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Patients With Substance Use Disorders
Overview
Without a doubt, substance use disorders (SUDs) present one of the gravest difficulties currently facing the United States healthcare system. Over the past two decades, the number of patients treated for substance use-related problems in the United States has grown steadily, and over the past 5 years it has reached epidemic proportions. Data from the Centers for Disease Control and Prevention (CDC) indicate that in the 10 years between 2004 and 2014, the mortality rates attributed to drug overdoses increased by 137%, including a staggering 200% increase in the rate of overdose deaths attributed to opioids. The increased mortality rates were independent of sex, age group, or ethnicity, and were evident across the country. In fact, the CDC estimates that nearly half a million persons in the United States died from drug overdoses between 2000 and 2014, and that drug-related fatalities were one and a half times higher than deaths from motor vehicle crashes in 2014. Up to 80% of all drug-related fatalities appear to be unintentional, with 13% attributed to suicide, and the remainder classified as undetermined.
The increase in drug use has also led to increased utilization of healthcare services. The Drug Abuse Warning Network (DAWN) and the Substance Abuse and Mental Health Service Administration (SAMHSA) estimate that over 5 million Emergency Department (ED) visits in 2011 were related to drug use—a 100% increase over their 2004 data. Of these, nearly 2.5 million ED visits were attributed to medical emergencies related to drug abuse.
Clinical presentations in this domain are also becoming more complex. Of the 2.5 million ED visits identified by DAWN/SAMHSA in 2011, nearly one-half involved complications related to use of prescription medications, with the remainder being attributed to use of non-prescription illicit drugs. While the use of opioids, marijuana, and cocaine are seen most commonly, more than 50% of the patients present with co-ingestion of multiple substances, and there has been an increase in use of CNS stimulants, “club drugs,” and hallucinogens.
Successful treatment of this expanding group of patients requires that clinicians improve their management skills for SUDs and their sequelae. This involves timely and correct diagnosis of the substance use problem, recognition of key symptoms associated with intoxication or acute discontinuation/withdrawal, and appropriate initial management and treatment. It also involves meaningful engagement (including motivational enhancement techniques to assess readiness for recovery), identification of outpatient addiction resources, and use of medications to reduce craving and to maintain recovery. The chronic, relapsing, nature of substance use may inspire resignation and hopelessness in consulting clinicians, leading to a misperception that the consultation is unnecessary, or even futile. Because most clinicians fail to appreciate that the relapse rate for other common chronic medical disorders (e.g., diabetes, hypertension, asthma) exceeds that for SUDs, they do not treat substance abuse patients with comparable therapeutic diligence. The Massachusetts General Hospital (MGH) has dedicated considerable effort and resources to adequately address the substance use epidemic within our local communities, starting with a hospital-wide effort to ensure that problems related to substance use are addressed with the same degree of compassion and persistence directed at other common relapsing medical disorders. Medical and surgical hospitalizations often provide extended periods during which patients are separated from their substance use, and thus hospitalization may present a unique opportunity to engage the patient in meaningful interventions.
Case 1
Mr. B, a 36-year-old homeless man with a history of substance use and abuse (benzodiazepines, opiates, and stimulants), was admitted to the vascular surgery service with ischemia to his right hand and forearm. The injury was sustained when he relapsed on “heroin” (after 2 months of recovery), and became obtunded with a protracted period of immobility. An initial urine toxicology screen was positive for benzodiazepines and opioids, with further toxicology testing that confirmed the presence of clonazepam, methadone, and fentanyl. Psychiatric consultation was requested to assist with pain management and to provide assistance with addiction recovery treatment referral and resources.
On interview, Mr. B was alert, oriented, lucid, and forthcoming. He reported surprise, and then frank fear, that he “ended up this way—after all I only used once.” He also appeared surprised that the toxicology screen revealed evidence of fentanyl and benzodiazepines, as he was “certain” he used heroin. He complained of pain, despite being on his methadone maintenance (75 mg/day), and expressed concern that his pain would be under-treated because of his history of substance use. His mood was appropriate to the clinical context: there was no evidence of depression.
Following initial stabilization, Mr. B underwent amputation of his right forearm and hand. During the perioperative period, he received a combination of long-acting opioids for basal analgesic control, as well as short-acting opioids for breakthrough pain. His methadone dose was increased to 90 mg/day, and was split into three-times-a-day dosing to optimize pain management. His short-acting opioids (intravenous [IV], then oral hydromorphone) were tapered gradually over 2 weeks while he remained in the inpatient setting.
