The Diseases of Addiction: Opiate Use and Dependence
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Opioid broadly refers to all compounds related to opium. The term opium is derived from opos, the Greek word for "juice," as the drug is derived from the juice of the opium poppy Papaver Somniferum. Opiates are drugs derived from opium, including the natural products morphine, codeine, and thebaine, and numerous semisynthetic derivatives. The narcotic analgesics can be categorized into three groups. The first group includes the natural opium derivatives (heroin, morphine, and codeine) and the semi-synthetic derivatives from this group, including hydromorphone, oxymorphone, hydrocodone, oxycodone, dihydrocodeine, and buprenorphine. The two other groups are synthetic chemicals: the phenylpiperidines, including meperidine and fentanyl, and the pseudopiperidines, including methadone and propoxyphene. In 1914, the Harrison Act was passed, which had the effect of criminalizing addiction and led to significant apprehension among physicians in treating narcotic addicts. Treatment for opiate dependence was basically nonexistent until 1935, when U.S. Public Health Services opened a hospital in Lexington, Kentucky, devoted to the treatment of opiate dependence. However, treatment was entirely detoxification-based at that time. In 1963, the New York Academy of Sciences recommended that clinics be established to dispense narcotics to opioid-dependent patients. During this time, research identified methadone as a possibly efficacious agent because of its long half-life, which allowed once-daily dosing. In 1972, the Food and Drug Administration (FDA) created stringent regulations governing methadone, reducing the flexibility of practitioners caring for opioid-dependent patients. The Office of National Drug Control Policy subsequently made changes in the 1995 Federal Regulations of Methadone Treatment to encourage the development of a less restrictive approach and to give physicians more latitude in prescribing methadone.
The purpose of this document is to provide the reader with a current, evidence-based overview of opiate abuse and dependence and its treatment. Topics covered in this review include the history and demographics of illicit and prescription opiate abuse; risk factors, background characteristics, and comorbid conditions of opiate abusers; the pharmacology of opiate drugs; the biological and behavioral characteristics of opiate dependence; and management of opiate dependence, including treatment of overdose, detoxification and withdrawal, agonist replacement therapy, and drug-free approaches. Additional areas of the course will be devoted to the abuse liability of prescription opiates and the impact of abused opiates on the fetus.
A confusing aspect of the body of research on opiate abuse and dependence is the inconsistent use of important terminology that describes the nature and severity of involvement with therapeutic and illicit opiates. The following definitions have been proposed in an effort to encourage more correct usage of this terminology:
The most widely used definition of opiate dependence syndrome is the DSM-IV-TR diagnostic criteria. The DSM-IV-TR defines opiate dependence as a maladaptive pattern of opiate use, leading to clinically significant impairment or distress. Opiate dependence may be diagnosed if a patient exhibits three or more of the following (2)(3):
In summary, the term dependence is used to describe two separate phenomena. Pharmacologically, drug dependence is characterized by the presence of tolerance and a withdrawal syndrome. Psychiatrically, drug dependence is characterized by compulsive use, inability to reduce use, preoccupation, drug-seeking behaviors, and a heightened vulnerability to relapse after abstinence (4).
Epidemiology of Opiate Abuse and Dependence
The estimated worldwide annual prevalence of opiate use is 0.4%, and roughly 8 million people abuse opiates (5). Substantial regional differences in opiate abuse patterns exist. In the majority of Europe, heroin is the most prevalent illegally consumed opioid. In North America, illegally diverted prescription opioids, including hydromorphone, oxycodone, codeine, meperidine, morphine, and hydrocodone, are increasingly the primary illegal opioids (6). The Drug Abuse Warning Network (DAWN) provides estimates of the health consequences of nonmedical use of individual drugs, including opiate medications. DAWN emergency departments mentions are collected from affiliated hospital emergency departments to identify abused substances, assess associated adverse health consequences, and monitor drug misuse patterns and trends on local, state, and national levels (3). The definition of drug abuse in the DAWN system is the nonmedical use of a substance for psychic effect, dependence, or suicide attempt or gesture (3).
