15 Mladen Nisavic, M.D

Patients With Substance Use Disorders 15 Mladen Nisavic, M.D. Shamim H. Nejad, M.D.

OVERVIEW readiness for recovery), identification of outpatient addiction resources, and use of medications to reduce craving and to Without a doubt, substance use disorders (SUDs) present maintain recovery. The chronic, relapsing, nature of sub- one of the gravest difficulties currently facing the United stance use may inspire resignation and hopelessness in States healthcare system. Over the past two decades, the consulting clinicians, leading to a misperception that the number of patients treated for substance use-related problems consultation is unnecessary, or even futile. Because most in the United States has grown steadily, and over the past clinicians fail to appreciate that the relapse rate for other 5 years it has reached epidemic proportions. Data from the common chronic medical disorders (e.g., diabetes, hyperten- Centers for Disease Control and Prevention (CDC) indicate sion, asthma) exceeds that for SUDs, they do not treat that in the 10 years between 2004 and 2014, the mortality substance abuse patients with comparable therapeutic dili- rates attributed to drug overdoses increased by 137%, gence.3 The Massachusetts General Hospital (MGH) has including a staggering 200% increase in the rate of overdose dedicated considerable effort and resources to adequately deaths attributed to opioids. The increased mortality rates address the substance use epidemic within our local com- were independent of sex, age group, or ethnicity, and were munities, starting with a hospital-wide effort to ensure that evident across the country. In fact, the CDC estimates that problems related to substance use are addressed with the nearly half a million persons in the United States died from same degree of compassion and persistence directed at other drug overdoses between 2000 and 2014, and that drug-related common relapsing medical disorders. Medical and surgical fatalities were one and a half times higher than deaths from hospitalizations often provide extended periods during which motor vehicle crashes in 2014.1 Up to 80% of all drug-related patients are separated from their substance use, and thus fatalities appear to be unintentional, with 13% attributed hospitalization may present a unique opportunity to engage to suicide, and the remainder classified as undetermined. the patient in meaningful interventions. The increase in drug use has also led to increased utiliza- tion 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 CASE 1 were related to drug use—a 100% increase over their 2004 Mr. B, a 36-year-old homeless man with a history of sub- data. Of these, nearly 2.5 million ED visits were attributed stance use and abuse (benzodiazepines, opiates, and to medical emergencies related to drug abuse. stimulants), was admitted to the vascular surgery service Clinical presentations in this domain are also becoming with ischemia to his right hand and forearm. The injury more complex. Of the 2.5 million ED visits identified by was sustained when he relapsed on “heroin” (after 2 months DAWN/SAMHSA in 2011, nearly one-half involved of recovery), and became obtunded with a protracted complications related to use of prescription medications, period of immobility. An initial urine toxicology screen with the remainder being attributed to use of non-prescription was positive for benzodiazepines and opioids, with further illicit drugs. While the use of opioids, marijuana, and cocaine toxicology testing that confirmed the presence of clonaz- are seen most commonly, more than 50% of the patients epam, methadone, and fentanyl. Psychiatric consultation present with co-ingestion of multiple substances, and there was requested to assist with pain management and to has been an increase in use of CNS stimulants, “club drugs,” provide assistance with addiction recovery treatment and hallucinogens.2 referral and resources. Successful treatment of this expanding group of patients On interview, Mr. B was alert, oriented, lucid, and requires that clinicians improve their management skills for forthcoming. He reported surprise, and then frank fear, SUDs and their sequelae. This involves timely and correct that he “ended up this way—after all I only used once.” He diagnosis of the substance use problem, recognition of also appeared surprised that the toxicology screen revealed key symptoms associated with intoxication or acute evidence of fentanyl and benzodiazepines, as he was discontinuation/withdrawal, and appropriate initial manage- “certain” he used heroin. He complained of pain, despite ment and treatment. It also involves meaningful engagement being on his methadone maintenance (75 mg/day), and (including motivational enhancement techniques to assess 149 Downloaded for Anonymous User (n/a) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 16, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 150 Chapter 15 Patients With Substance Use Disorders

neutralization by the acidic milieu of the stomach). More expressed concern that his pain would be under-treated commonly, cocaine is injected, insufflated or inhaled (as because of his history of substance use. His mood was “crack”) as the latter methods greatly increase the bioavail- appropriate to the clinical context: there was no evidence ability of the drug. of depression. Following initial stabilization, Mr. B underwent amputa- Pharmacology and Mechanism of Action tion of his right forearm and hand. During the perioperative Cocaine increases the monoamine neurotransmitter activ- period, he received a combination of long-acting opioids ity in the central nervous system (CNS) by blocking the for basal analgesic control, as well as short-acting opioids pre-synaptic re-uptake transporters for dopamine, norepi- for breakthrough pain. His methadone dose was increased nephrine, and serotonin. Given the potent effects of cocaine to 90 mg/day, and was split into three-times-a-day dosing on dopamine’s availability within the CNS, much of the to optimize pain management. His short-acting opioids drug’s stimulant and addictive effects have been ascribed (intravenous [IV], then oral hydromorphone) were tapered to its effects on the corticomesolimbic dopamine reward gradually over 2 weeks while he remained in the inpatient circuits.5,6 In addition to these effects, cocaine also acts by setting. blocking voltage-gated sodium ion channels, an action that With improved pain control, Mr. B more readily engaged accounts for its effect as a local anesthetic and contributes in readiness work via motivational interviewing and he to its cardiac toxicity. accepted addiction recovery services. He identified The route of administration greatly influences the methadone maintenance as a key element to his recovery bioavailability of the drug, including its onset and duration and noted no cravings on the higher dose of his medication. of intoxication. Smoking (i.e., inhalation) and IV use gener- He found inspiration in his survival, and despite grieving ally lead to near instantaneous (seconds to minutes) effects, the loss of his limb, expressed a strong readiness to maintain and most patients note that the drug’s effects wear off within recovery. He worked closely with the consultation team 30 minutes. Intranasal administration results in slower onset to identify triggers for relapse and secured a safe disposition of symptoms (within 30 minutes) and the effects of the drug plan. By the end of his 2-week hospital stay, Mr. B held are similarly extended to up to 1 hour. regular meetings with Narcotics Anonymous (NA) peers Cocaine is commonly co-administered with alcohol, in the hospital. He maintained continuous contact with which leads to the formation of cocaethylene, a compound his methadone provider and allowed the consultation team with stimulant effects similar to that of cocaine, albeit with to share their impressions with the clinic. a longer half-life. This compound has also been noted to Mr. B was discharged to his parents’ home, with a plan to carry greater cardiac toxicity compared with cocaine alone. follow-up with his methadone clinic and NA. He expressed Cocaine is extensively metabolized by the liver, and its (appropriate) anxiety on discharge, as he readily admitted metabolites are eliminated in the urine, most commonly as that the road ahead of him would be challenging, but also benzoylecgonine. This metabolite (rather than the parent noted hope and readiness to battle his addiction. 