With improved pain control, Mr. B more readily engaged in readiness work via motivational interviewing and he accepted addiction recovery services. He identified methadone maintenance as a key element to his recovery and noted no cravings on the higher dose of his medication. He found inspiration in his survival, and despite grieving the loss of his limb, expressed a strong readiness to maintain recovery. He worked closely with the consultation team to identify triggers for relapse and secured a safe disposition plan. By the end of his 2-week hospital stay, Mr. B held regular meetings with Narcotics Anonymous (NA) peers in the hospital. He maintained continuous contact with his methadone provider and allowed the consultation team to share their impressions with the clinic.
Mr. B was discharged to his parents' home, with a plan to follow-up with his methadone clinic and NA. He expressed (appropriate) anxiety on discharge, as he readily admitted that the road ahead of him would be challenging, but also noted hope and readiness to battle his addiction.
Stimulants
Cocaine
Cocaine is a tropane alkaloid naturally found in leaves of the Erythroxylum coca plant, a bush native to the Andes Mountains region of South America. To this day, leaves of the plant continue to be used by the indigenous people (typically chewed), for their anesthetic, stimulant, and hunger-suppressant effects. Over the past two centuries, the discovery of methods to reliably isolate the alkaloid combined with the ever-increasing demand for the compound, has led to cocaine becoming one of the most commonly abused drugs worldwide. An estimated 17 million people (about 0.4% of the world population) have used cocaine, a number only surpassed by cannabis and alcohol. The widespread use of the drug, combined with potent stimulant effects has led to cocaine being one of the leading drugs of abuse (in terms of the frequency of ED contacts, general hospital admissions, violence, and other social problems). The DAWN ED data for 2011 reported 505,224 ED visits related to cocaine, compared with 455,668 ED visits for marijuana, and 258,482 ED visits related to heroin use—a staggering 40% of all ED visits related to illicit drug use. Traditionally, the coca leaf is chewed to release the cocaine alkaloid, yet isolated cocaine is rarely ingested (commonly with a highly alkaline compound to prevent neutralization by the acidic milieu of the stomach). More commonly, cocaine is injected, insufflated or inhaled (as “crack”) as the latter methods greatly increase the bioavailability of the drug.
Pharmacology and Mechanism of Action
Cocaine increases the monoamine neurotransmitter activity in the central nervous system (CNS) by blocking the pre-synaptic re-uptake transporters for dopamine, norepinephrine, and serotonin. Given the potent effects of cocaine on dopamine's availability within the CNS, much of the drug's stimulant and addictive effects have been ascribed to its effects on the corticomesolimbic dopamine reward circuits. In addition to these effects, cocaine also acts by blocking voltage-gated sodium ion channels, an action that accounts for its effect as a local anesthetic and contributes to its cardiac toxicity.
The route of administration greatly influences the bioavailability of the drug, including its onset and duration of intoxication. Smoking (i.e., inhalation) and IV use generally lead to near instantaneous (seconds to minutes) effects, and most patients note that the drug's effects wear off within 30 minutes. Intranasal administration results in slower onset of symptoms (within 30 minutes) and the effects of the drug are similarly extended to up to 1 hour.
Cocaine is commonly co-administered with alcohol, which leads to the formation of cocaethylene, a compound with stimulant effects similar to that of cocaine, albeit with a longer half-life. This compound has also been noted to carry greater cardiac toxicity compared with cocaine alone.
Cocaine is extensively metabolized by the liver, and its metabolites are eliminated in the urine, most commonly as benzoylecgonine. This metabolite (rather than the parent compound) is detected by urine drug tests for cocaine; it can be detected as early as 4 hours after intake, and may remain detectable for up to 1 week after cocaine is used. There are no common false positives for urine cocaine screen.
