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:
- Misuse: Patients' incorrect use of a medication, including use for an unintended purpose, exceeding the prescribed amount, or taking the drug more frequently or for longer than prescribed (1).
- Abuse: Definition varies widely depending on the context. The Drug Enforcement Agency (DEA) defines abuse as the use of a schedule II-V drug in a manner or amount inconsistent with the medical or social pattern of a culture (1). Abuse is also defined as the use of prescription medications beyond "the scope of sound medical practice" (1). Abuse and misuse often overlap when referring to prescription medication. The American Psychiatric Association defines abuse as "a maladaptive pattern of substance use, leading to clinically significant impairment or distress as manifested by one or more behaviorally based criteria" (2).
- Addiction: Defined by the American Society of Addiction Medicine (ASAM) as "a primary chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing the development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving" (1). Addiction is also referred to a psychological dependence.
- Dependence: This term has replaced the term "addiction" in some contexts. Opioid dependence, as defined in the latest Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), refers to both psychological dependence (and addiction) and physical dependence (2). Physical dependence consists of neurobiological adaptation (development of tolerance) from chronic exposure.
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):
- Tolerance (need to increase the dose to achieve the desired effect)
- Withdrawal symptoms when use stops or abruptly declines
- Loss of control
- Persistent desire or unsuccessful attempts to cut down or control use
- Preoccupation with obtaining opiate medications (e.g., multiple doctors, trips to the emergency department)
- Important social, occupational, or recreational activities forfeited or reduced because of opiate use
- Use despite the awareness of adverse physical or psychological problems caused or worsened by opiates
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).
- Initiation: During the initiation phase, acute reinforcement of the initial drug effect is mediated by muopioid receptors and dopamine that inhabit the ventral tegmental area and nucleus accumbens. This results in conditioned responses and drug craving (6).
- Continuation: The second phase of continued drug use is characterized by diverse neurotransmitter involvement, including dopamine in the nucleus accumbens, corticotrophin-releasing hormone in the amygdala, and glutamate in the frontal-cingulate circuit. As tolerance develops, the dose and route of administration often change, with progression to IV use a frequent outcome (4).
- Detoxification and Withdrawal: During detoxification and withdrawal from opiates and other central nervous system depressants, glutamate and norepinephrine in the locus coeruleus are primarily involved in causing the associated symptoms (6).
- Relapse Following Sustained Absence: Brain regions implicated in relapse to opiate use include the orbitofrontal cortex, anterior cingulate gyrus, and amygdala. Norepinephrine and corticotrophin-releasing hormones are involved in stress-induced relapse. Gamma-aminobutyric acid (GABA) and glutamate mediate brain systems are involved in compulsive and habitual behavior and mediate cue-induced relapse (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):
- Changes in mood and reward behavior;
- Disruption of neuro-endocrine function;
- Alteration of respiration;
- Changes in gastrointestinal and cardiovascular function;
- Other effects: Opioid agonists may also affect reflexes; particularly swallow/cough reflexes and pupillary dilation. Morphine and related opioids depress the cough reflex by direct action on the cough center in the medulla (5). Morphine and most mu and kappa agonists also constrict the pupils through excitation of the parasympathetic nerve stimulating the pupil (5).
Specific Opiate Drugs
Heroin, or diacetylmorphine, is a highly potent, semisynthetic analgesic produced by the anhydrous acetylation of morphine. Heroin is generally believed to have no significant opioid receptor activity; however, heroin is rapidly metabolized to 6-monoacetylmorphine and then to morphine. While diacetylmorphine and 6-monoacetylmorphine readily cross the blood-brain barrier, morphine itself is much slower to do so; thus, heroin can be considered a prodrug that facilitates the brain entry of morphine (17). The drug rapidly enters the brain after IV administration, where it binds to mu, kappa, and other stereospecific opiate-receptor binding sites in the locus coeruleus (4). The onset of euphorigenic action is approximately 30 minutes after intranasal ingestion, 15 minutes after subcutaneous injection, and almost instantaneously after IV injection, with duration of about 3 to 4 hours (4). As with many other opiates, heroin reduces the anticipatory anxiety associated with emotional or physical pain and alters the perception of pain (4).