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 STIMULANTS no common false positives for urine cocaine screen. Cocaine Cocaine intoxication is associated with potent stimulant effects, including increased energy and alertness, bright (to Cocaine is a tropane alkaloid naturally found in leaves of frankly euphoric) affect, insomnia, as well as anorexia. Similar the Erythroxylum coca plant, a bush native to the Andes to other stimulants, cocaine is associated with an intensely Mountains region of South America. To this day, leaves of pleasurable state and is commonly used to potentiate sexual the plant continue to be used by the indigenous people activity. With higher doses, the unintended effects of cocaine (typically chewed), for their anesthetic, stimulant, and may become apparent, including anxiety and panic attacks, hunger-suppressant effects. Over the past two centuries, restlessness, agitation, and violent behavior, as well as the discovery of methods to reliably isolate the alkaloid psychosis (manifesting as paranoid ideation, hallucinations, combined with the ever-increasing demand for the com- or delusional thinking). Signs of adrenergic hyperactivity pound, has led to cocaine becoming one of the most (e.g., hyperreflexia, tachycardia, diaphoresis, mydriasis) may commonly abused drugs worldwide. An estimated 17 million also be seen. More severe symptoms (e.g., hyperpyrexia, people (about 0.4% of the world population) have used hypertension, cocaine-induced vasospastic events, such as cocaine, a number only surpassed by cannabis and alcohol.4 stroke or myocardial infarction) are relatively rare among The widespread use of the drug, combined with potent recreational users but are seen more commonly in patients stimulant effects has led to cocaine being one of the leading who present to the ED for cocaine-related issues. Patients drugs of abuse (in terms of the frequency of ED contacts, may manifest motor signs of CNS excitability, including general hospital admissions, violence, and other social tremor, myoclonus, and stereotyped movements of the problems). The DAWN ED data for 2011 reported 505,224 mouth, face, or extremities (e.g., skin picking, “crack ED visits related to cocaine, compared with 455,668 ED dancing,” “boca torcida”). Infrequently, seizures may occur, visits for marijuana, and 258,482 ED visits related to heroin even with first time use of the drug—most commonly these use—a staggering 40% of all ED visits related to illicit drug are manifest as generalized tonic-clinic seizures within the use.2 Traditionally, the coca leaf is chewed to release the first 90 minutes after drug use. cocaine alkaloid, yet isolated cocaine is rarely ingested Given its potent effects on the central and peripheral (commonly with a highly alkaline compound to prevent monoamine neurotransmitter systems, it is not surprising

Downloaded for Anonymous User (n/a) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 16, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 15 Patients With Substance Use Disorders 151 that cocaine has significant effects on most organ systems. In take both into consideration. As with all acute toxidromes, addition to stimulant and pro-ictal effects described previously, the ABC (airway, breathing, circulation) of stabilization are cocaine has been associated with increased rates of hemor- essential to initial patient management. Given the stimulant rhagic and ischemic stroke, an effect postulated to be due to effects of cocaine outlined above, monitoring for tachycardia, increased heart rate and blood pressure (due to sympathetic hypertension, and associated end-organ damage (e.g., coro- nervous system (SNS) activation), cerebral vasoconstriction, nary ischemia, stroke) is essential with acute intoxication. and vasospasm. Cocaine similarly increases risk for ischemic Mild-to-moderate tachycardia and hypertension may respond cardiac phenomena, and chest pain is one of the most frequent to use of IV benzodiazepines. For refractory or severe complaints in cocaine users who seek medical attention. hypertension, alpha-adrenergic agents (e.g., phentolamine) Cocaine use has been associated with increased heart rate and are commonly used. The use of beta-blockers in acute cocaine blood pressure (via increased peripheral adrenergic activity), as intoxication remains controversial, but this class of medica- well as vasoconstriction, both of which lead to reduced cardiac tions has been traditionally avoided for concerns of unop- oxygen availability and increased risk for cardiac complications, posed alpha-adrenergic stimulation and associated increased including myocardial infarction. Furthermore, cocaine action chances for vasospasm and cardiac ischemia. as a sodium channel-blocker leads to an increased risk for Acute psychomotor agitation and anxiety can similarly cardiac arrhythmias, and even sudden death. be managed with benzodiazepines, while antipsychotics may Intranasal cocaine use has been associated with rhinitis, be administered in cases of severe psychosis. In our experi- sinusitis, and in severe cases, perforation of the nasal septum. ence, co-administration of IV lorazepam and IV haloperidol Inhalation use leads to common respiratory symptoms, is often beneficial in these situations, with rapid resolution including shortness of breath, wheezing, and cough, but in agitation. may also cause bronchitis, pulmonary edema, hemorrhage, Sub-acute management of cocaine use may involve a and even a pneumothorax. While cocaine has not been brief course of benzodiazepines (for refractory anxiety and shown to be a significant source of hepatotoxicity in humans, insomnia), as well as dopamine antagonists (for residual it can contribute to renal damage through direct (vasocon- psychosis). The former should be used judiciously so as to striction of renal arteries) as well as indirect effects (through avoid complications related to benzodiazepine misuse (e.g., cocaine-induced rhabdomyolysis). dependence, diversion). Cocaine discontinuation leads to an unpleasant, though Longitudinally, cocaine use disorder is primarily managed rarely medically concerning, withdrawal syndrome. Nonethe- through behavioral interventions, such as therapy and peer less, DAWN data indicate that up to one-fourth of all support groups. Most medications (including antidepressants, drug-related detoxification-related ED visits were attributable e.g., citalopram, dopamine antagonists; most anticonvulsants, to cocaine withdrawal. Patients commonly present with e.g., carbamazepine, gabapentin; and certain dopamine symptoms opposite to those seen with cocaine intoxication, agonists) have not shown consistent effectiveness in treating including depression, fatigue, anhedonia, difficulties con- cocaine dependence. Disulfiram, varenicline, and naltrexone centrating, as well as increased sleep and appetite. Patients have also been used, again with mixed results. Agonist may also exhibit drug cravings. In some cases, depression substitution therapy with long-acting oral stimulants (e.g., and psychomotor retardation observed with cocaine with- amphetamine) alone, or in combination with topiramate, drawal may be so severe as to be accompanied by prominent has shown some promise; however, considerable risks hopelessness and suicidal ideation. In comparison with its regarding diversion and cardiac safety often present barriers behavioral effects, physical signs of cocaine withdrawal are to treatment.7 A randomized clinical trial (RCT) of topira- usually mild and clinically unremarkable. mate for the treatment of cocaine addiction showed evidence of greater efficacy than placebo at increasing the mean weekly Psychiatric Sequelae of Cocaine Use proportion of cocaine non-use days and associated measures Cocaine use has been associated with the development of of clinical improvement among cocaine-dependent individu- cocaine use disorder in up to one-sixth of all individuals als.8 Various therapeutic approaches have also been utilized exposed to the drug. Although euphoria is an intended effect to manage cocaine use disorder, including supportive, of the drug, patients acutely intoxicated by cocaine may cognitive-behavioral, and motivational therapies, as well as present with symptoms that resemble acute mania, a primary peer support groups (such as Cocaine Anonymous), with anxiety disorder, or a primary depressive disorder. The most mixed results. The behavioral intervention with the best serious psychiatric finding associated with cocaine intoxica- evidence-based outcomes for the treatment of cocaine is tion is cocaine-induced psychosis, which frequently manifests the Matrix Model. This model provides a framework for as visual and auditory hallucinations, paranoid delusions, engaging patients (as they learn about issues critical to and (in severe cases) violent behavior. Some studies estimate addiction and relapse, receive direction and support from its prevalence at 80% of all individuals with a cocaine use a trained therapist, and become familiar with self-help disorder. While these symptoms resemble those of a primary programs). Patients are also monitored closely for drug use psychotic process, cocaine-induced psychosis may be dif- through urine testing. Treatment includes elements of relapse ferentiated by its transient nature, relative absence of negative prevention, family and group therapies, drug education, symptoms, as well as more prominent visual and tactile and self-help participation. Detailed treatment manuals hallucinations (e.g., “coke bugs”). contain worksheets for individual sessions; other components include family education groups, early recovery skills groups, Management relapse prevention groups, combined sessions, urine tests, Cocaine intoxication can lead to significant medical as well 12-step programs, relapse analysis, and social support groups. as psychiatric consequences, and acute management should A number of studies have demonstrated that participants