Cocaine intoxication is associated with potent stimulant effects, including increased energy and alertness, bright (to frankly euphoric) affect, insomnia, as well as anorexia. Similar to other stimulants, cocaine is associated with an intensely pleasurable state and is commonly used to potentiate sexual activity. With higher doses, the unintended effects of cocaine may become apparent, including anxiety and panic attacks, restlessness, agitation, and violent behavior, as well as psychosis (manifesting as paranoid ideation, hallucinations, or delusional thinking). Signs of adrenergic hyperactivity (e.g., hyperreflexia, tachycardia, diaphoresis, mydriasis) may also be seen. More severe symptoms (e.g., hyperpyrexia, hypertension, cocaine-induced vasospastic events, such as stroke or myocardial infarction) are relatively rare among recreational users but are seen more commonly in patients who present to the ED for cocaine-related issues. Patients may manifest motor signs of CNS excitability, including tremor, myoclonus, and stereotyped movements of the mouth, face, or extremities (e.g., skin picking, “crack dancing,” “boca torcida”). Infrequently, seizures may occur, even with first time use of the drug—most commonly these are manifest as generalized tonic-clinic seizures within the first 90 minutes after drug use.
Given its potent effects on the central and peripheral monoamine neurotransmitter systems, it is not surprising that cocaine has significant effects on most organ systems. In addition to stimulant and pro-ictal effects described previously, cocaine has been associated with increased rates of hemorrhagic and ischemic stroke, an effect postulated to be due to increased heart rate and blood pressure (due to sympathetic nervous system (SNS) activation), cerebral vasoconstriction, and vasospasm. Cocaine similarly increases risk for ischemic cardiac phenomena, and chest pain is one of the most frequent complaints in cocaine users who seek medical attention. Cocaine use has been associated with increased heart rate and blood pressure (via increased peripheral adrenergic activity), as well as vasoconstriction, both of which lead to reduced cardiac oxygen availability and increased risk for cardiac complications, including myocardial infarction. Furthermore, cocaine action as a sodium channel-blocker leads to an increased risk for cardiac arrhythmias, and even sudden death.
Intranasal cocaine use has been associated with rhinitis, sinusitis, and in severe cases, perforation of the nasal septum. Inhalation use leads to common respiratory symptoms, including shortness of breath, wheezing, and cough, but may also cause bronchitis, pulmonary edema, hemorrhage, and even a pneumothorax. While cocaine has not been shown to be a significant source of hepatotoxicity in humans, it can contribute to renal damage through direct (vasoconstriction of renal arteries) as well as indirect effects (through cocaine-induced rhabdomyolysis).
Cocaine discontinuation leads to an unpleasant, though rarely medically concerning, withdrawal syndrome. Nonetheless, DAWN data indicate that up to one-fourth of all drug-related detoxification-related ED visits were attributable to cocaine withdrawal. Patients commonly present with symptoms opposite to those seen with cocaine intoxication, including depression, fatigue, anhedonia, difficulties concentrating, as well as increased sleep and appetite. Patients may also exhibit drug cravings. In some cases, depression and psychomotor retardation observed with cocaine withdrawal may be so severe as to be accompanied by prominent hopelessness and suicidal ideation. In comparison with its behavioral effects, physical signs of cocaine withdrawal are usually mild and clinically unremarkable.
Psychiatric Sequelae of Cocaine Use
Cocaine use has been associated with the development of cocaine use disorder in up to one-sixth of all individuals exposed to the drug. Although euphoria is an intended effect of the drug, patients acutely intoxicated by cocaine may present with symptoms that resemble acute mania, a primary anxiety disorder, or a primary depressive disorder. The most serious psychiatric finding associated with cocaine intoxication is cocaine-induced psychosis, which frequently manifests as visual and auditory hallucinations, paranoid delusions, and (in severe cases) violent behavior. Some studies estimate its prevalence at 80% of all individuals with a cocaine use disorder. While these symptoms resemble those of a primary psychotic process, cocaine-induced psychosis may be differentiated by its transient nature, relative absence of negative symptoms, as well as more prominent visual and tactile hallucinations (e.g., “coke bugs”).
Management
Cocaine intoxication can lead to significant medical as well as psychiatric consequences, and acute management should take both into consideration. As with all acute toxidromes, the ABC (airway, breathing, circulation) of stabilization are essential to initial patient management. Given the stimulant effects of cocaine outlined above, monitoring for tachycardia, hypertension, and associated end-organ damage (e.g., coronary ischemia, stroke) is essential with acute intoxication. Mild-to-moderate tachycardia and hypertension may respond to use of IV benzodiazepines. For refractory or severe hypertension, alpha-adrenergic agents (e.g., phentolamine) are commonly used. The use of beta-blockers in acute cocaine intoxication remains controversial, but this class of medications has been traditionally avoided for concerns of unopposed alpha-adrenergic stimulation and associated increased chances for vasospasm and cardiac ischemia.
