Case 1: Discussion
Methamphetamine is a synthetic chemical stimulant, similar in structure to amphetamine and other stimulants, but it produces more pronounced central nervous system effects than most other stimulants. The drug is known by various street names depending on its formulation, with pure crystalline methamphetamine referred to as "ice," "crystal," "glass," "crystal meth," and "tina," and the less pure crystalline powder form known as "chalk," "meth," "speed," and "crank". The drug can be swallowed, inhaled, snorted, dissolved sublingually, injected, or inserted rectally--the so-called "booty bump". Preferred routes of administration vary geographically (Figure 1). Methamphetamine can easily be produced by the one-step chemical reduction of ephedrine or pseudoephedrine--drugs without strong euphoric effects that are readily available in over-the-counter cold and decongestant medications. In addition, a number of household products contain the essential compounds required in the chemical reduction process. The methamphetamine sold on the street is often diluted with chemicals used in the synthesis process, or with inert substances, such as inositol. Medically manufactured methamphetamine (Desoxyn) is classified as a Schedule II stimulant and is FDA-approved for the treatment of attention-deficit disorder and exogenous obesity; it is also used off-label to treat narcolepsy.
Methamphetamine and Mechanism of Action
The mechanism of action for methamphetamine is highly complex and incompletely understood. The initial "rush" that occurs after methamphetamine ingestion primarily results from an immediate increase in neurotransmitter levels of epinephrine, serotonin, and dopamine[1,3]. Most of the subsequent physiologic responses associated with methamphetamine appear to be related to a marked increase in dopamine at the synaptic level; these changes result from increases in release of dopamine stores in vesicles and inhibition of dopamine reuptake transporters. The euphoria and the addictive properties caused by methamphetamine are thought to result from the increased release of dopamine from neurons in the presynaptic ventral tegmental area into the nucleus accumbens, a region of the brain considered to be the major reward center. Levels of dopamine in the nucleus accumbens substantially decline during methamphetamine withdrawal. Long-term heavy use of methamphetamine can cause sustained and major decreases in dopamine levels, as well as long-lasting neurodegenerative effects.
Epidemiology of Methamphetamine Use
Worldwide, more than 35 million people use methamphetamine regularly, more than 3 times the number of individuals who use heroin. In the United States in 2004, 1.4 million people reported methamphetamine use within the prior year, and 40% of them acknowledged use within the prior month. Although the overall prevalence of methamphetamine use in the United States remained stable from 2002-2004, the proportion of methamphetamine users meeting criteria for dependence on an illicit drug doubled (from 10.6 to 22.3% of users) during this time period. Methamphetamine use has been a problem for decades in many areas of the western United States, particularly Honolulu, San Diego, Denver, and Los Angeles, but more recently the epidemic has expanded into the midwestern and eastern United States (Figure 2). Nationally, methamphetamine use is highest among Hawaiian natives and Native Americans and is lowest among Asians and African Americans. Prevalence is higher in males and in individuals 18 to 25 years old (Figure 3).
Methamphetamine Use and HIV Transmission
As with intravenous opiate use, needle sharing with intravenous methamphetamine use is a risk factor for acquiring and transmitting blood-borne pathogens, most importantly HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV). Methamphetamine use has also been linked to the sexual transmission of HIV, particularly among men who have sex with men (MSM)[7,8,9]. Among a cohort of gay and bisexual men in California seeking drug treatment for methamphetamine use, 61% were HIV infected. In a survey of gay and bisexual methamphetamine users in New York City, most men who used methamphetamine did so to enhance sexual experiences. Other studies that involved HIV-infected MSM have reported similar motivations for using methamphetamine, such as having better sex, having more sex, increasing energy, improving work productivity, and coping with stress[7,11]. In addition, methamphetamine use has been associated with high-risk sexual practices, including sex with casual or anonymous partners, multiple sex partners, unprotected anal sex, sexual marathons, and rough sexual practices[7,12]. The process of prolonged sex, particularly with rougher sex, would presumably result in increased mucosal exposure and damage, thus likely increasing the probability of HIV transmission. Moreover, rectal insertion of incompletely dissolved methamphetamine may increase the risk of HIV transmission by causing condom abrasion and by directly inflaming the anal mucosa.