Downloaded for Anonymous User (n/a) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 16, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 152 Chapter 15 Patients With Substance Use Disorders treated using the Matrix Model show statistically significant Acute intoxication on amphetamine compounds closely reductions in drug and alcohol use, improvements in psy- resembles that of cocaine, and is marked by central and chological indicators, and reduced high-risk behaviors peripheral hyperactivity, including physiologic changes associated with HIV transmission.9 (tachycardia, hypertension, hyperthermia, diaphoresis, and mydriasis) and mental status changes (euphoria, as the Amphetamines and Other CNS Stimulants intended effect; anxiety, agitation, and violent behavior, as unintended effects). Cardiac problems, including chest pain, Amphetamines include a diverse class of CNS stimulants cardiac ischemia, and arrhythmias are rarely seen, but when that have been used since antiquity for medicinal, as well present can lead to serious complications. Signs of CNS as recreational purposes. The practice of chewing Khat hyperexcitability, including seizures, tremors, and myoclonus, leaves in Ethiopia and Yemen, as well as use of the Ephedra may occur with acute intoxication. Electrolyte abnormalities, sinica plant in ancient China offer some of the earliest related to dehydration due to reduced intake and insensible examples of amphetamine use. Amphetamine was initially losses through hyperthermia, can lead to significant complica- synthesized in 1887, but it was not until the 1930s that tions (including cardiac arrhythmias and renal failure). In these drugs became widely used for treatment of colds and particular, use of ecstasy (MDMA) has been linked with congestion and to promote alertness in battle-fatigued troops severe hyponatremia (in the setting of free-water losses) during the Second World War. In the 1950s, stimulants leading to obtundation and potentially fatal cerebral edema. re-gained popularity as weight-loss aides, and soon thereafter became widely used as drugs of abuse. Despite increasing Psychiatric Sequelae of Amphetamine Use efforts to regulate the production and distribution of Acute intoxication with amphetamines may present in a stimulants, the number of synthetic amphetamine compounds fashion similar to a number of primary psychiatric condi- has risen in recent decades, and now includes not only the tions, including panic attacks, mania (with decreased need traditional amphetamines, but also methamphetamine (crystal for sleep, excitability, distractibility, euphoria, increased meth), MDMA (ecstasy), and synthetic cathinones (bath sexuality), or severe psychosis. Acute onset of symptoms salts). without a prodrome characteristic for a primary psychiatric Ongoing popularity of CNS stimulants as drugs of abuse disorder, presence of visual and tactile hallucinations, a is reflected in the epidemiologic data. According to data positive toxicology screen, and a history of drug use may from DAWN, the number of ED visits related to non-medical all provide clues towards a secondary etiology of symptoms. use of CNS stimulants among adults aged 18 to 34 increased Amphetamine-associated psychosis may persist considerably from 5605 in 2005 to 22,949 in 2011. As stimulants can beyond the initial drug use, and may even recur during mask the sedating effects of alcohol, the two compounds periods of abstinence from the drug. Physical examination are commonly used in conjunction, and about 30% of all may offer invaluable findings, including evidence of pupillary ED visits related to non-medical CNS stimulant use also dilatation, poor dentition (“meth teeth” due to chronic dry involve alcohol.2 Methamphetamine has been hailed as the mouth) and excoriations consistent with increased itching/ fastest rising drug of abuse worldwide, and an estimated skin picking. Furthermore, up to 30% to 40% of all patients 4.7 million Americans are reported to have tried the drug. who use amphetamines will have a co-morbid primary As the number of various amphetamines is considerable, psychiatric disorder, including primary psychotic disorder and no toxicology tests will reliably screen for all compounds, (28.6%), primary mood disorder (32.3%), primary anxiety it is essential that consulting physicians be familiar with the disorder (26.5%), or ADHD (30% to 40%).11 pharmacology of these drugs so as to be prepared to rec- Depressive symptoms are commonly seen with discon- ognize the drug-related toxidrome and to provide appropriate tinuation of the drug, and may be severe enough to meet management. the diagnostic criteria for major depressive disorder. While amphetamine discontinuation does not lead to a life- Pharmacology and Mechanism of Action threatening withdrawal, it is important to assess the patient Similar to cocaine, most amphetamines exert their effect for presence of depression and even consider psychiatric through stimulation of CNS alpha- and beta-adrenergic hospitalization in severe cases. receptors, leading to a toxidrome marked by increased Amphetamine use has been associated with deficits in alertness, euphoria (or in severe cases anxiety and agitation), episodic memory, executive functioning, language and motor tachycardia, hypertension, and mydriasis. The specific skills, although the clinical relevance of these findings remains mechanism of action is often drug-dependent, but most uncertain. Some of the changes are thought to be related CNS stimulants propagate the release of amine neurotrans- to amphetamine-induced CNS toxicity. Animal research mitters, including dopamine, serotonin and norepinephrine, data have shown that methamphetamine use increases the although some may also act through re-uptake inhibition. permeability of blood–brain barrier (most importantly at The propensity of a specific amphetamine drug for a specific the hippocampus), and may play a direct neurotoxic role set of neurotransmitters may also differ, and this may in through excitotoxic mechanisms (e.g., excessive glutamate part be reflected by significant variability in clinical findings release) and oxidative stress.12 observed with these compounds. As an example, methamphetamine exerts its effect by increasing dopamine availability Management in the synaptic cleft through promoting the release of the Acute amphetamine intoxication is managed in a manner neurotransmitter, blocking its re-uptake and degradation, similar to that of acute cocaine intoxication. IV benzodiaz- and increasing the activity of enzymes necessary in dopamine epines are commonly used as a first-line agent for both synthesis.10 management of agitation/anxiety, and for centrally mediated

Downloaded for Anonymous User (n/a) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 16, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 15 Patients With Substance Use Disorders 153 hypertension and tachycardia. Alpha-blockers, such as receptors in the neocortical pyramidal cells.14 Sympatho- phentolamine, have been preferred for severe hypertension mimetic effects, including pupillary constriction, tachycardia, refractory to benzodiazepine treatment, while beta-blockers hypertension, and hyperthermia are seen, though commonly have been avoided for fear of exacerbating cardiovascular they are not as severe as with stimulants and cocaine. A toxicity. brief overview of the most-commonly used hallucinogenic No medications have shown consistent efficacy for compounds is presented below: long-term management of stimulant use disorder. This noted, both bupropion and mirtazapine have been studied • Lysergic acid diethylamine (LSD): LSD is commonly used in methamphetamine users, and show some promise, as a pill, or in liquid form (e.g., added to blotter paper). especially in milder cases, or if used in conjunction with Its intended effect is to produce visual illusions, often therapy. In particular, the data (albeit limited) appear to characterized by intense colors and distortions, as well favor mirtazapine—a 12-week trial of mirtazapine versus as emotional changes marked by euphoria and deper- placebo in methamphetamine-dependent men-who-have- sonalization. Time perception may also be distorted, sex-with-men showed that the mirtazapine-treated group with users often describing experience of reality as if in of patients was less likely to submit positive urine drug “slow motion.” Most recreational users will maintain screens compared with the group receiving placebo.13 The awareness that their experiences are drug-induced. Matrix Model has shown some promise as a therapeutic Unintended effects are commonly seen with ingestion approach to long-term behavioral management of patients of higher doses of LSD and may include intense dys- with stimulant use disorders. phoria, anxiety, or agitation. Panic, overwhelming fear, and even paranoia are classically described, and patients HALLUCINOGENS may lack the awareness that their bad trip is drug-induced. This, in turn, may cause impairment in judgment and Hallucinogens comprise a broad and diverse class of drugs lead to unintentional injury or even death. of abuse, the unifying effect of which is their intended mode • Dextromethorphan (DXM): DXM is easily available in of action—to produce alteration in thinking, sensation, and various cough remedies, and is most commonly used in reality perception. Widely used across many cultures, this the adolescent population (“robo tripping”). The intended group includes natural (e.g., hallucinogenic mushrooms, effect is to produce a trance-like dissociative state, though Peyote, Salvia divinorum) as well as synthetic compounds overdoses may also lead to paranoia, hallucinations, and (e.g., lysergic acid diethylamine [LSD]). While these in severe cases, coma. As DMX is commonly sold mixed compounds have traditionally been used to heighten spiritual/ with other compounds (including anticholinergic religious experiences, most modern hallucinogen use is compounds and acetaminophen), all cases of suspected recreational, with the desired intent to produce perceptual DMX intoxication should be monitored for potential alterations, including hallucinations or illusions, or to additional toxicity related to these compounds. enhance emotional states. Commonly, the term “tripping” • Mescaline: Mescaline is the active ingredient found in is used to describe acute intoxication with a hallucinogen, the peyote cactus (Lophophora williamsii), a plant native with the term “bad trip” used to describe acute intoxication to the south-west United States. It is ingested as a tea marked by unintended sequelae (including anxiety, agitation, prepared from the plant or as dried “buttons.” Its effect and paranoia). is similar to that of LSD, though generally milder. While LSD, synthesized in 1938 by Albert Hofmann, was the mescaline can be legally used by the members of Native first synthetic hallucinogen and one of the best studied American Church, reflecting its traditional use in religious drugs in this class. Initially marketed as an anesthetic and ceremonies, all other use of the compound is considered adjunct for psychotherapy, the drug became popular as a illegal. psychedelic drug in the 1960s, and was listed as a drug of • Psilocybin: This hallucinogen compound is found in a abuse, by 1966. Over the past two decades, use of LSD number of mushroom species native to the Pacific has diminished, as more users turn to alternative (and Northwest and southern United States, commonly known more readily available) compounds, including synthetic by their street name of “magic mushrooms” or “shrooms.” cannabinoids, phencyclidine (PCP), ketamine, and naturally The mushrooms are commonly dried (to aid with storage/ occurring hallucinogen compounds. transport) and consumed with food. The intended effect Hallucinogen use is often sporadic, and relatively uncom- is similar to LSD, though again milder, and may be mon when compared with opioids and stimulants. Approxi- preceded by significant gastrointestinal symptoms (nausea, mately 4.2 million individuals in the United States used vomiting) immediately upon consuming the compound. hallucinogens in 2014, and these drugs account for only Accidental ingestion of otherwise toxic mushrooms can 7% of all United States ED visits related to illicit drugs.2 occur, as can unintended ingestion of other hallucinogens (e.g., lacing edible mushrooms with LSD). Pharmacology and Mechanism of Action • Salvinorin A: This compound is a kappa opioid agonist found in the leaves of the Salvia divinorum plant. It can Given the sheer number and diversity of compounds be freely obtained through the Internet, and is not a characterized as hallucinogens, a detailed account of specific federally controlled substance in the United States, biochemical properties of each is beyond the scope of this further contributing to its rising popularity. Much like chapter. Nonetheless, most of these compounds exert other hallucinogens, it can produce sensory distortions, their effect through modulation of serotonin, dopamine, although most users primarily reflect on emotional and glutamate—in particular through binding the 5-HT2A changes, including elevated mood, euphoria, as well as

introspection. It has a relatively short duration of action it often arises weeks to months after the discontinuation of (generally 1–2 hours), especially when compared with the drug. other hallucinogenic compounds. Serotonin syndrome has been described with a number • Phencyclidine (PCP, Angel dust): PCP is a non-competitive of hallucinogens, including LSD, and may occur in patients antagonist of N-methyl-D-aspartate (NDMA) receptors, who take hallucinogens while also on other serotonergic initially developed as an anesthetic agent. The drug can agents, including SSRIs, MAOIs, or lithium. be insufflated, smoked, ingested, or used intravenously. At low doses, PCP produces a sense of detachment from one’s surroundings and may lead to dissociation as well CANNABIS AND SYNTHETIC as amnesia. At higher doses, PCP intoxication may present CANNABINOIDS with markedly bizarre (and often severely violent) behavior, hallucinations, and even catatonia. Physical Cannabis remains the most commonly used drug of abuse examination may elicit nystagmus (vertical and horizon- worldwide, with an estimated 2.5% of the world population tal), as well as signs of sympathomimetic toxicity (147 million people) having used the drug in 2014.15 Cannabis (including mydriasis). Severe agitation is often a present- use is particularly high in the adolescent and young adult ing problem for PCP-intoxicated patients, and appropriate populations across the United States. While cannabis remains measures to ensure the safety of healthcare staff must illegal on the federal level, a growing number of states have be considered when dealing with this toxidrome. passed legislation that legalizes possession and medical use • Ketamine (Special K): Structurally similar to PCP, ketamine of marijuana. Long-term effects of liberalization of marijuana exerts its effect chiefly through NMDA receptor antago- use on the prevalence and severity of cannabis use disorder nism. Dependent on dosage, ketamine is capable of remain to be seen. producing a wide variety of CNS effects, ranging from Besides cannabis, there has been a steady increase in the euphoria and dissociation to agitation, hallucinations, availability and use of synthetic cannabinoids over the last and coma. When used in the hospital setting, ketamine two decades. Commonly sold as “herbal remedies” and is a safe anesthetic, leading to conscious sedation and “natural products” these compounds go by a variety of street anesthesia. As a drug of abuse, ketamine is utilized to names, the most common of which are “K2” and “Spice.” alter sensory perceptions, diminish alertness, and cause While synthetic cannabinoid intoxication resembles a mild sedation. With overdose, patients may present with marijuana “high,” these drugs can be incrementally more obtundation or even coma, while emergence from seda- potent and are often associated with pronounced psychiatric tion may be marked by dissociation, confusion, and and neurologic pathology. As the number of synthetic agitation. Respiratory and cardiovascular support is thus cannabinoids available far exceeds the detection ability of an essential component of acute management of ketamine most common drug assays, familiarity with this drug class intoxication. While ketamine overdose can be fatal, most and its effects remains essential. complications have been described in patients co-ingesting drugs (e.g., stimulants or other sedatives). Physical exam Pharmacology and Mechanism of Action may show nystagmus (though less common than with PCP), increased muscle tone, and pupillary dilatation. Recreationally, cannabis is used in a variety of modes, Chronic ketamine use can cause ketamine-induced including most commonly through inhalation and ingestion. ulcerative cystitis, which presents as incontinence, The chemical exerts CNS effects primarily through the hematuria, and decreased bladder compliance/volume. cannabinoid receptor (CB-1) found in the basal ganglia, substantia nigra, cerebellum, hippocampus, and cerebral Psychiatric Sequelae and Management cortex. CB-1 activation is associated with inhibition of release of several neurotransmitters including acetylcholine, glu- Acute intoxication with hallucinogens may present in a tamate, GABA, norepinephrine, and dopamine. Synthetic fashion similar to mania (euphoria, overwhelming sense of cannabinoids act on the same receptors as cannabis, but well-being), as well as psychosis (given sensory mispercep- may differ in their potency (up to 800 times greater) and tions). Prominent visual phenomena, patient’s awareness thus their clinical effects, because of differences in binding that the symptoms are drug-induced, dissociative experiences, strength and affinity. Some of the synthetic cannabinoids and distorted sense of time may all point towards acute have been shown to interact with other receptors, including intoxication. The presence of severe vital sign changes is NDMA and serotonin receptors. uncommon with these drugs, and if seen should raise concerns for co-ingestion. Containment and safety may be Psychiatric Sequelae of Cannabis Use the only interventions warranted with milder cases of intoxication, though IV benzodiazepines co-administered Recreational cannabis use is seldom associated with medically with dopamine antagonists have been used to manage the significant side effects. Most cases of mild intoxication agitated delirium observed in severe cases. present with CNS depression (e.g., somnolence), while While hallucinogens are not known to induce primary severe cases are often accompanied by unintended behavioral psychosis, they may unmask latent psychotic illness, as changes, including anxiety, dysphoria, or even agitation. well as lead to brief psychotic episodes (commonly lasting Physical examination is classically notable for dry mouth, days to a week). Psychiatric containment may be warranted conjunctival injection, increased appetite (“munchies”), in these cases. Patients may also describe “flashback” experi- slurring of speech, and ataxia/nystagmus. Hyperemesis may ences similar to those that develop with acute intoxication; be observed, often with chronic cannabis use, and may be