Acute psychomotor agitation and anxiety can similarly be managed with benzodiazepines, while antipsychotics may be administered in cases of severe psychosis. In our experience, co-administration of IV lorazepam and IV haloperidol is often beneficial in these situations, with rapid resolution in agitation.
Sub-acute management of cocaine use may involve a brief course of benzodiazepines (for refractory anxiety and insomnia), as well as dopamine antagonists (for residual psychosis). The former should be used judiciously so as to avoid complications related to benzodiazepine misuse (e.g., dependence, diversion).
Longitudinally, cocaine use disorder is primarily managed through behavioral interventions, such as therapy and peer support groups. Most medications (including antidepressants, e.g., citalopram, dopamine antagonists; most anticonvulsants, e.g., carbamazepine, gabapentin; and certain dopamine agonists) have not shown consistent effectiveness in treating cocaine dependence. Disulfiram, varenicline, and naltrexone have also been used, again with mixed results. Agonist substitution therapy with long-acting oral stimulants (e.g., amphetamine) alone, or in combination with topiramate, has shown some promise; however, considerable risks regarding diversion and cardiac safety often present barriers to treatment. A randomized clinical trial (RCT) of topiramate for the treatment of cocaine addiction showed evidence of greater efficacy than placebo at increasing the mean weekly proportion of cocaine non-use days and associated measures of clinical improvement among cocaine-dependent individuals. Various therapeutic approaches have also been utilized to manage cocaine use disorder, including supportive, cognitive-behavioral, and motivational therapies, as well as peer support groups (such as Cocaine Anonymous), with mixed results. The behavioral intervention with the best evidence-based outcomes for the treatment of cocaine is the Matrix Model. This model provides a framework for engaging patients (as they learn about issues critical to addiction and relapse, receive direction and support from a trained therapist, and become familiar with self-help programs). Patients are also monitored closely for drug use through urine testing. Treatment includes elements of relapse prevention, family and group therapies, drug education, and self-help participation. Detailed treatment manuals contain worksheets for individual sessions; other components include family education groups, early recovery skills groups, relapse prevention groups, combined sessions, urine tests, 12-step programs, relapse analysis, and social support groups. A number of studies have demonstrated that participants treated using the Matrix Model show statistically significant reductions in drug and alcohol use, improvements in psychological indicators, and reduced high-risk behaviors associated with HIV transmission.
Amphetamines and Other CNS Stimulants
Amphetamines include a diverse class of CNS stimulants that have been used since antiquity for medicinal, as well as recreational purposes. The practice of chewing Khat leaves in Ethiopia and Yemen, as well as use of the Ephedra sinica plant in ancient China offer some of the earliest examples of amphetamine use. Amphetamine was initially synthesized in 1887, but it was not until the 1930s that these drugs became widely used for treatment of colds and congestion and to promote alertness in battle-fatigued troops during the Second World War. In the 1950s, stimulants re-gained popularity as weight-loss aides, and soon thereafter became widely used as drugs of abuse. Despite increasing efforts to regulate the production and distribution of stimulants, the number of synthetic amphetamine compounds has risen in recent decades, and now includes not only the traditional amphetamines, but also methamphetamine (crystal meth), MDMA (ecstasy), and synthetic cathinones (bath salts).
Ongoing popularity of CNS stimulants as drugs of abuse is reflected in the epidemiologic data. According to data from DAWN, the number of ED visits related to non-medical use of CNS stimulants among adults aged 18 to 34 increased from 5605 in 2005 to 22,949 in 2011. As stimulants can mask the sedating effects of alcohol, the two compounds are commonly used in conjunction, and about 30% of all ED visits related to non-medical CNS stimulant use also involve alcohol. Methamphetamine has been hailed as the fastest rising drug of abuse worldwide, and an estimated 4.7 million Americans are reported to have tried the drug. As the number of various amphetamines is considerable, and no toxicology tests will reliably screen for all compounds, it is essential that consulting physicians be familiar with the pharmacology of these drugs so as to be prepared to recognize the drug-related toxidrome and to provide appropriate management.