Research has indicated that there were 164,572 heroin-related emergency department episodes in 2005 (7). Opiate/opioid analgesic misuse was also encountered frequently in emergency departments. In 2005, hydrocodone and its combinations accounted for 51,225 emergency department visits, and oxycodone and its combinations resulted in 42,810 visits to the emergency department (7). Research has indicated a significant increase in the number of emergency department mentions for hydrocodone and oxycodone between 1996 and 2000 (1)(7). An estimated 3.7 million people in the U.S. have used heroin at least once in their lives; approximately 800,000 are addicted to the drug (8). According to the 2003 National Survey on Drug Use and Health, the annual number of new heroin users from 1995 to 2002 ranged from 121,000 to 164,000. Most new users are older than 17 years of age and male. In 2003, 57.4% of past-year heroin users were believed to have developed heroin abuse or dependence, and an estimated 281,000 persons received treatment for heroin abuse. It is important to note that this survey underestimates heroin use, possibly to a substantial extent, as obtaining accurate statistics on illicit drug use is difficult (8). Nonmedical use of prescription opioids has caused increasing concern among law enforcement officials and regulatory, pain relief advocacy, and drug abuse organizations (9). The prevalence of lifetime nonmedical oxycodone use increased from 11.8 million users (5%) in 2002 to 13.7 million users (5.8%) in 2003. In contrast, the estimated lifetime prevalence for heroin use is 1.8% (9). Among high school seniors, an estimated 9.6% used hydrocodone/acetaminophen (Vicodin) nonmedically. More than 85 million prescriptions were written for hydrocodone/acetaminophen in 2003, making it the most prescribed drug in the U.S. for that year (9).
Natural History of Opiate Dependence
Although the time from initiation to daily use and serious physiological and psychological dependence is highly variable, the different stages of opiate dependence are clearly delineated (4). These stages include initiation, continuation, withdrawal, and relapse. Each stage is characterized by specific neurotransmitter action, involvement of specific brain structures, and activation of specific neural circuits. An understanding of these different processes is crucial to develop an understanding of the therapeutic strategies (6).
Opiate Tolerance: Tolerance refers to a decrease in effectiveness of a drug with repeated administration. Tolerance to opioid effects is encountered in both the clinical use of opioids for pain relief and in recreational use of heroin (10). Acute tolerance stems from transient administration of opioids; sustained administration leads to the development of classical or chronic tolerance. Short-term receptor desensitization may underlie the development of tolerance, probably involving phosphorylation of the mu and delta receptors by protein kinase C, protein kinase A, and beta-adrenergic receptor kinase (beta ARK). Long-term tolerance is believed to be associated with increases in adenylyl cyclase activity, a counter-regulation to the decrease in cyclic adenosine monophosphate levels (5). The degree of tolerance can be influenced by changes in the environment in which drug use occurs. In the presence of cues previously associated with drug ingestion, tolerance is markedly enhanced, compared to the tolerance observed in a novel environment. Thus, administration of an opioid in an environment not previously associated with administration of the drug will be associated with lower tolerance and therefore a higher risk of overdose (10).
Opiate Dependence: Opiate dependence is best described as a central nervous system disorder characterized by neurobiological changes leading to compulsive drug-taking behaviors. As the result of chronic use, the cells producing endogenous opiates cease to function and degenerate, causing the user to become physically dependent on exogenous opiates (11). According to the classical theory of addiction, opiate dependence results from the need to reduce distress, as withdrawal is a physical expression of distress. This is referred to as negatively reinforced behavior. This hypothesis has been challenged by the finding that the degree of physical dependence does not predict the intensity of subsequent craving, nor does detoxification and recovery from physical dependence prevent recidivism. Additionally, the motivational aspects of withdrawal are independent of the intensity and pattern of the physical symptoms of withdrawal (12). Alternative hypotheses focus on the role of the mesocorticolimbic dopamine system, an anatomical pathway that originates from the ventral tegmental area in the midbrain and projects to several forebrain regions, including the nucleus accumbens and medial prefrontal cortex (12). Dependence on most drugs of abuse is characterized by an altered physiological state inferred from the emergence of a withdrawal syndrome following cessation of drug administration. Alleviation of an increasingly severe, withdrawal-induced negative affective state may reinforce continued drug taking and directly contribute to the development of dependence (11).