Downloaded for Anonymous User (n/a) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 16, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Chapter 15 Patients With Substance Use Disorders 155 indicative of cannabis hyperemesis syndrome. Classically, familiarity with medications used to manage sequelae of patients will report a pattern of chronic cannabis use, cyclical both, is an essential skill of acute inpatient management. episodes of nausea/vomiting, and symptom relief with hot Lastly, efforts should be made to ensure that all patients showers. receive appropriate longitudinal assistance with their drug Synthetic cannabinoids may present with more pro- use, including maintenance opioid treatment strategies, nounced symptoms compared with cannabis, including medication-assisted strategies for abstinence, expanded access delirium, psychosis, severe psychomotor agitation, and to naloxone, and behavioral treatment resources. (rarely) seizures. These drugs have also been associated with higher rates of cardiovascular and CNS toxicity. Pharmacology and Mechanism of Action Management All opioid compounds exert their effect through interaction with one of three opioid receptor classes (mu, kappa, delta). Most cases of marijuana intoxication are mild and generally Structurally, all opioid receptors are coupled to G proteins, self-limited. Most patients respond to supportive measures which in turn activate second-messenger pathways in the that target reduction of the level of stimulation and reas- target cell, including cAMP and calcium-mediated pathways. surance. Severe or persisting cases should raise concerns Although the opioid receptors are abundant throughout for exposure to synthetic cannabinoids or alternative psy- the central and peripheral nervous system, the distribution choactive compounds. As with stimulants, use of short-acting of specific receptor subtypes, the type of second-messenger benzodiazepines may reduce symptoms of anxiety that are pathway, and downstream effect on neurotransmitter release often seen with the acute toxidrome. Synthetic cannabinoids is markedly variable from site to site and accounts for the may present with severe agitation, and thus may require wide range of clinical effects observed with opiates. Activation considerably higher doses of benzodiazepines to achieve of mu receptors in the CNS is associated with euphoria sedation. Monitoring and prompt management of medical and reward pathway activation (via dopamine increase in sequelae is essential, including assessment of electrolyte the mesolimbic system), anxiolysis (via noradrenergic neurons abnormalities (related to insensible fluid losses and rhab- in locus ceruleus), and analgesia (via inhibition of nociceptive domyolysis), hyperthermia, and monitoring for seizures. In information). Central mu receptor activation is also respon- most severe cases, patients will warrant inpatient medical sible for respiratory depression and sedation, while the or psychiatric admission for assistance with symptom stimulation of peripheral mu receptors results in cough management. suppression and gastrointestinal dysmotility. Mioisis, a classic sign of opioid intoxication, is mediated through kappa 16 HEROIN AND OTHER OPIOIDS receptor activation. Opiates are some of the most important medicinal com- Management of Opioid Intoxication pounds, widely used for their ability to provide effective and Withdrawal analgesia. They also constitute one of the most commonly encountered classes of drugs of abuse. With their use Acute intoxication with opioids presents with a clinical stretching back over millennia (opium was originally extracted syndrome characterized by CNS depression (sedation), from the poppy plant P. somniferum), opiates have played a withdrawn to elated mood, and slurred speech. Physical significant role in religion, culture, and medicine. Over the examination is notable for mioisis, decreased bowel sounds, last decade, recreational use of opioids has steadily risen and may create cutaneous findings that confirm IV drug across the United States, as have the associated unintended use (e.g., track-marks, fresh injection sites). Patients who consequences (including overdoses and fatalities). Between inject a drug subcutaneously (“skin popping”) may present 2004 and 2014, the number of heroin-related fatalities with multiple soft tissue infections and abscesses at the increased by a factor of five (3.3 deaths per 100,000 popula- injection sites. Vital signs are notable for reduced respiratory tion), while fatalities involving all opioids increased to nine rate and normal-to-low heart rates. Hypothermia may be deaths per 100,000 population. In 2014, 61% of all drug seen with severe overdose, as a result of prolonged envi- overdose-related fatalities involved some type of opioid ronmental exposure versus impaired thermogenesis, while compound.1,2 Natural and semi-synthetic opioids (e.g., hyperthermia may alert to acute infection (e.g., aspiration oxycodone) account for the majority of all opioid-related pneumonia, bacteremia, or endocarditis). unintended overdoses and fatalities, likely reflective of the Acute opioid overdose is a medical emergency and close widespread use of these drugs as pain-killers. Overdoses attention should be paid to the patient’s alertness and related to synthetic opioids (e.g., fentanyl) are becoming respiratory status. In severe cases, coma and respiratory more prevalent, often as a result of clandestine drug manu- arrest may ensue, requiring intensive care unit (ICU) level facturing. Fueled by relatively low prices and widespread of care. Naloxone, a short-acting opioid antagonist, should availability, rates of heroin use continue to increase, as do be administered in all cases of suspected opioid overdose. the numbers of overdoses/fatalities attributed to the drug. It is available in a variety of formulations, including intra- Clinicians across all disciplines have considerable venous (IV), intramuscular (IM), and nasal, and it is a responsibility to prevent and reverse the epidemic of opioid- generally safe medication that lacks acute toxicity beyond related morbidity and mortality. Judicious prescribing of the risk of precipitating acute withdrawal at higher doses. opioids for pain relief remains an essential step in reducing While initial doses of 0.05 mg can be used in patients with availability of the drugs. Prompt recognition of the symptoms spontaneous ventilation, higher doses (0.2–1 mg) should be associated with opioid intoxication and withdrawal, including given to patients who are apneic or who present with

Downloaded for Anonymous User (n/a) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 16, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 156 Chapter 15 Patients With Substance Use Disorders cardiopulmonary arrest (2 mg). Naloxone should be admin- Specific starting doses may be challenging to determine, istered to secure adequate ventilation rather than intact and will depend on the patient’s pattern of use; most level of consciousness. With increasing presence of fentanyl patients note improvement of withdrawal symptoms, as the adulterant in the heroin supply, patients may require with doses between 10 and 30 mg/day. Methadone can multiple doses of naloxone (e.g., up to 8 doses) in the field be administered as a single daily dose, or divided into and the ED. If withdrawal is accidentally precipitated, it three doses. The latter approach is favored in the inpatient should be managed through supportive measures; further setting, as it minimizes the risk of over-sedation and opioid administration is not recommended. Once stabilized, allows for rapid dose titration, if needed. The QTc should the patient should be monitored for re-emergence of opioid be monitored, especially with dose escalation and initia- toxicity and multiple administrations of naloxone may be tion of treatment. Once the patient reaches a stable dose required to maintain adequate respiration (due to naloxone’s of methadone that leads to resolution of most withdrawal relatively short half-life). symptoms, the medication can be tapered by 10% to Urine toxicology and urine opioid drug screening are 25% per day until it has been discontinued. Patients not absolutely necessary for management of