Short-Term Effects of Methamphetamine
The interval between the administration of methamphetamine and its onset, as well as the intensity of the effects on the central nervous system, varies by route of administration. For example, smoking and injecting methamphetamine produce an instantaneous, intense sense of euphoria that may last for only a few minutes. Snorting and ingesting produce a less intense but longer lasting sense of euphoria, with onset and duration of 3 to 5 minutes and 20 minutes, respectively[1,2]. Some effects of methamphetamine may last for up to 12 hours. Users may experience increased attention, increased libido, insomnia, irritability, paranoia, hallucinations, and decreased appetite. Other effects include tachycardia, tachypnea, increased activity, and hyperthermia. During a binge, individuals will repeatedly take more of the drug to maintain the high, sometimes sustaining the high over a period of several days. Withdrawal symptoms typically peak 24 hours after last use, but may be notable for up to one week. The withdrawal or rebound period is characterized by exhaustion, depression, hunger, and drug craving. Serious potential medical complications associated with short-term use include seizures, arrhythmias, malignant hyperthermia, rhabdomyolysis, tissue necrosis (from vasoconstriction or vasculitis), and suicide (Figure 4). In some areas, lead acetate may be used as a reagent in methamphetamine production, and there have been case reports of acute lead poisoning associated with methamphetamine use.
Potential Long-Term Effects of Methamphetamine Use
Long-term heavy exposure to methamphetamine is associated with neurotoxicity and a variety of psychiatric manifestations (Figure 4). Chronic users can develop impaired motor functioning and deficits in auditory verbal learning that may not significantly improve after a year of abstinence. Among HIV-infected individuals already at risk for developing neurologic disorders, the neurotoxic effects of methamphetamine can be more pronounced, leading to an additive or synergistic effect. In addition, methamphetamine users can display violent behavior, paranoia, depression, and delusions. Moreover, approximately 10% of heavy long-term users develop psychosis, which may be difficult to distinguish from schizophrenia[1,8]. Other potential medical complications associated with chronic methamphetamine use include periodontal and dental disease ("meth mouth"), malnutrition, methicillin-resistant Staphylococcus aureus (MRSA) skin infections, and endocarditis[2,8]. Methamphetamine use during pregnancy can also result in premature delivery and perinatal complications. Finally, methamphetamine use may cause devastating social consequences. Many users lose employment and resort to crime to pay for the drug. They may eventually neglect or abandon their children or dependents.
Methamphetamine Use and Antiretroviral Therapy
Unfortunately, HIV-infected methamphetamine users frequently avoid medical care and many may have indications for antiretroviral therapy. Failure to engage HIV-infected methamphetamine users into medical care can have grave consequences, and even those individuals who do receive routine medical care often have difficulty with medication adherence in the face of ongoing methamphetamine addiction[16,17,18]. Methamphetamine users report that methamphetamine can negatively affect adherence to HAART through sleep pattern disruption, erratic schedules, and missed meals. Moreover, some methamphetamine users skip doses intentionally, either as part of a "drug holiday" during periods of drug use or because of concerns about drug interactions with methamphetamine. Indeed, active methamphetamine users have significantly higher viral loads while taking antiretroviral therapy than non-users. Nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) do not have specific interactions with methamphetamine, but the protease inhibitor ritonavir (Norvir) is processed through the same cytochrome p450 CYP2D6 pathway as methamphetamine and it can markedly elevate serum methamphetamine levels. Ritonavir has even been implicated in overdoses of methamphetamine and methylenedioxymethamphetamine (also known as MDMA or ecstasy)[8,20].