Molecular Basis: The diverse biological effects of opiates are manifested through specific opioid receptors distributed throughout the central and peripheral nervous system. Opioid receptors, upon the binding of opiate drugs (or endogenous opioid peptides), regulate a multitude of intracellular signaling pathways. Involvement of opioid receptors in opiate dependence is unequivocal. This is reliably demonstrated by the rapid precipitation of withdrawal syndromes in opiate addicts by opioid receptor antagonists such as naxolone (13). Repeated exposure to short-acting opioids can result in durable alterations in opioid receptor kinetics, transmembrane signaling, and post-receptor signal transduction (14). Opiate dependence requires sustained activation of opiate receptors, and this chronic signaling process ultimately leads to changes in protein functions of gene transcription (13). Opioid receptors are members of the G-protein receptor family, and each opiate receptor uses inhibitory G-proteins for signal transduction. Opioid receptors have the capacity to interact with five different forms of G proteins, regulating a diverse spectrum of effectors ranging from adenylyl cyclases and ion channels to mitogen-activated protein kinases. These isoform-specific and differential regulations of various classes of effectors are combined into a sophisticated signaling network that mediates opioid actions. The enormous diversity in opioid signaling stems from the array of effectors and signaling molecules that functionally interact with the G protein beta gamma complex (13). Prolonged administration of opiates causes molecular and cellular adaptations that rapidly develop into tolerance and dependence. An upregulation of adenylyl cyclase responsiveness, referred to as adenylyl cyclases superactivation, is a classic sign of this tissue adaptation (13). G-protein signals lead to changes in gene expression, and opioid-induced long-term functional alterations of the nervous system involve changes in gene expression. Many opioid-induced signals converge at the level of transcription factors, although little is known about the exact mechanisms of gene transcription in the development of opiate tolerance and dependence (13).
Mechanism of Reinforcement: Drugs with an abuse liability have habit-forming actions that can be localized in a variety of brain regions. Drugs of abuse mimic or enhance the actions of endogenous chemical messengers in the brain (15). The mesolimbic dopamine system is the likely substrate upon which opiates act to produce their reinforcing effects. Both the positive (rewarding) and negative (aversive) reinforcement of opiate mu- and kappa-receptor agonists are mediated by the mesolimbic dopamine system (12). Opioids produce reinforcement by inhibition of the GABA neurons that normally inhibit dopaminergic neurons in the ventral tegmental area. This results in a surge of dopamine in the nucleus accumbens and other mesolimbic-mesocortical brain regions (9). The neurochemical cascade begins with activation of mu- or kappa-opioid receptors differentially distributed on GABAergic cells in the ventral tegmental area and nucleus accumbens and dopamine terminals in the nucleus accumbens. This activation produces rewarding and aversive effects by increasing or decreasing dopamine release in the nucleus accumbens. Inhibition of medium spiny GABAergic neurons in the nucleus accumbens by dopamine and opiates can synergistically facilitate opiate reinforcement. Increases in glutamatergic afferents into the ventral tegmental area may facilitate opiate reinforcement by activating dopamine neurons. An increase in glutamate activity in the nucleus accumbens may decrease opiate action by activating nucleus accumbens GABAergic cells. Also, an increase in nucleus accumbens 5-HT by opiates modulates opiate reinforcement by activation of 5-HT1 and/or 5-HT3 receptors (14).
Risk Factors for Opiate Abuse/Dependence
Persons at heightened risk for heroin experimentation include those who abuse alcohol or marijuana, those with first-degree relatives addicted to alcohol or other drugs, and those with friends and associates addicted to heroin or at high risk of heroin experimentation (4). Of course, not all persons who ingest drugs regarded as having a high liability of abuse and dependence end up becoming addicted to the drug. Among persons who try heroin, an estimated 23% develop heroin dependence, a rate comparable to cocaine but greater than marijuana (16). The expected drug effect and the setting of use (context of administration) play important roles in the social learning of drug use. Because opioids, like other drugs that increase dopamine turnover, lead to conditional responses, the use of opiates may become conditioned to the activities of daily living. As a result, environmental stimuli become powerfully associated with opiate use, which can trigger cravings for the drug (15). The visibility of pharmaceutical marketing and advertising of medications may also play a role by changing the attitudes towards ingestion of these agents (15). For youth, a social learning aspect to drug use is likely, based on the modeling of drug use by adults in their families and social networks (15).