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).
Codeine is approximately 60% as effective orally versus parenterally as an analgesic and respiratory depressant. Several codeine analogs, such as levorphanol, oxycodone, and methadone, have a high ratio of oral-to-parenteral potency, with the greater oral bioavailability reflecting lower hepatic first-pass metabolism (5). Approximately 10% of ingested codeine is O-demethylated to morphine. Free and conjugated morphine can be found in the urine after therapeutic doses of codeine. Codeine has an exceptionally low affinity for opioid receptors, and the analgesic effect of codeine is due to its conversion to morphine. However, the antitussive effects of this drug may involve distinct receptors that bind codeine itself. The plasma half-life of codeine is 2 to 4 hours (5).
Tramadol, sold as Ultram, is a synthetic codeine analog and a weak mu-opioid receptor agonist. Tramadol is unusual among opiates in that a portion of its analgesic effect is produced by norepinephrine and serotonin uptake inhibition (5). Tramadol is as effective as morphine or meperidine in the treatment of mild-to-moderate pain. It is 68% bioavailable following a single oral dose and 100% available following intramuscular administration. The affinity of tramadol for the mu-opioid receptor is only 1/6000th that of morphine. However, the primary O-demethylated metabolite of tramadol is two to four times as potent as the parent drug and may partially explain the analgesic effect. Physical dependence with tramadol has been reported (5).
Levorphanol (brand name Levo-Dromoran) is the only commercially available opioid agonist of the morphinan series, and it possesses pharmacological effects very similar to those of morphine. Levorphanol is metabolized less rapidly than morphine and has a half-life of 12 to 16 hours (5).
Meperidine is predominantly a mu-receptor agonist. This agent, available under the brand name Demerol, is no longer recommended for treatment of chronic pain due to concerns of metabolic toxicity. Meperidine should not be used for longer than 48 hours or in doses greater than 600 mg/day. The central nervous system effects are similar but not identical to that of morphine. In equianalgesic doses, meperidine produces comparable sedation, respiratory depression, and euphoria as morphine. Some patients may experience dysphoria. Meperidine can cause central nervous system excitation, characterized by tremors, muscle twitches, and seizures, primarily due to accumulation of the metabolite normeperidine (1). Large doses repeated at short intervals by addicts who have developed a tolerance to the sedative effects can produce an excitatory syndrome characterized by hallucinations, tremors, muscle twitches, dilated pupils, hyperactive reflexes, and convulsions (5). Meperidine is primarily abused by health professionals (5).
Diphenoxylate and Lopermide
Diphenoxylate (in combination with atropine as Lomotil or Lonox) and loperamide (Imodium) are meperidine congeners that are approved by FDA for the treatment of diarrhea. These drugs slow gastrointestinal motility by affecting the circular and longitudinal muscles of the intestine, presumably through interaction with opioid receptors in the intestine (5).
Fentanyl and Congeners
Fentanyl is a synthetic opioid related to the phenylpiperidines. The actions of fentanyl and its congeners (sufentanil, remifentanil, and alfentanil) are similar to those of other mu-receptor agonists. Fentanyl is a popular drug in anesthesia practice because of its relatively short time to peak analgesic effect, rapid termination of effect after small bolus doses, and relative cardiovascular stability. Fentanyl is approximately 100 times more potent than morphine, and sufentanil is approximately 10 times more potent than fentanyl. These drugs are usually administered intravenously and are substantially more lipophilic than morphine. Time to peak analgesia is rapid, usually within 5 minutes. Respiratory depression potential is similar to other mu-receptor agonists with a more rapid onset. Fentanyl and sufentanil treatment of chronic pain has become more widespread, and transdermal patches that provide sustained release for 48 hours or more are available (5). Fentanyl is delivered via the transdermal route for up to 72 hours, with patches containing 2.5, 5, 7.5, or 10 mg of fentanyl. Abuse of both the injectable formulation of fentanyl (Sublimaze) and the transdermal patch is primarily, but not exclusively, a problem among health professionals due to availability and proximity. Fentanyl may be extracted from the patch and injected, or the patch contents may be chewed, ingested, or inhaled. Even a patch that has been used for 3 days contains sufficient fentanyl to be abused (1).