acute opioid with chronic methadone use may require a more pro- toxidromes, but are recommended to differentiate various tracted taper due to the long half-life of the drug. types of opioids ingested, and may alert the clinician to the • Buprenorphine: Buprenorphine is an efficacious alternative presence of any co-ingested substances. Initial laboratory to methadone for short-term inpatient opioid detoxifica- testing following acute overdose should also include serum tion. Patients are monitored for signs of opioid withdrawal glucose, serum electrolytes, and creatine kinase level (that and treated with sublingual doses of buprenorphine 2 may signal rhabdomyolysis). An ECG should be considered to 4 mg. Once acute withdrawal symptoms have been in cases where methadone overdose is suspected, so as to stabilized, buprenorphine can be tapered over the course monitor for QTc prolongation. Chest imaging may be helpful of 3 to 5 days. Patients typically report that a buprenor- to rule out aspiration. Once stabilized, patients may benefit phine detoxification is more comfortable than is detoxi- from infectious disease screening (including HIV, hepatitis, fication with either methadone or clonidine. syphilis) and liver function assessment (especially if maintenance treatment is considered). Although techniques that permit a safe, rapid, and medically The classic signs of opioid withdrawal are easily recog- effective detoxification from opiates seem highly attractive nized and usually begin 8 to 12 hours after the last dose. in an era of managed care, clinicians must understand that The patient generally admits to the need for drugs and detoxification alone is rarely successful as a treatment for shows sweating, yawning, lacrimation, tremor, rhinorrhea, any addiction. Unless the patients are started on appropriate marked irritability, dilated pupils, and an increased respiratory maintenance treatment (either with opioid agonists or rate. More severe signs of withdrawal (e.g., tachycardia, naltrexone) and given access to appropriate long-term hypertension, nausea, vomiting, insomnia, abdominal cramps) addiction resources, relapse rates following acute detoxifica- occur 24 to 36 hours after the last dose. Untreated, the tion are extremely high. The resulting costs to the patient, syndrome subsides in 5 to 10 days, and while uncomfortable, to society, and to the healthcare system far outweigh any it is not life-threatening. Due to its longer half-life, patients savings realized from a rapid and supposedly cost-effective withdrawing from methadone may not show symptoms until detoxification protocol. 24 to 30 hours after the last dose, and once present, the symptoms may persist for 2 to 4 weeks. Pharmacotherapy for Maintenance of As data clearly show improved outcomes with opioid Opioid Use Disorder agonist therapy, acute detoxification is generally not recommended. However, in settings in which agonist therapy Once sobriety has been achieved and the patient has com- is not available or is potentially contraindicated, acute pleted detoxification, long-term abstinence from opiates detoxification from opioids can be managed with a variety should be pursued through maintenance pharmacotherapy of methods, including supportive care and/or use of replace- and/or behavioral interventions. There are considerable ment therapy to taper the patient off opioids. data to support the pharmacologic approach to opioid maintenance treatment over non-pharmacologic options, • Supportive care: Milder cases of opioid withdrawal can and inpatient medical/surgical hospitalization may present be managed by administering medications that counter an excellent opportunity to initiate treatment modalities and some of the most challenging withdrawal symptoms. identify support resources for the patient following discharge. This includes acetaminophen for muscle aches, clonidine for autonomic symptoms, dicyclomine for GI cramps Opioid Agonist Treatment and diarrhea, and lorazepam for insomnia and anxiety. Opioid agonist treatment involves the use of either metha- As this approach is generally less comfortable for the done or buprenorphine/naloxone to block the acute effects patient, it is associated with lower completion rates of other opiates, reduce drug cravings, and minimize compared with withdrawal management through the use behavioral consequences of chronic opioid use disorder. of opioid replacement therapy. Clonidine can be admin- While the patient remains physiologically dependent on an istered orally or as a transdermal patch, and patients opiate, maintenance therapy with either drug has not been should be monitored for hypotension and sedation. associated with psychosocial problems associated with illicit • Methadone: Methadone is available in a variety of formula- drug use. Both methadone and buprenorphine/naloxone tions (oral, IV, and IM), and its long half-life makes it have been shown to reduce mortality related to opioid use particularly suitable for management of opioid withdrawal. disorder.17

Methadone is a long-acting opioid agonist and a Schedule greater post-discharge follow-up with sobriety resources, II drug in the United States. As it carries a risk for diversion compared with patients assigned to detoxification alone.22 and abuse, methadone prescriptions are strictly regulated. Buprenorphine is relatively safe and appears to have a Only licensed treatment programs can initiate methadone lower potential for lethal overdose compared with metha- for opioid maintenance. In the general hospital setting, done. Most buprenorphine-related fatalities occur in patients methadone cannot be initiated for these purposes, and the who are abusing the drug intravenously, or with co-ingestion drug is commonly used in three specific situations—acute of other sedatives (e.g., benzodiazepines, alcohol). opioid withdrawal management, acute pain management, Buprenorphine is typically administered in conjunction and continuing maintenance treatment in patients already with naloxone as a sublingual tablet or strip. As naloxone on methadone therapy. To be eligible for methadone has poor GI absorption, it is inactive when ingested and maintenance, the patient must present with documentation will not precipitate withdrawal. If the drug is crushed/ confirming at least 1 year of continuous use of opiates, with dissolved and used intravenously, naloxone becomes active exceptions being patients who are pregnant, recently hospital- and will precipitate acute withdrawal—this effectively deters ized, or incarcerated, and patients who have been on patients from abusing buprenorphine-naloxone. As buprenor- methadone maintenance within the past 2 years. phine is a partial opioid agonist, it can displace full agonist Methadone has been shown to be a safe and effective opioids from the receptor and precipitate withdrawal. When treatment choice for opioid maintenance treatment. Com- initiating the medication, it is thus essential that patients pared with placebo, methadone maintenance treatment has have been abstinent from other opioids and show symptoms been associated with reduced rates of opioid-positive drug consistent with moderate opioid withdrawal. Most patients treatment, longer treatment duration, and greater retention in the outpatient setting are started on buprenorphine 4 mg rates. Methadone maintenance has also been associated with and monitored for resolution of withdrawal symptoms. a reduced rate of HIV spread and with reduced mortality Additional 2 to 4 mg doses are administered if withdrawal rates related to opioid use.18 symptoms persist 2 hours after the initial dose. On the Patients about to initiate long-term treatment with following day, the patient is given a single dose consisting methadone should be informed about the risks associated of the total doses received on the first day, and an additional with QTc prolongation, although in most cases, this risk is 2 to 4 mg may be given for any residual withdrawal symp- minimal compared with the risks presented by ongoing toms. In the inpatient hospital setting, buprenorphine/ opioid use. Patients should also be counseled about the naloxone can be initiated faster, with patients receiving possibility of overdose. As a full opioid agonist, methadone upwards of 8 to 12 mg over the first 24 hours in divided has greater potential for overdose compared with buprenor- doses of 2 to 4 mg every 4 hours. Most patients will stabilize phine, and these effects may be potentiated in patients still on doses of 8 to 16 mg/day, though some patients may abusing opioids while on methadone maintenance. require up to 32 mg/day. As with methadone, buprenorphine/ Methadone is generally administered as a single daily naloxone can be used for analgesia in patients with chronic dose, although split-dosing (e.g., three times a day) can be pain and opioid use. The patients commonly require split used in situations when methadone is prescribed for pain (e.g., TID) dosing of the drug, and should receive counseling in addition to opioid maintenance. Most patients will initiate that use of other opioid compounds for pain relief may treatment at 30 mg on their first day, with an additional precipitate acute withdrawal. 