Marked increases in prescriptions written for opioids in the U.S. and Internet access to prescription drugs may explain a portion of the increase in opiate abuse and dependence. However, although Internet access is a major problem and accounts for some of the increase in opioid drug abuse, the same rate of increase has not been observed for other prescription drugs, such as stimulants, suggesting that other factors are involved (15). Changes in the way medicine is practiced also influence prescription practices. Primary care physicians provide a greater proportion of care for pain patients rather than pain specialists, increasing the potential of diversion and abuse (15).The increase in emergency department mentions is not solely accounted for by an increase in prescriptions; for example, from 1994–2002, fentanyl mentions increased more than 50-fold while the number of prescriptions increased only 7.2-fold. Similar excessive increases in emergency department mentions relative to prescriptions have been observed with oxycodone but not morphine or hydrocodone (15).
Risk Factors for Prescription Opiate Abuse among Pain Patients: Predictors of dependence on opiate medications among pain patients include substance abuse-related diagnoses, positive toxicology for opiates, and other medical diagnoses. Other patients at risk include those with idiopathic pain (no clear etiology) or high levels of psychological distress or disability (3). Alcoholism and other drug dependence are often viewed as contraindications for opiate medications in chronic non-cancer pain.
Morphine and most other opioid agonists share in common the following physiological effects (5):
Specific Opiate Drugs
The sought-after effects of heroin include intense tranquility, euphoria, analgesia, and a clouding of the sensorium, with the state of ecstasy and contentment immediately following IV injection being the most desired. Many novice heroin users experience adverse effects, such as mild nausea and vomiting. However, tolerance to these effects is soon achieved (4). The lifestyle of the heroin addict seriously decreases life expectancy. Age-adjusted mortality rates have been found to be least seven times greater than that of the general population, adjusting for age, with death usually attributable to violence or drug effects. Also, the desire to replicate the most intense rush may compel the heroin addict to escalate the dose, resulting in acute heroin overdoses (4).
Diphenoxylate and Lopermide
Fentanyl and Congeners
Some of the characteristic properties of methadone are its analgesic activity, its efficacy by the oral route, its extended duration of action in suppressing withdrawal symptoms in physically dependent individuals, and its ability to demonstrate persistent effects with repeated administration (5). One of the most important advantages of methadone is that it alleviates cravings for opiates, a primary reason for relapse, and blocks many of the pleasurable effects of heroin, which helps reinforce abstinence (18). In methadone clinics, methadone is usually dispensed in prepared individual doses mixed with fruit juice to discourage IV use. Methadone is also prescribed for pain. Until recently, there had been little evidence that diversion of methadone from pain management was occurring on any substantial scale. The majority of diverted methadone is used by heroin addicts to self-medicate symptoms of opiate withdrawal. To date, there is no evidence that diversion of methadone from methadone clinics has resulted in significant numbers of new opiate addicts (1).
Levo-Alpha Acetylmethadol (LAAM)
Signs and Symptoms of Acute Opiate Intoxication
The misuse of opiates results in several acute and long-term effects. Signs and symptoms of acute opiate intoxication include drowsiness, decreased respiration, euphoria, and impaired judgment (27): constricted pupils (or dilated pupils with meperidine); euphoria; apathy; dysphoria; drowsiness; loss of consciousness; coma; psychomotor agitation or retardation; decreased respiration; decreased heart rate; pulmonary edema; impaired social judgment; slurred speech; impaired attention and memory; and impaired occupational functioning. Research suggests that the increase in the incidence of fatal overdose is not the result of an increase in the number of persons using opiates. Possible mechanisms of fatal overdose include loss of tolerance, synergistic interactions with other central nervous system depressants, or systemic factors (28). Although the risk for overdose occurs with the use of all opiates, heroin overdose is the most commonly seen.
Liability of Abuse/Dependence of Legitimately Prescribed Opiate Drugs
There is broad consensus that patients with acute and chronic pain have often received inadequate pain control out of a fear of creating dependence. This is typified by the results of a survey in which 35% of Canadian family physicians reported they would never prescribe opioids for moderate-to-severe chronic pain and 37% identified dependence as a major barrier to prescribing opioids (29). These statistics reflect an attitude among physicians that leads to under-treatment of pain and unnecessary suffering among patients experiencing pain (30). In response to this, the Joint Commission and other organizations have enacted accreditation standards that consider pain to be the fifth vital sign, assessed whenever other vital signs are measured (1). However, with the growing concern about the under-treatment of pain and the underuse of opioids in pain treatment, there is also a renewed concern about prescription opiate dependence and overdose deaths (1). The disparate concerns regarding under-treatment of pain and facilitation of dependence is underscored by the fact that, until recently, pain management and addiction specialists rarely communicated. Pain management physicians rightly concern themselves with alleviation of pain and have traditionally underestimated dependence among their patients, with such patients often simply dismissed from further care. Addiction specialists, on the other hand, seldom encounter pain patients whose quality of life is vastly improved by opioids, but instead see failed patients from pain treatment programs (1).