Healthcare for HIV-Infected Methamphetamine Users
Healthcare providers should recognize that developing the trust of an HIV-infected methamphetamine user may be a challenging and lengthy process, yet it is a crucial component of an effective provider-patient relationship. Thus, healthcare providers should be calm, approachable, and non-judgmental. During each clinic visit with an active methamphetamine user, clinicians should screen for depression and psychosis, assess the patient's readiness for cessation of methamphetamine, and provide harm-reduction messages. Depression is extremely common among methamphetamine users and can affect patients' motivation to seek treatment for their addiction and for HIV infection and to adhere to antiretroviral therapy. Thus, active screening for and aggressive treatment of depression in HIV-infected methamphetamine users is critical. In addition, open-ended questions about patients' drug use and stage of preparedness for cessation are key components of developing patient-centered plans for care. If a patient indicates readiness for treatment, the healthcare provider should offer specific referrals for methamphetamine treatment facilities and support groups. Narcotics Anonymous often has methamphetamine-only groups throughout the United States that can be accessed through the organization Crystal Meth Anonymous (www.crystalmeth.org). Clinicians should also familiarize themselves with the local availability of specific support groups for drug users. For example, HIV-infected gay or bisexual individuals may benefit from an MSM-specific support group, as sexual cues for methamphetamine use may vary significantly among groups of different sexual orientation. Furthermore, medical providers caring for HIV-infected methamphetamine users should emphasize harm reduction and prevention messages by screening for high risk behavior and providing counseling on safer sex and injection practices. Finally, because chronic users may have difficulty with auditory memory, providers should take care to write down all instructions.
Strategies For Treating HIV-infected Methamphetamine Users
Treating HIV-infected methamphetamine users may be challenging, but it can also be rewarding. Strategies to facilitate the delivery of care to this population include rethinking goals of care and the use of interdisciplinary teams of healthcare professionals. Although the primary goal of HIV clinicians is usually to decrease morbidity and mortality with HAART, adequate adherence to HAART may be impossible for active methamphetamine users. Thus, if providing HAART is a clinician's sole aim, it can set a methamphetamine user up to fail and lead to frustration for both the patient and provider. Providers should consider directly asking users what they want out of medical care, so that together they can set realistic goals, such as keeping appointments, receiving vaccinations, taking medications to prevent Pneumocystis pneumonia, or simply using less methamphetamine. Once patients are successful with these objectives, setting additional goals, such as taking HAART, may be more appropriate. 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 care of the methamphetamine user. Involvement with case managers in particular has been shown to improve several aspects of the care of HIV-infected patients, including HIV-infected substance users. Case management is associated with fewer unmet needs, greater utilization of health care services, and greater probability of taking HAART[21,22,23,24].
There are no specific therapies for acute methamphetamine intoxication. In general, patients should be approached with a calm demeanor and treated in a quiet environment. On occasion, benzodiazepine administration may be beneficial. Patients who have overdosed should receive close monitoring for seizures and hyperthermia and should be treated with anticonvulsants and cooling modalities as needed. Short-term neuroleptics may alleviate acute symptoms of psychosis. Long-term treatment of methamphetamine addiction can prove very difficult, and many traditional treatment programs may not be adequately prepared for the challenge. There is no well-established, effective pharmacologic therapy for methamphetamine addiction. Behavioral therapy is still the cornerstone of management of chronic methamphetamine addiction[1,5]. The Matrix Model remains the best-tested behavioral program; it consists of 4 months of intensive outpatient management that combines cognitive-behavioral therapy, family education, 12-step program participation, and additional behavioral approaches[1,5]. Unfortunately, funding for such extensive treatment is often not available. Finally, prompt diagnosis and treatment of depression is a key component to the maintenance of remission, as depression is very common after withdrawal and may persist for years. Interestingly, in a short-term study of medical therapy for methamphetamine users, the antidepressant bupropion (Wellbutrin), which has established efficacy in smoking cessation, reduced both cue-induced drug craving for methamphetamine (Figure 5) and subjective high after methamphetamine administration. Although bupropion's role in the treatment of methamphetamine dependence requires further study, it may be a reasonable first-line agent for the treatment of depression in methamphetamine dependent individuals.
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