Case 2: Discussion
Heroin, or diacetylmorphine, is an illegal, fast-acting, semi-synthetic opiate produced from the acetylation of morphine, a naturally occurring opiate present in certain types of poppy plants. British chemists first produced heroin in the late 19th century, and in the United States, the pharmaceutical company Bayer manufactured and marketed heroin as an analgesic and cough medicine until 1914, when it became classified as a controlled substance. In its relatively pure form, heroin is a fluffy white or brown powder and is known by a variety of nicknames, including "smack," "horse," "brown sugar," "H," "ferry dust," "skag," and "junk". Although the purity of street heroin has risen dramatically in recent years, some dealers still "cut" (mix) heroin with sugar, starch, powdered milk, quinine, or even strychnine. Black tar heroin is a dark sticky substance (or a hard nugget that resembles coal) and is crudely processed, typically in Mexico. Heroin can be injected subcutaneously ("skin-popping"), injected intravenously ("mainlining"), injected intramuscularly ("muscling"), smoked ("chasing the dragon"), or snorted. The preferred route of administration varies geographically (Figure 1). The simultaneous use of cocaine and heroin is known as "speedballing."
Epidemiology of Heroin Use
Although heroin use has decreased in recent years, the problem of heroin addiction remains an important national health issue. According to the 2004 National Survey on Drug Abuse and Health, 3.1 million people in the United States reported using heroin at least once in their lifetime. In that survey, approximately 166,000 individuals admitted to using heroin in the past month, and an estimated 118,000 people, with a mean age of 24 years, initiated heroin use in the prior year. In addition, at least 283,000 people received treatment for heroin dependence in 2004. Overall, injection drug use, including heroin use, accounted for at least 24% of adult AIDS cases through 2004 (Figure 2). Moreover, heroin is among the top 3 drugs associated with illicit drug-related emergency room visits in the United States, accounting for 47,604 visits to an emergency department in the last 6 months of 2003. Along with these problems associated with heroin use, the United States has experienced a major upsurge in addiction and abuse of opioid pain medications, particularly sustained-released oxycodone (OxyContin). For example, medical visits related to opioid abuse have increased dramatically in recent years, with a more than 5-fold increase for visits related to oxycodone.
Short-Term Effects of Heroin
After heroin is administered into the body, it is quickly converted to morphine and other metabolites that bind to opioid receptors in the limbic system of the brain and brainstem, producing a rush of pleasurable sensations, followed by depression of breathing and slowing of heart rate. Other effects may include sedation, flushing, dry mouth, a heavy sensation in the limbs, pruritis, nausea, and vomiting. Intravenous heroin produces an intense euphoria within 7 to 8 seconds, whereas intramuscular injection and inhalation (via smoking or snorting) give less intense highs with a slower onset of 5 to 8 minutes and 10 to 15 minutes, respectively. Regardless of the route, the sensation of euphoria often lasts for 1 to 3 hours. Even short-term use of heroin can lead to physical dependence. In patients with physical dependence, withdrawal symptoms typically begin 4 to 6 hours after heroin use and include drug craving, restlessness, insomnia, rhinorrhea, yawning, vomiting, diarrhea, myalgias, cold flashes, piloerection ("goose-bumps"), and leg movements[1,7]. Thus, many persons addicted to heroin use the drug 4 to 6 times per day, either to maintain the high or to avoid symptoms of withdrawal. The withdrawal symptoms peak within 48 to 72 hours of last use and usually subside within 7 to 10 days (Figure 3)[1,7]. Withdrawal from heroin is rarely life-threatening, but symptoms can be debilitating, frequently motivating users attempting to kick their heroin habit to re-initiate drug use.
Adverse Effects of Heroin Use
Acute heroin overdose can result in respiratory depression, pulmonary edema, hypotension, hyperkalemia, and central nervous system depression. Respiratory depression is the most common cause of death from heroin overdose. Even non-fatal overdoses can cause significant morbidity: falls, burns, peripheral neuropathy, aspiration pneumonia, and seizures. Naloxone (Narcan) is a short-acting opioid antagonist given intramuscularly or intravenously that reverses the effects of heroin overdose. Chronic heroin use can also cause a variety of medical complications. Heroin injection can lead to fibrosed veins, skin abscesses, osteomyelitis, endocarditis, methicillin-resistant Staphylococcus aureus infections, tissue infarction from the injection of impurities associated with cutting the heroin, and renal disease. Moreover, injection drug use markedly increases the risk of acquiring and transmitting HIV, hepatitis C virus (HCV), hepatitis B virus (HBV), and Mycobacterium tuberculosis. In addition, one study showed that users who inhale heroin, but have no history of injection drug use have a high HIV seroprevalence rate. Moreover, smoking heroin can also cause a decline in lung function, reactive airway disease, and leukoencephalopathy. Heroin use during pregnancy is associated with lack of prenatal care, low birth weight infants, and neonatal withdrawal syndrome. Finally, heroin use is a significant burden to society, as it often leads to unemployment, precarious social situations, and criminal behavior. One study estimated that in the United States in 1996, heroin use cost society .5 billion dollars through lost productivity, criminal activity, and medical care.