10 mg given if the patient exhibits significant withdrawal symptoms 1 hour after the 30 mg dose. The dose is titrated Opioid Antagonist Treatment in 5 to 10 mg increments every 3 to 5 days until a therapeutic Opioid antagonists are used to prevent the user from dose is reached (generally 60 to 80 mg methadone/day). experiencing opioid intoxication, and thus reinforce absti- Some patients require doses greater than 100 mg/day, but nence. This form of treatment is particularly effective in close attention should be paid to sedation and respiratory patients who are highly motivated or in patients who cannot compromise. be on opioid agonist treatment for personal/professional Buprenorphine is a partial µ-opioid agonist that has been reasons. Naltrexone has been used as oral daily treatment shown to be a viable alternative to methadone in the manage- (typically at doses of 50 mg/day), or as a long-acting inject- ment of opioid use disorder. When dispensed as a sublingual able administered every 4 weeks (set dose of 380 mg per tablet in combination with naloxone, it has minimal potential injection). The latter formulation appears to be overall more for IV misuse and has demonstrated efficacy for maintenance effective in treating opioid use disorder, as it requires less treatment.19 It has been approved for use in the office-based motivation from the patient. In comparison with placebo, treatment of opiate dependence and provides an attractive long-acting IM naltrexone has been shown to reinforce alternative to methadone treatment for higher-functioning abstinence and increase patient retention. It has also been patients with moderate to severe opioid use disorders. shown to be effective in reinforcing abstinence in patients Buprenorphine is classified as a Schedule III controlled using more than one drug. substance, and can be dispensed only by specially trained and certified clinicians. As with methadone, buprenorphine maintenance treatment has been associated with fewer BENZODIAZEPINES AND OTHER positive urines and greater treatment retention when SEDATIVE HYPNOTICS compared with patients managed with non-pharmacologic Benzodiazepines measures alone.20,21 Patients with untreated opioid use disorder started on buprenorphine maintenance during a Benzodiazepines are a class of sedative–hypnotic agents with medical hospitalization show increased drug sobriety and a wide variety of therapeutic roles, including management

Downloaded for Anonymous User (n/a) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 16, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 158 Chapter 15 Patients With Substance Use Disorders of anxiety disorders, seizures, insomnia, and GABA-mediated • Metabolism: Most benzodiazepines are metabolized withdrawal states. Discovered accidentally in 1954 by Leo through the P450 system, namely the CYP3A4 and Sternbach, chlordiazepoxide (Librium) was the first benzo- CYP2C19 enzymes. Drugs that inhibit the CYP3A4 diazepine to be synthesized, followed by diazepam (Valium) enzyme (e.g., grapefruit juice, macrolide antibiotics, HIV in 1963, and some 50 other benzodiazepine compounds protease inhibitors) may reduce benzodiazepine metabo- since. Nowadays, benzodiazepines are one of the staples of lism, and thus potentiate drug effect and potential toxicity. modern medicine and psychiatry—a versatile drug class The inducers of CYP3A4 (e.g., phenobarbital, phenytoin, commonly used in inpatient and outpatient settings, and carbamazepine) will increase benzodiazepine metabolism readily prescribed by specialists (e.g., psychiatrists) as well and clearance. Lower benzodiazepine doses should be as primary care physicians. While immensely useful in the used in patients with known hepatic dysfunction. appropriate clinical setting, benzodiazepines have a potential Lorazepam, oxazepam, and temazepam (easily remem- for abuse and dependence, and a withdrawal state produced bered by the brief mnemonic “LOT”) avoid first pass by discontinuation of the drug may be life-threatening. hepatic metabolism. These drugs are less susceptible to CYP interactions, and are considered to be safer in Pharmacology and Mechanism of Action patients with known hepatic disease.23 All benzodiazepines exert their effect via modulation of the gamma-aminobutyric acidA (GABAA) receptor. Unlike many Psychiatric Sequelae of Benzodiazepine Use other drugs discussed in this chapter, benzodiazepines do not change the expression or synaptic availability of GABA, The intended effect of benzodiazepine use is to provide but act to increase the binding of the neurotransmitter to a reduction in anxiety, facilitate sleep, or induce sedation. the GABAA receptor by modulating the receptor structure. When taken in excess, benzodiazepines may lead to overdose The resulting effect is that of hyper-polarization of the characterized by CNS depression similar to that seen with target neuron and decreased ability to initiate an action severe alcohol intoxication. Patients classically present with potential. While different benzodiazepines generally share slurred speech, ataxia, confusion (which may lead to belliger- a similar molecular structure, the presence of various side- ence or agitation), and somnolence. Respiratory depression is chains will account for the considerable variability observed uncommon with isolated benzodiazepine overdose, although in the metabolism pharmacodynamics and pharmacokinetics the risk is increased with co-ingestion of other sedatives, within the drug class. including alcohol, and opioids. Severe intoxication may lead It is clinically useful to categorize benzodiazepines based to stupor or coma and patients may require intubation for on their kinetics (e.g., onset of action, half-life), as well as respiratory support. Commonly, patients will have benign the primary site of metabolism. These characteristics often vital signs, despite considerable sedation, which may help determine how a particular drug is used clinically, and may rule out other life-threatening causes of CNS depression. also play an important role in its abuse potential. A detailed Toxicology screening will help differentiate between ben- account of pharmacokinetics of common benzodiazepines zodiazepines and other sedatives, including alcohol, and is beyond the scope of this chapter. However, some of the may help identify potential co-ingestion. key points are outlined below: Flumazenil, a specific benzodiazepine antagonist, reverses the life-threatening effects of a benzodiazepine overdose. • Onset of action: Benzodiazepines with relatively quick An initial IV dose of 0.2 mg can be given over 30 seconds, onset of action (e.g., midazolam) have an important role followed by a second 0.2 mg IV dose if there is no response in procedural sedation and management of acute anxiety after 45 seconds. This procedure can be repeated at 1-minute states (e.g., clonazepam, alprazolam). Clinical experience intervals up to a cumulative dose of 5 mg. Although readily suggests that the benzodiazepines with a faster onset of available, flumazenil is rarely used in clinical practice, as it action (e.g., alprazolam, clonazepam) appear to be more may precipitate seizures in patients dependent on benzo- likely sought after by patients abusing benzodiazepines diazepines, or in those taking tricyclic antidepressants. Most as they produce an acute “high” sensation, unlike drugs cases of benzodiazepine intoxication are thus managed with a slower onset of action (e.g., oxazepam).23 through supportive care. • Half-life: Benzodiazepines can be divided into three groups based on their half-life. Benzodiazepines with a short Benzodiazepine Withdrawal Management half-life (<12 hours) include oxazepam and midazolam. Generally, these drugs have few active metabolites, and Benzodiazepines can produce a state of physiologic depen- are metabolized in a manner unaffected by liver disease. dence, especially when used in high doses for prolonged Midazolam is used as an anesthetic, given its rapid onset periods. Up to 45% of patients who receive stable, long-term of action and quick clearance, while oxazepam is used doses show physiologic evidence of withdrawal with abrupt for withdrawal management in patients with known drug discontinuation. Withdrawal symptoms resemble those hepatic disease. Intermediate-acting benzodiazepines seen with alcohol and other sedative–hypnotics and include include lorazepam and temazepam (half-life between 12 a state marked by subjective anxiety, irritability, and insomnia. and 24 hours). Long-acting benzodiazepines (half-life Patients may show vital sign changes consistent with >24 hours) include most other benzodiazepine com- increased autonomic arousal (tachycardia, hypertension) and pounds, including diazepam and chlordiazepoxide. Most commonly present with a tremor (“shakes”). In severe cases, of these drugs demonstrate significant hepatic metabolism, patients may develop delirium tremens or have one or more may have active metabolites, and tend to accumulate in seizures—as both conditions are potentially life-threatening, tissues. Their long half-life makes these drugs a preferred prompt recognition and treatment of benzodiazepine choice for management of withdrawal states.23 withdrawal is a clinical priority.

