucose should be obtained immediately.
The primary goal of treatment is to sustain or restore vital functions and to immediately reverse the overdose with an opioid antagonist.
- 1.
Immediately assess the adequacy of airway, breathing, and circulation (ABC). Initiate intubation and resuscitation, and support vital functions as needed. Signs of overdose include slow or shallow breathing, loud snoring or gasping for air, cyanotic skin, bradycardia, and unresponsiveness to sternal rub. If there is no evidence of respirations, and the individual is not in a medical setting, activate emergency medical services (EMS) by calling 911.
- 2.
Establish an intravenous line and administer a 50% dextrose/water solution.
- 3.
In cases of suspected recent oral drug ingestion, gastric lavage should be initiated. Care must be taken to avoid aspiration; patients should be intubated if there is evidence of respiratory depression.
- 4.
Naloxone (Narcan) 0.2–0.4 mg intravenously will begin to reverse the effects of an opiate overdose within 1 minute. If there is no response to the initial dose, repeat doses may be administered every 2–3 minutes. If there is no response after a total dose of 10 mg naloxone, it can be assumed that the coma is not solely caused by an opiate. However, data from fentanyl overdoses appear to indicate that even higher doses of naloxone may be needed to reverse the overdose. Nevertheless, the patient should then be evaluated for other causes of coma, including the ingestion of other drugs, trauma, and diabetic coma. If not in a medical setting, naloxone rescue kits can also be used by lay people. Traditionally, naloxone kits required assembly by the person administering the dose, but more recently the FDA has approved both an intramuscular injector (Evzio Auto-Injector) and a nasal spray (Narcan Nasal Spray). Neither of the new kits require any assembly, and both come with instructions for lay people.
- 5.
All overdose patients should be hospitalized and monitored for a minimum of 24 h, particularly if an ingestion of multiple drugs is suspected.
- 6.
Patients who have overdosed on long-acting opioids such as methadone or propoxyphene need to be monitored for 24–48 h. Since the antagonist effects of naloxone will last for only 30–90 minutes, such patients should be monitored in an intensive care unit and placed on an intravenous naloxone drip.
- 7.
Patients who present with symptoms of interstitial pneumonia, pulmonary congestion, or edema should be treated with oxygen, and with intubation and assisted ventilation if required. In these circumstances, cardiac function is normal and there is no change in heart size. Treatment with diuretics and digitalis will be ineffective and should be avoided.
- 8.
Any overdose patient should have a psychiatric evaluation and should be referred for treatment for a substance use disorder. Physicians need to stress the importance of further treatment and to strongly encourage attempts to curb or eliminate further drug use. Whenever possible, opiate overdose kits containing intranasal naloxone or the intramuscular injector and instructions for managing overdoses should be provided to all drug-abusing individuals and their friends and families.
Opiate Withdrawal Syndromes
The withdrawal syndrome for short-acting opiates (heroin or morphine) begins 6–12 h after the last use. Early symptoms include opiate craving, anorexia, anxiety, and irritability. These are coupled with clinical signs of increased respirations and blood pressure, sweating and yawning, lacrimation, rhinorrhea, piloerection (gooseflesh), tremor, and dilated pupils. After 48–72 h, the symptoms progress to include nausea, vomiting, diarrhea, insomnia, tachycardia, abdominal cramps, and involuntary muscle spasms and limb movements. Observable signs subside over 5–7 days, but a prolonged state of craving, depression, irritability, and dysphoria may persist for months.
The signs and symptoms associated with withdrawal from longacting opioids such as methadone or propoxyphene are similar to those described above, but they may not begin until 24–48 h after the last dose and may last for 3 weeks or more. Individuals tapering from methadone maintenance also complain of deep bone pain that may last for weeks. As with individuals who are withdrawing from short-acting opiates, there is a similar protracted withdrawal state. Buprenorphine has a withdrawal syndrome similar to other long-acting opioids, but it is usually less intense and of shorter duration (see Fig. 25.5 ).
Opiate Withdrawal Treatment
Similar to the treatment of other withdrawal syndromes, the primary objective is to substitute the short-acting drug to which the patient is dependent with a longer-acting drug in the same class and gradually taper at a rate that prevents severe withdrawal and avoids intoxication or excessive sedation. The preferred medications for opiate withdrawal treatment are oral methadone and sublingual buprenorphine. Clinical experience suggests that methadone is preferred for less-motivated individuals with larger opiate habits, or for individuals with histories of polydrug abuse or significant psychiatric comorbidity. Buprenorphine is preferred for highly motivated individuals with smaller habits. In circumstances where opioids are not available, the alpha-adrenergic agonist clonidine may be substituted. Clonidine moderates autonomic withdrawal symptoms but does not control insomnia, restlessness, craving, or dysphoria. In combination with methadone, it may permit more rapid withdrawal treatment with lower doses of opioids. However, clonidine alone is not an adequate treatment for the withdrawal syndrome. Addicts rarely prefer clonidine, and relapse rates are higher than those seen with other medications.