Methadone was first synthesized as an analgesic in Germany during World War II as a response to the difficulty in obtaining raw opium (18). Methadone is a long-acting mu-receptor agonist with pharmacological properties quantitatively similar to those of morphine (5). Methadone is well-absorbed from the gastrointestinal tract and can be detected in plasma within 30 minutes of oral ingestion. Peak concentrations occur in the brain within 1 or 2 hours of subcutaneous or intramuscular administration (5). Oral bioavailability approaches 90% (18). In contrast to heroin, the activity of methadone is due almost exclusively to the parent drug rather than its metabolites. The drug is characterized by a long, but highly variable, half-life. One of the primary elimination pathways of methadone is N-demethylation, with cytochrome P450 3A4 (CYP 3A4) the major enzyme involved. Inhibition of CYP 3A4 with drugs such as ketoconazole and erythromycin may enhance and prolong the effect of methadone. Its induction with drugs such as rifampin, carbamazepine, and phenytoin will have the opposite effect (19). Liver disease can increase the half-life of methadone, but renal failure does not (18).
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).
Propoxyphene (Darvon) is structurally related to methadone and binds primarily to mu-opioid receptors to produce analgesic and other central nervous system effects similar to those seen with morphine-like opioids. As an analgesic, propoxyphene is about 50% to 65% as potent as codeine when given orally. The average half-life of propoxyphene in plasma after a single dose is 6 to 12 hours. Very large doses produce a degree of respiratory depression in morphine-tolerant addicts, suggesting incomplete cross-tolerance between propoxyphene and morphine. Administration via the intramuscular or intravenous routes results in severe damage to veins and soft tissues. The widespread popularity of propoxyphene has been largely a result of exaggerated concern about the addictive liability of codeine (5). Due to an increased risk for potentially serious or fatal heart rhythm abnormalities, the FDA asked the manufacturers to voluntarily withdraw propoxyphene from the market in 2010 (20).
Levo-Alpha Acetylmethadol (LAAM)
Levo-alpha acetylmethadol (LAAM) was first developed by German chemists in 1948. As early as 1952, LAAM was identified as an agent that could prevent opiate withdrawal symptoms for more than 72 hours. In 1993, the FDA approved LAAM for the treatment of opiate dependence (21). LAAM is a more potent derivative of methadone, and opioid replacement therapy with LAAM was designed to build on the strengths and improve on the drawbacks of methadone (18). Heightened concerns regarding the risk of arrhythmia and subsequent underutilization led the manufacturer of LAAM to withdraw the drug from the U.S. market in 2004 (18). The onset of action of LAAM, 90 minutes, is slower than methadone. However, the duration of action (48 to 72 hours) is significantly longer, enabling administration 3 times per week. Similar to methadone, LAAM suppresses the symptoms of withdrawal and produces cross-tolerance to illicit opioid use. The average daily dose is 75 to 115 mg, and adverse effects of LAAM are infrequent and comparable to methadone (18).
Hydrocodone is a semi-synthetic codeine derivative first used clinically as an antitussive and analgesic in the 1920s. Following a 10-mg oral dose, maximum serum level is observed in 1.3 hours (22). Hydrocodone exhibits a complex pattern of metabolism, including O-demethylation, N-demethylation, and 6-keto reduction to the corresponding 6-a- and 6-b-hydroxymetabolites. The 2D6 enzyme demethylates hydrocodone at the 3-carbon position into hydromorphone, which has much stronger mu binding than hydrocodone. Similar to codeine, it has been proposed that hydrocodone is a prodrug. Its analgesic properties are generally considered equipotent to codeine (22)(23).