The simplest approach to benzodiazepine detoxification vertical and/or horizontal nystagmus are commonly seen in the outpatient setting is a gradual reduction in dose that on the examination. Vital sign abnormalities may not be as may be extended over several weeks or months. This treat- pronounced as with alcohol intoxication, and patients may ment approach is commonly reserved to highly motivated lack the odor of ethanol on their breath. Toxicology screening patients and patients without significant concern for misuse is essential to rule out co-ingestion, and also to differentiate or diversion of the medication. When a more rapid inpatient benzodiazepine intoxication. detoxification is required, the use of phenobarbital, a longer- The behavioral effects of barbiturate intoxication can acting benzodiazepine, or controlled daily dosage reductions vary widely, even in the same person. With mild intoxication, of the benzodiazepine at 15% to 25% daily may be con- patients may appear somnolent or display disinhibition sidered. When phenobarbital is utilized, a target serum level (including excitement and loud behavior). More severe of 15–30 µg/mL is utilized, with a controlled taper over intoxication can present as aggressive behavior, or may lead the course, of at least 7 days. to encephalopathy and coma. Bradycardia may be observed, An alternative approach may involve discontinuing the but as with benzodiazepines, vital signs are generally unaf- offending benzodiazepine altogether and starting the patient fected in most patients. No specific antidotes are used for on a taper of a high-potency, longer-acting benzodiazepine barbiturate poisoning, and most patients are managed (e.g., clonazepam or diazepam). This strategy is particularly supportively with a focus on airway management and preven- useful for withdrawal from high-potency, intermediate-acting tion of secondary complications related to over-sedation benzodiazepines (e.g., lorazepam). A clonazepam taper may (e.g., aspiration events). mitigate acute withdrawal symptoms and also adequately manage the anxiety that most patients experience with rapid Withdrawal Management lorazepam discontinuation. Due to observed decreased sensitivity to other benzodiazepines, for alprazolam detoxi- Sedative–hypnotic withdrawal syndromes resemble those fication, we recommend either the use of a daily controlled seen with alcohol and benzodiazepines, and can present taper of alprazolam at no more than 15% daily or detoxifica- with a wide variety of symptoms already described in this tion with use of phenobarbital, as noted above. chapter (e.g., anxiety, insomnia, hyperreflexia, diaphoresis, Supplemental medication, such as the use of β-adrenergic nausea, vomiting, and sometimes delirium and convulsions). blockers (propranolol), α-adrenergic agonists (clonidine), Minor withdrawal symptoms begin 24 to 36 hours after the and dopamine antagonists, may offer some relief of subjective last dose—tachycardia, and in some cases tachypnea and complaints, including anxiety and general malaise. These fevers may also be seen. With more severe use, seizures and agents should never be utilized as monotherapy for the delirium tremens may occur. Grand mal seizures, if they detoxification of patients from benzodiazepines. occur, are seen between the 3rd and 7th days, although some cases occur as late as 14 days into a medically controlled SEDATIVE–HYPNOTICS detoxification. Several techniques are available for managing barbiturate Use of CNS depressants accounts for a considerable portion withdrawal. Patients may be gradually tapered off their drug of all ED visits related to suicide attempts and accidental of choice by a controlled taper of said agent. Alternatively, overdoses (consequent to recreational use and self- patients may be transitioned to a long-acting agent (e.g., medication). Although benzodiazepines are by far the most phenobarbital) that can be given as needed based on the commonly abused sedative–hypnotic drug class in the United presence of withdrawal symptoms. As with other substances States, there are still areas where the non-medical use of discussed in this chapter, following acute detoxification, most barbiturates, such as butalbital (Fiorinal and Esgic) and patients will benefit from referral to further addiction carisoprodol (Soma), causes serious clinical problems. services, including formalized outpatient addiction treatment and peer support groups. Pharmacology and Mechanism of Action A person intoxicated on a barbiturate typically presents with REFERENCES a clinical picture nearly identical to that seen with alcohol Access the reference list online at https://expertconsult. intoxication. Slurred speech, unsteady gait, and sustained inkling.com/.

REFERENCES 12. Silva AP, Martins T, Baptista S, et al: Brain injury associated with widely abused amphetamines: neuroinflammation, 1. Rudd RA, Aleshire N, Zibbell JE, et al: Increases in drug neurogenesis and blood–brain barrier. Curr Drug Abuse and opioid overdose deaths—United States. MMWR Morb Rev. 2010;3(4):239–254. Mortal Wkly Rep. 2016;64(50,51):1378–1382. 13. Colfax GN, Santos GM, Das M, et al: Mirtazapine to reduce 2. U.S. Department of Health and Human Services, Substance methamphetamine use: a randomized controlled trial. Arch Abuse and Mental Health Services Administration, Center Gen Psychiatry. 2011;68(11):1168–1175. for Behavioral Health Statistics and Quality: Drug Abuse 14. Fantegrossi WE, Murnane KS, Reissig CJ: The behav- Warning Network, 2011: National Estimates of Drug-Related ioral pharmacology of hallucinogens. Biochem Pharmacol. Emergency Department Visits. Available at https://www.samhsa. 2008;75(1):17–33. gov/data/sites/default/files/DAWN2k11ED/DAWN2k11ED/ 15. World Health Organization: Management of substance abuse— DAWN2k11ED.pdf. Accessed 12 June 2016. Cannabis. Available at http://www.who.int/substance_abuse/ 3. O’Brien CP, McLellan AT: Myths about the treatment of facts/cannabis/en/. Accessed 12 June 2016. addiction. Lancet. 1996;347(8996):237–240. 16. Waldhoer M, Bartlett SE, Whistler JL: Opioid receptors. 4. United Nations Office on Drugs and Crime: World Drug Annu Rev Biochem. 2004;73:953–990. Report 2015, United Nations publication sales No. E.15. 17. Gibson A, Degenhardt L, Mattick RP, et al: Exposure to XI.6. Vienna, 2015, United Nations. opioid maintenance treatment reduces long-term mortality. 5. Howell LL, Kimmel HL: Monoamine transporters and Addiction. 2008;103(3):462–468. psychostimulant addiction. Biochem Pharmacol. 2008;75(1): 18. Mattick RP, Breen C, Kimber J, et al: Methadone maintenance 196–217. therapy versus no opioid replacement therapy for opioid 6. Dackis CA, O’Brien CP: Cocaine dependence: a disease of dependence. Cochrane Database Syst Rev. 2009;(3):CD002209. the brain’s reward centers. J Subst Abuse Treat. 2001;21(3): 19. Ling W, Charuvastra C, Collins JF, et al: Buprenorphine 111–117. maintenance treatment of opiate dependence: a multicenter, 7. Mariani JJ, Pavlicova M, Bisaga A, et al: Extended-release randomized clinical trial. Addiction. 1998;93(4):475–486. mixed amphetamine salts and topiramate for cocaine 20. Mattick RP, Breen C, Kimber J, et al: Buprenorphine main- dependence: a randomized controlled trial. Biol Psychiatry. tenance versus placebo or methadone maintenance for opioid 2012;72(11):950–956. dependence. Cochrane Database Syst Rev. 2014;(2):CD002207. 8. Johnson BA, Wang XQ, Penberthy JK, et al: Topiramate for 21. Fudala PJ, Bridge TP, Herbert S, et al: Office-based the treatment of cocaine addiction: a randomized clinical treatment of opiate addiction with a sublingual-tablet trial. JAMA Psychiatry. 2013;70(12):1338–1346. formulation of buprenorphine and naloxone. N Engl J Med. 9. Rawson R, Shoptaw SJ, Obert JL, et al: An intensive out- 2003;349(10):949–958. patient approach for cocaine abuse: The Matrix Model. J 22. Liebschutz JM, Crooks D, Herman D, et al: Buprenor- Subst Abuse Treat. 1995;12(2):117–127. phine treatment for hospitalized, opioid-dependent 10. Barr AM, Panenka WJ, MacEwan GW, et al: The need for patients: a randomized clinical trial. JAMA Intern Med. speed: an update on methamphetamine addiction. J Psychiatry 2014;174(8):1369–1376. Neurosci. 2006;31(5):301–313. 23. Greenblatt DJ, Shader RI, Divoll M, et al: Benzodiazepines: a 11. Salo R, Flower K, Kielstei A, et al: Psychiatric comor- summary of pharmacokinetic properties. Br J Clin Pharmacol. bidity in methamphetamine dependence. Psychiatry Res. 1981;11(suppl 1):11S–16S. 2011;186(2,3):356–361.