Until the 1990s, Schedule II opiate analgesics were primarily used in operating rooms and in-patient settings, as they were administered intravenously or intramuscularly. More recently, non-parenteral Schedule II opioids have been approved by the FDA for use in the treatment of moderate-to-severe pain. Many of these newer agents are high-dose, extended-release formulations of pre-existing opiates, including OxyContin (a controlled-release oral formulation of oxycodone), MS Contin (a formulation of morphine sulfate), and Palladone XL (a formulation of hydromorphone hydrochloride), all of which have fulfilled a genuine clinical need by providing an elevated, constant plasma level for extended periods without the fluctuations seen with the short-acting versions. These long-acting formulations may both reduce euphoric effects of the drug and reduce pain more effectively by treating pain before it becomes established (pre-emptive effect) rather than after, when higher doses may be required. However, these formulations can be abused by crushing the tablet or capsule and ingesting the powder intranasally, sublingually, or orally or dissolving the powder in water and injecting the substance. These approaches to ingestion alter the pharmacokinetics by disabling the slow-release mechanism and make a very high dose of the substance available, which substantially increases the reinforcing effects compared with oral consumption of the drug in its unaltered form (14).
Development of Dependence: The dependence of a patient to a drug initially prescribed for a medical condition is referred to as iatrogenic dependence. Opioid prescriptions fall into two major subgroups: treatment of acute pain with short-term opioids and treatment of chronic pain with long-term opioids. In contrast to the rare association of dependence with short-term use, long-term administration of opioids is estimated to result in opiate abuse or dependence in 2.8% to 18.9% of patients, which parallels the rate of abuse or dependence among opioid users in the general population (15). One way to gauge the adequacy of pain control is to consider whether the use of added opiates has resulted in improvements in the functional restoration, physical capacity, psychological well-being, family and other social interactions, and healthcare resource use, which are weighed against unwanted effects such as daytime sedation, mental confusion, constipation, and other side effects. The final word on the dilemma of balancing the desire for patient pain relief with the desire to minimize the chance of iatrogenic abuse or dependence comes from the authoritative pharmacology textbook The Pharmacological Basis Of Therapeutics, which states, "neither the presence of tolerance and dependence nor the fear that they may develop should ever interfere with the appropriate use of opioids for pain relief."
Management of Opiate Abuse and Dependence
Treatment for opiate dependence was basically non-existent until 1935, when U.S. Public Health Services opened a hospital in Lexington, Kentucky, devoted to the treatment of opiate dependence. However, treatment was entirely detoxification-based at that time. In 1963, the New York Academy of Sciences recommended that clinics be established to dispense narcotics to opioid-dependent patients. During this time, research identified methadone as a possibly efficacious agent because of its long half-life, which allowed once-daily dosing. Today, management of opiate dependence entails different methods to achieve different goals, depending on the health situation and treatment history of the patient. These treatment approaches include (6):
Crisis Intervention: In response to acute overdose, the short-acting opioid antagonist naloxone is considered the gold standard. Naloxone is effective in reversing respiratory depression and coma in overdose patients. There is no evidence that subcutaneous or intramuscular use is inferior to intravenous naloxone. This has prompted discussion of making naloxone available to the general public for administration outside of the healthcare setting to treat acute opiate overdose (6).
Harm Reduction: Harm reduction measures are primarily employed to minimize the morbidity and mortality from opiate abuse and to reduce public nuisance (31). As a part of this effort, measures to prevent and minimize the frequency and severity of overdoses have been identified. Enrollment in opioid substitution therapy, with agents such as methadone and buprenorphine, substantially reduces the risk of overdose as well as the risk for infection and other sequelae of illicit opiate use (31).
Education: Reducing the risk for harm involves education on polydrug use and needle-exchange programs (31). The authors of one review noted that there was positive evidence, though limited, to support education regarding non-injecting routes of administration, brief interventions, and supervised injecting facilities (32). To improve response to overdoses, opiate abusers and their friends and families should be taught simple cardiopulmonary resuscitation skills to keep comatose users alive until emergency medical personnel arrive. Associates of users should be encouraged to call an ambulance when overdose occurs. The provision of naloxone to opiate users should be tested and evaluated; naloxone could be distributed through existing outlets, such as needle and syringe exchanges, pharmacies, urgent care facilities, or treatment agencies. Heroin users should also be encouraged to switch to non-injecting routes of administration to reduce related morbidity and mortality (31).