Before starting withdrawal medication, the client should have a thorough physical with urine toxicology and a complete drug and medical history. Except in those patients who are currently on medication-assisted treatment with either methadone or buprenorphine, it is almost impossible to accurately estimate the person’s level of physical dependence. Clients’ reports are often misleading, and it is highly dangerous to estimate the quality and quantity of street drugs. Even when clients are transferred from maintenance programs, the clinician must always contact program staff to verify the dose before starting treatment. The only safe way to avoid an inadvertent overdose is to document the presence of mild opiate withdrawal before initiating treatment. This is best done using a standard opiate withdrawal scale such as the Clinical Opiate Withdrawal Scale or the Objective Opiate Withdrawal Scale. Once clients score in the mild to moderate withdrawal range on the Clinical Opiate Withdrawal Scale, they can be given an initial dose of 20 mg methadone orally or 4 mg buprenorphine sublingually.
For younger individuals with minimal habits, it is prudent to start with 10 mg methadone or 2 mg buprenorphine. Clients should be periodically monitored with a withdrawal scale and can be redosed in 2–4 h if withdrawal symptoms do not subside. If 10–20 mg methadone was effective as an initial dose, it may be repeated in 12 h if necessary. In no circumstance should the total 24-h dose exceed 40 mg methadone or 12 mg buprenorphine. If symptoms progress on the second treatment day, the total daily dose may be increased to 60 mg methadone or 16 mg buprenorphine, but doses in this range are rarely necessary in inpatient settings. Once symptoms are adequately controlled, the dose should be tapered at a rate that prevents further withdrawal and minimizes distress. Methadone can be decreased 5 mg/day or a maximum of a 20% dose reduction per day. Inpatient methadone withdrawal treatment can usually be completed in 5–7 days. Buprenorphine can be decreased at the rate of a 50% dose reduction per day, although a more gradual reduction spread over 13 days has a better outcome and was significantly more effective than clonidine. . One review compared buprenorphine withdrawal treatment with clonidine and methadone. Compared with clonidine, buprenorphine-treated clients stayed in treatment longer (particular in outpatient withdrawal treatment), had fewer withdrawal symptoms, and were more likely to complete treatment. There was no significant difference in outcome comparing methadone to buprenorphine in severity of withdrawal or completion of treatment, but withdrawal symptoms resolved more quickly in buprenorphine-treated individuals.
Although withdrawal treatment can be accomplished on either an inpatient or an outpatient basis, the best results are seen with very prolonged outpatient tapers, or with a 1- to 2-week inpatient withdrawal treatment followed by long-term residential care. Brief (3- to 4-day) inpatient treatment has a very high relapse rate, averaging 90%–95% within 1 year. Better outcomes are seen with multiyear maintenance treatment followed by gradual outpatient medication taper. Yet, in the best of circumstances, there is an 80% relapse rate within 1 year. Because the fatality rate for active opiate use disorder ranges from 8% to 20% per year, addicts need to understand the risks when withdrawal treatment is not followed by long-term residential treatment.
Other protocols for opiate withdrawal treatment have involved a rapid inpatient clonidine taper combined with a transition to narcotic antagonist treatment utilizing naltrexone or naloxone. Naltrexone is used to precipitate withdrawal, and then increasing doses of clonidine are used to suppress withdrawal symptoms as naltrexone is quickly increased to antagonist maintenance levels. Although this approach provides a quick and cost-effective model for withdrawal treatment, there is no evidence that it produces higher levels of long-term abstinence as compared with other treatment approaches. Ultra-rapid withdrawal treatment protocols have been proposed utilizing escalating doses of naltrexone given under general anesthesia or heavy sedation. O’Connor and Kosten reviewed the existing literature on rapid and ultra-rapid withdrawal treatment and concluded that the studies were inadequate because of the small numbers of subjects included, variations in protocols utilized, lack of randomized design and/or control groups, and lack of long-term follow-up. Well-designed, long-term studies are necessary to demonstrate that these procedures have greater efficacy over standard treatment protocols beyond the short-term treatment period. In addition, deaths have been reported during the 16–40 h following ultra-rapid withdrawal treatment ; for this reason alone, ultra-rapid withdrawal treatment procedures cannot be recommended.
Other medications have been proposed for opiate withdrawal treatment, but none have been studied adequately. Proposed agents include N -methyl- d -aspartate (NMDA) receptor antagonists, such as dextromethorphan and memantine, and the serotonin type 1A receptor agonist buspirone. Buydens-Branchey et al. compared placebo with a methadone taper versus two dose levels of buspirone. There was no significant difference noted between the subjects treated with a methadone taper and those treated with either buspirone dose.
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