Oxycodone is similar in structure to hydrocodone, with the addition of a hydroxyl group at the 14-carbon. Oxycodone, as a hydrochloride salt, is a pure agonist opioid that has been in clinical use since 1917. Unlike codeine and hydrocodone, oxycodone is a potent analgesic in its own right and not a prodrug, although 2D6 activity creates the active opioid analgesic metabolite oxymorphone (synthesized and marketed as the analgesic Numorphan). Oxycodone is suitable for oral administration due to high bioavailability (60%) but may also be given intramuscularly, intravenously, subcutaneously, or rectally. In terms of analgesic potency and lipophilicity, oxycodone is comparable to morphine, and both drugs possess similar abuse potential. With the exception of hallucinations, which occur more rarely with oxycodone than with morphine, the side effects of these drugs are highly similar (24). Since 1995, oxycodone has been marketed in the U.S. as OxyContin, a Schedule II controlled-release oral tablet formulation. Oxycodone is also available in immediate-release tablets in combination with aspirin or acetaminophen under various trade names, including Percodan and Percocet, which contain 2.5 mg to 10 mg of oxycodone. The oxycodone content of OxyContin ranges from 10 mg to 80 mg. When taken orally, OxyContin tablets release oxycodone over a 12-hour period. However, when the controlled-release mechanism is destroyed by crushing the tablet, the oxycodone can be snorted, ingested, or injected. It is this delivery of a large amount of the active drug in a relatively brief time period (compared to the intact tablet and the low-dose immediate-release form) that underlies addicts' interest in OxyContin (1).
Hydromorphone is a semi-synthetic hydrogenated ketone of morphine and shares the pharmacologic properties typical of mu-opioid agonists. Hydromorphone is a more potent analgesic than morphine; on a milligram basis, hydromorphone is 5 times as potent orally and 8.5 times as potent intravenously. Hydromorphone can be administered by infusion, intramuscularly, orally, or rectally (25). Following oral administration of conventional-release hydromorphone, the drug is rapidly absorbed and undergoes hepatic first-pass elimination of approximately 50%. The terminal elimination half-life after IV administration is 2.5 to 3 hours. The primary mode of elimination is by urinary excretion as hydromorphone-3-glucuronide, the primary metabolite. Some metabolites may have greater analgesic activity than hydromorphone itself but are unlikely to contribute to the pharmacological activity. Side effects are comparable to morphine (25).
Mixed agonist-antagonist compounds have been developed with the hope that they would have less addictive potential and create less respiratory depression than morphine and related drugs. However, achieving the same degree of analgesia produces a similar magnitude of side effects, and a "ceiling effect," limiting the amount of analgesia attainable, is often seen with these drugs. Also, some mixed agonist-antagonist drugs, such as pentazocine and nalorphine, can produce side effects not often seen with pure agonists, including severe, irreversible psychotomimetic effects (5). Drugs such as nalbuphine and butorphanol are competitive mu-receptor antagonists, with their kappa receptor agonist action mediating the analgesic effect. Pentazocine qualitatively resembles these drugs but is a weaker mu-receptor antagonist or partial agonist while retaining its kappa-agonist activity. Buprenorphine is a partial mu-receptor agonist (5).
Pentazocine was developed in an effort to synthesize an effective analgesic with little or no abuse potential. With agonistic actions and weak opioid antagonistic activity, the pattern of central nervous system effects is similar to that of morphine-like opioids, including analgesia, sedation, and respiratory depression. Dysphoric and psychotomimetic effects can be precipitated by higher doses (60 to 90 mg) (5).
Nalbuphine, available under the trade name Nubain, is an agonist-antagonist opioid related to naloxone and oxymorphone, with a spectrum of effects that qualitatively resembles that of pentazocine but with a lower potential to produce dysphoric side effects. Although doses of 10 mg or less produce few side effects, much higher doses (70 mg) can produce psychotomimetic side effects such as dysphoria, racing thoughts, and distorted body image. Prolonged administration of nalbuphine can produce physical dependence and withdrawal (5).
Butorphanol is a morphinan congener with a profile of actions similar to those of pentazocine. It is generally more suitable for the relief of acute pain than chronic pain. Major side effects include drowsiness, weakness, sweating, feelings of floating, and nausea. Although the incidence of psychotomimetic side effects is lower than that with equianalgesic doses of pentazocine, they are qualitatively similar. Physical dependence to butorphanol can develop from regular use (5).