Needle Exchange Programs: Needle-exchange programs have been shown to be effective in reducing drug-related health problems, reducing injection frequency, and increasing entry and retention in drug treatment (8). According to one review, there is sufficient evidence of efficacy, effectiveness, and financial benefit to recommend needle-exchange and outreach programs (33). It is important to note that information regarding infection prevention strategies be provided to all participants in needle-exchange programs, as increased incidences of HIV and other blood-borne pathogens have been noted in this population (33).
Injection Rooms: Medically supervised injecting rooms are officially designated areas where injecting opiate users, often persons who use heroin, can inject without fear of arrest and with knowledge that medical assistance is available if overdose occurs. Such facilities have existed in Switzerland since 1986, in Germany since 1994, and in the Netherlands since 1996. The goal of user rooms is to promote health and reduce risk behaviors and public nuisance, with a specific focus on overdose reduction and hygiene. Several descriptive studies have shown significant effects on harm reduction and reduction of public nuisance (33).
Heroin Maintenance: Heroin maintenance is the implementation of heroin prescriptions under medical supervision. This option may improve health and reduce heroin overdoses, illicit opioid use, and crime. However, formidable barriers to heroin maintenance exist in the U.S. (32).
Detoxification and Withdrawal
The process of tapering opioid-dependent patients from agonist therapy is often referred to as detoxification (24). Detoxification alone should not be considered a treatment and should only be promoted in the context of a well-planned relapse-prevention program (8). The three primary treatment modalities used for detoxification are opioid agonists, non-opioid medications, and rapid and ultra-rapid opioid detoxification (24). The most frequently employed method of opiate withdrawal is a slow, supervised detoxification during which an opiate agonist, usually methadone, is substituted for the abused opiate (34). Methadone is the most frequently used opiate agonist due to the convenience of its once-a-day dosing (24). Methadone is highly bound to plasma proteins and accumulates more readily than heroin in all body tissues. Methadone also has a longer half-life, approximately 22 hours, which makes withdrawal more difficult than from heroin. Substitution therapy with methadone has a high initial dropout rate (30% to 90%) and an early relapse rate. Alternative pharmacological detoxification choices include clonidine (with or without methadone), midazolam, trazodone, or buprenorphine (34).
Ultra-Rapid Opioid Detoxification
Ultra-rapid opiate detoxification (UROD) has been developed as a means of avoiding the physical symptoms of withdrawal from opiates through the use of general anesthesia. UROD consists of naltrexone-assisted detoxification under heavy sedation or full anesthesia. Chemical sedation has been used since the early 1940s in the management of drug withdrawal. The major breakthrough in the management of opiate withdrawal occurred with the addition of an opiate antagonist during chemical sedation (35). UROD was introduced in 1990 primarily by private practitioners in a for-profit setting (35).
UROD is also referred to as rapid, ultra-rapid, or anesthesia-assisted detoxification. One reason for the proliferation of terms is that the anesthesia-assisted procedure was commercially used and was submitted as a registered trademark or patent. Therefore, other researchers had to devise novel names for the process. Suggested classification is (35):
The common underlying themes in all UROD techniques are a desire to condense the detoxification process into a shorter period to blunt the awareness of physical discomfort and to shorten the time lag between a patient's last dose of opioid and transfer to naltrexone maintenance (35). This is accomplished by precipitating withdrawal following the administration of opioid antagonists under deep sedation or anesthesia. Absolute contraindications include pregnancy; a history or clinical suspicion of cardiac disease; chronic renal impairment; liver disease; current dependence on benzodiazepines, alcohol, or stimulants; and history of psychotic illness. Relative contraindications include a history of treatment for depression and unstable social circumstances. A comprehensive plan to stabilize such patients should be undertaken before the procedure. Patients with chronic pain syndromes requiring opioid medication are not good candidates unless their pain can be controlled by alternative methods (34).