Pharmacology and Mechanism of Action
Similar to cocaine, most amphetamines exert their effect through stimulation of CNS alpha- and beta-adrenergic receptors, leading to a toxidrome marked by increased alertness, euphoria (or in severe cases anxiety and agitation), tachycardia, hypertension, and mydriasis. The specific mechanism of action is often drug-dependent, but most CNS stimulants propagate the release of amine neurotransmitters, including dopamine, serotonin and norepinephrine, although some may also act through re-uptake inhibition. The propensity of a specific amphetamine drug for a specific set of neurotransmitters may also differ, and this may in part be reflected by significant variability in clinical findings observed with these compounds. As an example, methamphetamine exerts its effect by increasing dopamine availability in the synaptic cleft through promoting the release of the neurotransmitter, blocking its re-uptake and degradation, and increasing the activity of enzymes necessary in dopamine synthesis.
Acute intoxication on amphetamine compounds closely resembles that of cocaine, and is marked by central and peripheral hyperactivity, including physiologic changes (tachycardia, hypertension, hyperthermia, diaphoresis, and mydriasis) and mental status changes (euphoria, as the intended effect; anxiety, agitation, and violent behavior, as unintended effects). Cardiac problems, including chest pain, cardiac ischemia, and arrhythmias are rarely seen, but when present can lead to serious complications. Signs of CNS hyperexcitability, including seizures, tremors, and myoclonus, may occur with acute intoxication. Electrolyte abnormalities, related to dehydration due to reduced intake and insensible losses through hyperthermia, can lead to significant complications (including cardiac arrhythmias and renal failure). In particular, use of ecstasy (MDMA) has been linked with severe hyponatremia (in the setting of free-water losses) leading to obtundation and potentially fatal cerebral edema.
Psychiatric Sequelae of Amphetamine Use
Acute intoxication with amphetamines may present in a fashion similar to a number of primary psychiatric conditions, including panic attacks, mania (with decreased need for sleep, excitability, distractibility, euphoria, increased sexuality), or severe psychosis. Acute onset of symptoms without a prodrome characteristic for a primary psychiatric disorder, presence of visual and tactile hallucinations, a positive toxicology screen, and a history of drug use may all provide clues towards a secondary etiology of symptoms. Amphetamine-associated psychosis may persist considerably beyond the initial drug use, and may even recur during periods of abstinence from the drug. Physical examination may offer invaluable findings, including evidence of pupillary dilatation, poor dentition (“meth teeth” due to chronic dry mouth) and excoriations consistent with increased itching/skin picking. Furthermore, up to 30% to 40% of all patients who use amphetamines will have a co-morbid primary psychiatric disorder, including primary psychotic disorder (28.6%), primary mood disorder (32.3%), primary anxiety disorder (26.5%), or ADHD (30% to 40%).
Depressive symptoms are commonly seen with discontinuation of the drug, and may be severe enough to meet the diagnostic criteria for major depressive disorder. While amphetamine discontinuation does not lead to a life-threatening withdrawal, it is important to assess the patient for presence of depression and even consider psychiatric hospitalization in severe cases.
Amphetamine use has been associated with deficits in episodic memory, executive functioning, language and motor skills, although the clinical relevance of these findings remains uncertain. Some of the changes are thought to be related to amphetamine-induced CNS toxicity. Animal research data have shown that methamphetamine use increases the permeability of blood–brain barrier (most importantly at the hippocampus), and may play a direct neurotoxic role through excitotoxic mechanisms (e.g., excessive glutamate release) and oxidative stress.
Management
Acute amphetamine intoxication is managed in a manner similar to that of acute cocaine intoxication. IV benzodiazepines are commonly used as a first-line agent for both management of agitation/anxiety, and for centrally mediated hypertension and tachycardia. Alpha-blockers, such as phentolamine, have been preferred for severe hypertension refractory to benzodiazepine treatment, while beta-blockers have been avoided for fear of exacerbating cardiovascular toxicity.
No medications have shown consistent efficacy for long-term management of stimulant use disorder. This noted, both bupropion and mirtazapine have been studied in methamphetamine users, and show some promise, especially in milder cases, or if used in conjunction with therapy. In particular, the data (albeit limited) appear to favor mirtazapine—a 12-week trial of mirtazapine versus placebo in methamphetamine-dependent men-who-have-sex-with-men showed that the mirtazapine-treated group of patients was less likely to submit positive urine drug screens compared with the group receiving placebo. The Matrix Model has shown some promise as a therapeutic approach to long-term behavioral management of patients with stimulant use disorders.
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