Buprenorphine was initially suggested in 1978 as an alternative oral opiate substitution therapy for opiate addicts. Buprenorphine is a semi-synthetic opiate derivative made from thebaine, one of the numerous naturally-occurring alkaloids in opium (26). Buprenorphine, sold as Buprenex or Subutex, is a long-acting partial opioid agonist that is classified as a Schedule III narcotic, in contrast to methadone and LAAM, which are Schedule II (18). The minimum daily dose needed to suppress opiate use is about 4 mg. Higher doses of buprenorphine (32 mg) result less in an increase in therapeutic effect but more in an extension of the effect, which can last for up to 48 hours (26). Buprenorphine use is contraindicated for patients with alcohol intoxication, delirium tremens, and treatment with monoamine oxidase (MAO) inhibitors. Cases of lethal buprenorphine intoxication almost always involve polyintoxication (26). Upon discontinuation, a withdrawal syndrome develops, with a delayed emergence in 2 days to 2 weeks. Signs and symptoms of buprenorphine withdrawal are typical of a milder morphine-type withdrawal and last roughly 1 to 2 weeks (5). The more benign withdrawal syndrome is due to its partial agonist property at the mu receptor and weak antagonist property at the kappa receptor (24).
Opioid antagonists have obvious therapeutic value in the treatment of opioid overdose. Relatively minor changes in the structure of an opioid can convert an agonist drug into one with antagonistic actions at one or more opioid receptor types. Opioid antagonists include nalorphine, levallorphan, naloxone, naltrexone, and nalmefene. Interestingly, naloxone also appears to block the analgesic effects of placebo medications and acupuncture. Naltrexone and naloxone have little or no potential for abuse (5).
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: Directed at immediate survival by reversing the potentially lethal effects of overdose with an opiate antagonist;
- Harm reduction: Intended to reduce morbidity and mortality associated with use of dirty needles and overdose;
- Detoxification/withdrawal: Aims to remove the opiate of abuse from the patient's body, either through gradual taper and substitution of a long-acting opiate or through ultra-rapid opiate detoxification;
- Maintenance treatment or opiate (agonist) replacement therapy: Aimed at reduction/elimination of illicit opioid use and lifestyle stabilization. Maintenance follows detoxification/withdrawal, whereby the patient is tapered from short-acting opiates and introduced to long-acting opiate agonist, such as methadone or buprenorphine. Patients remain on agonist therapy short-term, long-term, or indefinitely depending on individual needs;
- Abstinence-oriented therapy: Treatment directed at cure. The patient is tapered off of short-acting opiates during the detoxification/withdrawal process and may be placed on an opiate antagonist with the goal of minimizing relapse.
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):
- Ultra-rapid opiate detoxification (UROD): General anesthesia; duration <6 hours;
- Rapid opiate detoxification (ROD): Deep sedation; duration 6 to 72 hours;
- Compressed opiate detoxification (COD) and naltrexone-compressed opiate detoxification (NCOD): Duration 3 to 6 days; preceded by a period of abstinence from opioids under sedation prior to introduction of naltrexone.
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
Two principle treatment modalities are offered for opiate dependent patients: agonist maintenance or detoxification followed by outpatient or residential drug-free treatment. Both can be effective, with no clear indication for each, although agonist maintenance leads to greater treatment retention (37). A reasonable approach would be an initial outpatient or residential treatment referral for patients relatively new to treatment, with agonist maintenance appropriate for patients with history of treatment failures, greater disease severity, or a history of drug overdoses. Naltrexone is best reserved for patients with strong legal incentives to abstain, family involvement to monitor treatment, or concurrent enrollment and involvement in a psychosocial intervention (37). At present, there are no direct interventions that are capable of reversing the effects of drugs of dependence on learning and motivation systems.
The first demonstrated efficacy of methadone treatment for opioid dependence was published in 1965. Methadone is now the most inexpensive and empirically-validated agent available for use in opiate replacement therapy. Studies have shown one-year treatment retention rates of 80%, with significant reductions in illicit opioid use (24). Individual and group counseling are the main ancillary therapies and consist primarily of cognitive-behavioral and supportive-expressive approaches. There is some evidence that augmentation of methadone with intensive psychosocial therapy significantly improves outcomes (24). Efforts to provide methadone in an office-based setting have been successful, although federal regulation has limited the flexibility of providers (36).
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).