There are a number of drawbacks to UROD relative to other detoxification methods. Serious adverse events related to the anesthetic procedure have been reported. A randomized, controlled trial directly comparing naltrexone-assisted detoxification with and without full anesthesia clearly stated that heavy sedation or full anesthesia should not be used because it does not confer any advantages in withdrawal symptom severity or increased rates of initiation or maintenance and it increases the potential for life-threatening adverse events. A trial comparing naltrexone-induced, anesthesia-assisted detoxification with buprenorphine- or clonidine-assisted detoxification found no difference in withdrawal severity and rates of completion. However, potentially life-threatening adverse events associated with the UROD anesthesia were observed. The authors concluded that the data do not support use of anesthesia for detoxification (36). Heavy sedation compared to light sedation does not confer additional benefits in terms of less severe withdrawal or increased rates of initiation and retention on naltrexone maintenance treatment. The risk for adverse events, the high monetary cost, and use of scarce intensive care resources suggest that this form of treatment should not be pursued.
Agonist Replacement or Abstinence Therapy
Treatment is initiated with a dose of 25 to 30 mg and is gradually titrated in 5- to 10-mg increments per day to a desired range of 60 to 120 mg. Low-dose treatment is associated with less positive outcomes than doses of 80 mg per day or greater (24). Methadone is cost-effective. To contrast, the estimated 6-month costs are about $21,000 for an untreated drug abuser, $20,000 for an incarcerated drug abuser, and $1750 for a patient enrolled in a methadone maintenance program (24). Frequently, there may be a belief that opiate users should be able to stop using all drugs. Although some successfully stop, dependence is a chronic problem for most patients, associated with frequent relapses, serious health risks, and psychosocial impairment (37). Unfortunately, a serious stigma surrounds methadone treatment, which is experienced most acutely by patients but also by professionals. This may pose a barrier to treatment support (38). A review of the efficacy literature concluded that high doses of methadone (>50 mg daily) are more effective than low doses (<50 mg daily) in reducing illicit opiate use. Additionally, high doses of methadone are more effective than low doses of buprenorphine (<8 mg daily). High dosages of methadone are comparable to high dosages of buprenorphine (>8 mg daily) on measures of treatment retention and reduction of illicit opiate use (38).
Slow-Release Oral Morphine
Agonist Replacement and Psychosocial Therapy
Opioid Antagonist Therapy
Narcotics Anonymous (NA)
Methadone Anonymous (MA)
Opiate Use in Pregnancy
Number of women with substance dependence continues using additive substances despite awareness of the potential harm to the fetus. In utero exposure to opiates is associated with withdrawal symptoms of variable onset and severity in as many as 55% to 94% of exposed infants (45). Opioid withdrawal is a physiologic rebound from the chronic drug effects on brain function. In pregnant women, rapid opioid withdrawal may precipitate preterm labor; in neonates it may be fatal (46). Reports of adverse effects of opiate use on fetuses and neonates include (46):
Neonatal abstinence syndrome (NAS) may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss, and seizures (47). Compared to supportive care only, opiate treatment of NAS reduces the time to regain birth weight, reduces the duration of supportive care, and increases the length of hospital stay. There is no evidence of effect on treatment failure. Treatment with opiates has been shown to be superior to phenobarbital and diazepam in the infants with NAS (48). In treating pregnant women with substance dependence, psychological and pharmacologic treatments are often combined. Psychosocial treatments include contingency treatment, community reinforcement, behavioral marital therapy, cognitive-behavioral skills training, motivational enhancement, and 12-step approaches.
Heroin: Heroin rapidly crosses the placental blood barrier. Roughly one-third of infants born to IV heroin users exhibit signs of neonatal withdrawal, with a small minority showing neonatal seizure activity (4). Methadone maintenance has been found to be an effective harm-reduction strategy and can reduce acute neonatal withdrawal problems, including seizures (4).
Methadone: Pregnant women who are opioid dependent should be maintained on the lowest effective dose of methadone; detoxification, if attempted, should be done in the second trimester (47). Outcomes are poor for patients who leave treatment. Fetal exposure can result in lower birth weight, smaller head circumference, jaundice, and thrombocytosis, although the cause of these conditions is difficult to distinguish between methadone and other concurrently-used substances. Methadone in the newborn infant will produce physical dependence and subsequent withdrawal symptoms that may not emerge until 48 hours after birth, regardless of maternal dose. Methadone-exposed infants function within a normal range of cognition at 1- and 2-year evaluations (49). Methadone levels in breast milk appear to be small (49).