Medical Care of the HIV-Infected Heroin User
There are few contemporary estimates of the prevalence of heroin use among HIV-infected individuals, but most urban HIV clinics have substantial experience with heroin users. For example, among a cohort of HIV-infected patients admitted to a Baltimore teaching hospital, a history of heroin use was reported in 62% of African American women, 62% of African American men, 61% of Caucasian women, and 30% of Caucasian men. In this same cohort, 43% of HIV-infected men and 32% of HIV-infected women felt that they were dependent on heroin. Heroin users who also are HIV-infected have a particularly high risk for medical complications of heroin use. Indeed, studies performed prior to the widespread use of combination antiretroviral therapy revealed that HIV-infected injection-drug users experienced more medical complications prior to an AIDS diagnosis and had shorter survival than HIV-infected non-drug users.
Healthcare providers for HIV-infected heroin users need to be mindful of potential medical complications of heroin use, such as the possibility of endocarditis in a HIV-infected injection-heroin user who presents with a fever. In addition, clinicians should regularly screen for tuberculosis with tuberculin skin testing, vaccinate susceptible patients against HBV, and provide counseling for preventing the acquisition and transmission of HCV. Furthermore, to prevent potential complications from heroin use, patients should receive information on needle-exchange programs, counseling on safer injection and sexual practices, and appropriate referrals to drug treatment.
Although HIV-infected individuals often have very real sources of acute and chronic pain, control of pain can be particularly difficult in HIV-infected patients with heroin dependence. In general, non-narcotic medications should be the first-line agents for opioid-dependent patients. Some patients receiving methadone may require additional narcotic analgesics for adequate pain relief. If narcotic medications are needed, such patients typically require larger dosages and more frequent dosing due to tolerance. Even when cared for in HIV clinics, active injection-drug users are less likely to receive HAART than non-drug users, and they may have lower adherence with HAART[17,18].
Approach to HIV-Infected Heroin Users
Treating HIV-infected heroin users may pose significant challenges, yet it can also be satisfying. Key strategies to facilitate the delivery of care to this population include adjusting goals and providing interdisciplinary care. Providers should clearly communicate with the heroin user regarding what the patient wants out of medical care, and together they can set realistic goals, such as keeping appointments, receiving vaccinations, taking medications to prevent Pneumocystis pneumonia, or simply using fewer opioids. Given that active heroin users may have difficulty adhering to antiretroviral medication, initiating HAART with the expectation of perfect adherence and maximal virologic suppression may set a heroin user up to fail, leading to both patient and provider frustration. Once patients successfully achieve simple goals, setting additional goals, such as taking HAART, may be more appropriate, particularly if the active addiction becomes better controlled. Now that physicians can prescribe buprenorphine (Subutex) and buprenorphine-naloxone (Suboxone), many HIV providers now are uniquely situated to intervene in a HIV-infected patient's heroin addiction. Along with primary care providers, other health care providers, such as social workers, case managers, substance abuse counselors, mental health providers, nutritionists, adherence counselors, and pharmacists, should be involved in the drug users' health care. Involvement with case managers improves several aspects of the care of HIV-infected substance users and is associated with fewer unmet needs experienced by patients, a higher likelihood of utilizing health care services, and a greater probability of taking HAART[19,20].
Overview of Treatment for Heroin Dependence
Most individuals who are dependent on heroin require medical assistance to successfully stop heroin use. Some patients abstain from heroin use after a period medical withdrawal and intensive substance abuse counseling. Appropriate candidates for such medical withdrawal therapy include adolescents and young adults, those using heroin for less than two years, and individuals who do not want long-term opioid therapy. Nevertheless, chronic opioid therapy is associated with better outcomes than medical withdrawal for most heroin users, particularly those with longer histories of dependence. The goal of chronic opioid replacement therapy is to substitute a long-acting opioid for short-acting heroin to reduce the craving for heroin and diminish the psychosocial consequences of opioid addiction. Addiction counseling services also play a key role in conjunction with chronic opioid therapy. Unfortunately, only 44 states allow chronic opioid treatment centers (methadone clinics), and the demand for opioid dependence treatment currently outstrips supply. Indeed, fewer than 20% of opioid-dependent individuals are enrolled in substance abuse treatment programs.