Buprenorphine offers several advantages over methadone, including milder withdrawal symptoms following abrupt cessation, lower risk of overdose, and longer duration of action, allowing alternate-day dosing (24). Identifying subpopulations of opiate addicts who differentially respond to buprenorphine versus methadone has not been clearly established. However, patients with less chronic and less severe heroin dependence benefit more fully from buprenorphine than from a pure opioid agonist like methadone (24). Studies support buprenorphine as a viable alternative for opioid maintenance therapy. However, its mixed agonist/antagonist action entails special considerations. Buprenorphine may precipitate opioid withdrawal, and patients being switched from short-acting opioids must abstain from illicit opioid use for at least 24 hours before initiating buprenorphine therapy. Another drawback is associated with the sublingual route of administration. This administration presents some difficulties because the tablet is relatively large and slow to dissolve under the tongue and swallowing diminishes its effectiveness. Also, the transition to buprenorphine from long-acting opioids is difficult (19). Higher doses of buprenorphine (12 mg or greater) are more effective than lower doses in reducing illicit opioid use, with comparable efficacy to methadone on major treatment-outcome measures. The primary advantage of buprenorphine over methadone is its superior safety profile (19).
Slow-Release Oral Morphine
Slow-release formulations of morphine that are effective with once-daily dosing are a viable alternative in the treatment of opioid dependence. These formulations considerably delay time to peak concentration after oral administration, resulting in delayed onset of action and making the reinforcing effects very weak when it is administered orally. Several trials suggest that slow-release morphine has approximately equal efficacy with methadone (19).
The pharmacokinetic properties of heroin make it less than ideal for use as a maintenance drug, and the main rationale for heroin maintenance has been the treatment of patients who simply do not respond to any other treatment modality. Although preliminary results seem to be positive, suggesting that heroin treatment may be have a place with a subpopulation of patients, further studies using standardized protocols are needed. Significantly, studies so far clearly indicate that heroin maintenance, with or without methadone, can be implemented safely. The relatively high cost of heroin maintenance compared with standard methadone or buprenorphine treatment is a drawback of this approach. However, at least one study suggests that heroin combined with methadone may be more cost-effective than methadone alone (19).
Agonist Replacement and Psychosocial Therapy
The addition of any psychosocial support to agonist replacement therapy significantly reduces illicit use during treatment; treatment retention and results at follow-up are also improved (33). There are two general types of psychosocial therapy used for treating addictive disorders. The first includes therapies developed for treating depression and anxiety that were later adapted for treating persons with addictive disorders, examples of which include cognitive behavioral therapy, supportive expressive therapy, and interpersonal therapy. The second type includes therapies developed specifically for persons with addictive disorders, such as the closely-related motivational interviewing and motivational enhancement therapy (39). Drug counseling, another approach specific to addictive disorders, emphasizes abstinence, involvement in 12-step programs, and assistance with social, family, and legal problems. Drug counseling is not considered psychotherapy because it focuses on behaviors and external events rather than the intrapsychic processes (39). Most studies of psychotherapy with opiate-dependent patients have been conducted in methadone programs and are actually pharmacotherapy/psychotherapy studies. In addition to pharmacological intervention, methadone programs typically use behavioral contingencies that are based on cessation of illicit drug use and other improvements (39).
The primary goal of abstinence-oriented interventions is cure, which is defined as long-term, stable abstinence from all opioids. Abstinence is achieved in two phases: detoxification and relapse prevention. Outcomes in abstinence-oriented programs are generally poor (33). The primary goal of pharmacotherapy during detoxification is to alleviate opiate withdrawal severity and associated distress and medical complications and to enhance patient motivation to continue treatment. Withdrawal can also be reduced by psychosocial measures, such as contingency management or counseling, and as discussed, the addition of psychosocial therapy to pharmacological treatment increases efficacy. Buprenorphine and clonidine are both used to manage withdrawal symptoms, but buprenorphine's advantages, compared with clonidine, are related to its favorable side effect profile and positive effects on well-being and psychosocial variables (33).