Buprenorphine: Buprenorphine has been administered successfully to opioid-dependent pregnant women as a maintenance replacement opioid. Placental transfer may be less than methadone, reducing fetal exposure and subsequent dependence and withdrawal. Buprenorphine has a low incidence of labor and delivery complications and of neonatal abstinence syndrome (46). However, buprenorphine enters breast milk, and treatment with buprenorphine is strongly advised against during the nursing period (49).
Oxycodone: Oxycodone is metabolized to noroxycodone, oxymorphone, and their glucuronides and primarily excreted through urine. Oxycodone has been detected in breast milk, and although not found to be a teratogenic in experimental animals, it is not recommended for use in pregnancy. Management of infants born to mothers abusing oxycodone is of particular concern because the drug and its metabolites are difficult to detect by the enzyme immunoassay methods typically used for urine and meconium opiate screens (48).
Prognosis of Treatment for Opiate Dependence
The relapse rate among patients receiving treatment for opiate dependence and other substance abuse is high, comparable to that of other patients with chronic relapsing conditions, including hypertension and asthma. Many cases of relapse are attributable to treatment noncompliance and lack of lifestyle modification (39). Duration of agonist replacement therapy is usually recommended as a minimum of 1 year, and some patients will receive agonist replacement therapy indefinitely. Longer durations of treatment are associated with higher rates of abstinence from illicit opioids (42). Much remains unknown about patient outcomes following termination of long-term opioid replacement therapy. Some patients aim to achieve total abstinence from all opiates, but little is known about patient characteristics and strategies used among those who remain abstinent. It is likely that at least some of the patients who remain abstinent from all opiates do so with the help of a 12-step support program, such as NA (42).
An estimated 11 million people are dependent on heroin or other opioid drugs, a condition associated with a high morbidity and 15-fold mortality from causes including overdose and infections such as human immunodeficiency virus (HIV), tuberculosis (TB) and hepatitis (50). Approximately 10% of HIV infections worldwide are thought to be due to injecting drug use, and approximately 230 million people worldwide are estimated to have chronic hepatitis C. Compliance with treatment for HIV and TB is difficult to achieve in this group, and contributes to the spread of drug resistance, including multi-drug resistant TB. Where it has been measured, the social cost of illicit drug use has been found to rival that of tobacco and alcohol, due to a combination of health care costs, lost productivity and crime. Recent World Health Organization (WHO) guidelines have endorsed methadone maintenance treatment as the mainstay of opioid dependence treatment. It has been shown to reduce premature mortality by two thirds and opioid overdose mortality ten-fold (50). Further, it dramatically reduces illicit opioid use, crime and HIV spread, and improves adherence to HIV, TB and hepatitis treatment. Since the first studies of methadone treatment were published in the 1960s, methadone has been used extensively for the treatment of opioid dependence and has saved millions of lives worldwide.
Despite the high need for treatment, global coverage of methadone and other services for people with opioid dependence is poor, with most treatment limited to high-income countries. Many countries have started pilot and small-scale programs, which have demonstrated similar effectiveness to those in high-income settings. However, only a few low- and middle-income countries have managed to rapidly increase the number of people receiving treatment for opioid dependence and other harm reduction measures to prevent the spread of HIV, TB and viral hepatitis. China is one example, as rapid expansion of methadone maintenance treatment programs (initiated in 2004, and now covering more than 300,000 opiate users) has made remarkable improvements in the quality of life of drug users and their families and in reducing HIV spread in this population (50). The Islamic Republic of Iran is another country that has rapidly increased its treatment of opioid dependence. Unfortunately however, this affordable and effective treatment for opioid dependence remains unavailable in most other low- and middle-income countries, as they still face many challenges in expanding methadone maintenance treatment programs. As a result, both drug use and drug-related HIV epidemics are continuing to have devastating effects in these countries (50).
Dependence on opioids is associated with serious morbidity and mortality, and advances in the understanding of the dependence have led to the development of effective treatments. More recently, the abuse of prescription opiates has become considerably more widespread, fueled in part by the availability of such drugs over the Internet. This has resulted in opiate abuse and dependence in populations seldom afflicted in the past. Thus, medical, mental health, and other healthcare professionals in a variety of settings may encounter patients with an opiate use disorder. The knowledge gained from the contents of this course can greatly assist the healthcare professional in identifying, treating, and providing an appropriate referral to patients with opiate use disorders.