Medical withdrawal, or detoxification, provides pharmacologic therapies to minimize the symptoms of withdrawal. The alpha-antagonist clonidine (Catapres) may help alleviate autonomic symptoms of withdrawal, such as diaphoresis and hypertension, and to a lesser extent, nausea and diarrhea[8,9]. Clonidine, however, does not have current FDA approval for opioid withdrawal and carries a significant risk of side effects, most notably hypotension. Lofexidine (Britlofex), an alpha-antagonist that has a lower risk of hypotension than clonidine, will likely be submitted for FDA approval in 2006 for treatment of opioid withdrawal. Anti-emetics, anti-diarrheal agents, and acetaminophen can also help alleviate specific symptoms of withdrawal. Finally, opioid tapers with methadone (Methadose) or buprenorphine may be prescribed for medical withdrawal in hospitals, outpatient treatment centers, and in the case of buprenorphine, in outpatient clinics by qualified physicians. Outpatient healthcare providers who are not affiliated with an opioid treatment center may only prescribe a 3-day supply of methadone for opioid dependence. Unfortunately, medical withdrawal alone does little to prevent relapse for most chronic users. Studies demonstrate that rates of continued abstinence from heroin after medical withdrawal alone are less than 15% at one year.
Methadone Maintenance Treatment
Methadone is a synthetic long-acting opioid agonist which has a half-life of 24 to 36 hours and may be administered daily (Figure 4). Methadone relieves drug craving, withdrawal symptoms, blocks the euphoric and sedating effects of heroin, and, at stable dosages, does not cause euphoria or sedation[24,25]. Standard initiation dosages of methadone are low, typically 20 to 30 mg per day, but are titrated upward to achieve reduced symptoms of withdrawal without sedation. A typical maintenance treatment dosage is 50 to 60 mg of methadone per day, but many patients require up to 80 to 120 mg per day to eliminate the craving for heroin[25,26]. Methadone is a relatively safe drug, and when used as prescribed during maintenance therapy, the most common adverse events are perspiration and constipation. Additional complications of methadone maintenance therapy include overdose, accidental poisoning of children, diversion (selling the drug), hypogonadism, drug-drug interactions, and hypersensitivity reactions[9,27,28]. In the United States, only methadone maintenance clinics administer methadone maintenance therapy. Patients must fulfill specific criteria for admittance to a methadone maintenance program (Figure 5). Methadone maintenance therapy is associated with significantly reduced heroin use and other positive outcomes for both patient and society (Figure 6)[24,25]. Notably, higher doses of methadone and concomitant counseling improve rates of treatment retention and abstinence from heroin[1,9,25,27]. Regrettably, approximately two-thirds of patients who leave a methadone clinic in good standing relapse into heroin use. Current Substance Abuse and Mental Health Services Administration (SAMHSA) guidelines recommend a minimum of 1 year of therapy with methadone and recognize that many patients may require long-term maintenance therapy. In addition, the updated guidelines attempt to make opioid maintenance therapy more accessible than in the past and thus allow treatment centers to dispense solid rather than liquid methadone, permit more flexible dosage adjustment, and authorize a larger supply of take-home medication for appropriate patients.
Buprenorphine and Buprenorphine-Naloxone Treatment
Buprenorphine is a partial agonist at the mu opioid receptor that competitively inhibits full opiate agonists, such as morphine, from eliciting their full effect (Figure 7). As an opioid agonist, buprenorphine produces subjective and physical opioid effects, but because it is a partial agonist, it exhibits a ceiling effect beyond which dosage increases do not elicit additional effects. Thus, it has a wider safety margin than full mu agonists such as methadone. Buprenorphine also has a long half-life (24-60 hours) and typically is given once daily at a dosage of 8 to 24 mg[9,28]. Two sublingual preparations of buprenorphine are available: one formulation contains buprenorphine alone (Subutex), and a second formulation consists of a buprenorphine combined with the opiate antagonist naloxone in a fixed coformulation (Suboxone)[21,28]. The naloxone component is not significantly absorbed via the sublingual route and does not increase the efficacy of treatment; instead it functions to deter possible diversion of buprenorphine via a parenteral route. As with methadone, buprenorphine may be used for both detoxification and maintenance therapy. Given that naloxone may enhance withdrawal symptoms, the combined buprenorphine-naloxone formulation is not generally recommended for medical management of withdrawal or for the initial transition from other long-acting opioids. Most patients on maintenance therapy will receive buprenorphine-naloxone. For suppression of heroin use and treatment retention, buprenorphine maintenance therapy is significantly better than placebo but inferior to high dose methadone. One large, randomized, placebo-controlled trial was terminated early because buprenorphine and buprenorphine-naloxone demonstrated greater efficacy than placebo in reducing both craving for heroin and heroin use (Figure 8). Notably, buprenorphine was the first schedule III medication to receive approval under the Drug Addiction Treatment Act of 2000 (Data 2000) for use in office-based treatment programs. In general, good candidates for outpatient buprenorphine therapy include patients with relative psychiatric and social stability and no history of multiple opioid treatment failures (Figure 9).