Opioid Antagonist Therapy
Relapse-prevention programs have traditionally involved long-term residential placement of 9 months or more, often using the therapeutic community format. More recently, pharmacotherapeutic agents, such as naltrexone, have been added to reduce relapse risk. A drawback with opiate antagonist therapy is the high dropout rate during detoxification, which results in highly selective patient samples in most of the naltrexone maintenance studies. Naltrexone maintenance or relapse-prevention treatment should be reserved only for those patients who are highly motivated for long-term total abstinence and who are otherwise psychosocially stable. Relapse prevention with naltrexone may also be suitable for pregnant women who are unable to stabilize on methadone or buprenorphine. Patients should be warned that reduced tolerance following naltrexone treatment may increase the risk of overdose. The primary problem with naltrexone treatment is low compliance, with retention in treatment ranging from 6% to 45% (40). Strategies to improve treatment compliance include combining naltrexone maintenance with contingency management, involving the provision of vouchers redeemable for goods and services contingent on naltrexone intake and drug-free urines (40). At present, reviewers conclude "there is no sufficient evidence of efficacy of naltrexone to justify its use in the maintenance treatment of opioid dependence" (40).
Twelve-step programs for opiate abuse and dependence include Narcotics Anonymous (NA) and Methadone Anonymous (MA) and are modeled after Alcoholics Anonymous (AA), an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA is widely considered the most successful treatment for alcoholism and has helped hundreds of thousands of alcoholics achieve sobriety (41). The 12-step model emphasizes acceptance of dependence as a chronic progressive disease that can be arrested through abstinence but not cured. Additional elements include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support (41). Although research on efficacy and patient outcomes in NA and MA is very limited, many prominent researchers emphasize the important role ongoing involvement in 12-step programs plays in recovery from substance abuse (41).
Narcotics Anonymous (NA)
Relative to the more established AA, there are few studies published on NA. However, some research has revealed important information about how NA functions to help both new and long-term members abstain from opiates and other drugs. Being active as an NA sponsor over a 1-year period was found to be strongly associated with substantial improvements in sustained abstinence rates for the sponsors. This suggests that providing direction and support to other newer addicts is a way to enhance the likelihood of one's own abstinence (42).
Methadone Anonymous (MA)
MA was begun in 1991 when a staff member of a methadone maintenance treatment clinic in Baltimore attended an NA meeting and observed women receiving an "Anniversary Chip" in recognition of abstinence from heroin, only to be told to return the chip when she shared that methadone maintenance helped make it possible. This staff person went on to develop a 12-step program for methadone patients (43). MA is based on the belief that "methadone is a therapeutic tool of recovery that may or may not be discontinued in time, dependent upon the needs of the individual," and that continued abstinence from drugs of abuse, including alcohol, is the foremost goal of recovery. Most MA meetings are hosted by methadone clinics, and there are at least 600 MA chapters worldwide (43).
Auricular acupuncture is the most common acupuncture approach for substance abuse, including opiate abuse and dependence, in the U.S. and the United Kingdom. This technique consists of bilateral insertion of acupuncture needles in the outer ears (44). There is controversy surrounding the presumed mechanism of action of acupuncture. Western scientists attempt to explain its action on the body's electromagnetic system, with the acupuncture needle creating a difference in electrical potential that stimulates extracellular ion flow. Chinese practitioners, who have been using acupuncture for several thousand years to treat a wide range of maladies, attribute its effects to unblocking or removing an excess of "qi", or life energy, along key channels referred to as meridians (44). Results from well-designed studies indicate that auricular acupuncture treatment is not sufficient in efficacy as a stand-alone treatment for opiate dependence. The placebo response rate is substantial, and the body of evidence does not demonstrate the type of qualitative and quantitative rigor needed to validate acupuncture efficacy in the treatment of opiate-addicted patients. Common adverse events from acupuncture include needle pain, fatigue, and bleeding; fainting and syncope are uncommon. Feelings of relaxation are reported by as many as 86% of patients (44). There is some evidence that differences in efficacy may be influenced by racial physiological differences among persons of European and Asian descent.
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):
- Fetal growth restriction;
- Intrauterine withdrawal with increased fetal activity;
- Depressed breathing movement;
- Preterm delivery;
- Preterm rupture of membranes;
- Meconium-stained amniotic fluid;
- Perinatal death.
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.
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