Abuse Potential and Adverse Effects Buprenorphine Preparations
The buprenorphine-naloxone preparation is more often used in clinical practice because it minimizes the potential for diversion. If a drug user crushes and injects the buprenorphine-naloxone pill, the naloxone will have a high affinity for the mu receptor, and the individual will immediately experience opioid withdrawal. Buprenorphine's partial versus full agonist effect also plays an important role in its lower risk of diversion: the opioid user with a high tolerance level will experience withdrawal rather than a "high." In addition, higher doses of buprenorphine can competitively inhibit full-agonist opioids, potentially inducing withdrawal if administered to a patient who still has a full opioid in the bloodstream, or diminishing the high from illicit opioid administration in a patient on buprenorphine. Potential adverse events associated with buprenorphine include respiratory depression, constipation, and headache. One report from France described 20 fatalities associated with buprenorphine, notably in individuals who crushed and injected buprenorphine pills (the buprenorphine-naloxone preparation is not available in Europe); these individuals also appear to have used concomitant psychotropic medications, mainly benzodiazepines.
Physician Prescribing of Buprenorphine and Buprenorphine-Naloxone
Physicians interested in providing opioid treatment in their practice settings need to receive a waiver from the Center for Substance Abuse Treatment (CSAT). Physician assistants and advanced nurse registered practitioners are not eligible to prescribe buprenorphine. To obtain the waiver, the physician must meet one of a number of qualifications (Figure 10). Most physicians without prior addiction certification will need to complete 8 hours of training on the treatment of opioid-addicted patients and these trainings are now offered on-line or at all-day conferences (buprenorphine.samhsa.gov/training.html). In addition, physicians are restricted to treating a total of 30 patients with buprenorphine at one time and must have the ability to refer patients for appropriate counseling. The SAMHSA web site maintains a section that serves as a state-by-state locator for physicians eligible to prescribe buprenorphine (www.buprenorphine.samhsa.gov/bwns_locator/). The SAMHSA CSAT has issued a document Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction that addresses key issues related to prescribing buprenorphine. In addition, a recent article by McCance-Katz provides a concise, practical review of implementing buprenorphine treatment in an office-based practice.
Other Treatment Options
Levacetylmethadol hydrochloride (LAAM) is a derivative of methadone that has been associated with prolonged QT syndrome and was recently withdrawn from the market in the United States and Europe. The opioid antagonist naltrexone (Depade, ReVia) can also be used to deter relapse into heroin use after detoxification. Because it does not diminish the craving for heroin, naltrexone is most appropriate for certain highly motivated patients with ample social and psychological support.
Heroin Addiction Treatment in HIV-infected Individuals
Successful treatment of heroin dependence can prevent many medical and social consequences of heroin use in HIV-infected individuals and may improve patient adherence to antiviral medications. In addition, treatment of heroin addiction in HIV-infected patients provides important public health benefits, particularly by reducing the risk of HIV-transmission. A recent meta-analysis revealed that opioid maintenance therapy significantly reduces the risk of HIV transmission among heroin users, primarily by reducing injection risk behavior. Unfortunately, in some geographic areas there may be long waiting lists for opioid maintenance therapy. Incorporating buprenorphine maintenance therapy into HIV care can make opioid maintenance therapy much more accessible for many heroin-dependent HIV-infected patients. There are several potential models for the integration of buprenorphine therapy and HIV treatment, including (1) provision of buprenorphine exclusively by the HIV primary care provider, (2) provision of buprenorphine by an addiction specialist within an HIV clinic, (3) provision of buprenorphine by the HIV primary care provider after induction and stabilization at an outside facility, and (4) administration of HIV care at drug treatment facilities. Nevertheless, in early 2006, relatively few HIV-care physicians had applied for the federal waiver to administer buprenorphine. Long-term studies are underway to better evaluate the effects of incorporating buprenorphine maintenance therapy into HIV care for HIV-infected opioid addicts.
Drug-Drug Interactions between Opioid Therapies and HAART
Antiretroviral medications can have significant drug-drug interactions with methadone treatment; a detailed discussion of these interactions can be found in the case Antiretrovirals and Methadone in the section Drug-Drug Interactions. Efavirenz (Sustiva) can also lower serum buprenorphine levels, but it is less likely to precipitate opioid withdrawal with buprenorphine than with methadone. Healthcare providers should continue to be alert for any symptoms of drug-drug interactions between opioid medications and antiviral agents, particularly as buprenorphine becomes more commonly prescribed and as newer antiviral agents are available.
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