Section 17: Toxicology and Addiction

INTRODUCTION

This chapter will review common overdoses and withdrawal syndromes encountered in the hospital setting following admission from the Emergency Department. According to American Association of Poison Control Centers (AAPCC), the top four substances most frequently involved in adult exposure are prescription medications. Analgesics, sedatives, antipsychotics, antidepressants, and cardiovascular medications accounted for over 150,000 exposures in 2013 (23% of all substances). The top three substance category associated with the most fatalities included prescription sedatives or hypnotics, cardiovascular medications, and opioids. For further prescribing information (see Chapter 73 [Patient Safety and Quality Improvement in Post-Acute Care, section on polypharmacy], Chapter 48 [Perioperative Pain Management], Chapter 99 [Pain], Chapter 216 [Palliation of Common Symptoms], and Chapter 223 [Mood and Anxiety Disorders]).

INITIAL APPROACH TO SUSPECTED OVERDOSE

The general initial evaluation for most overdoses occurs in the emergency department (ED). The assessment and management of a suspected overdose always begin with the stabilization (­Airway, Breathing, Circulation [ABCs]). Emergency physicians quickly establish if a patient has stable vital signs, evaluate the need for respiratory support or intubation for airway protection, and provide fluid resuscitation. Admitting hospitalists should determine what was done in the emergency department, initial impressions of the ED staff, pending tests, red flags that might alter triage plans, and next best steps. Clinicians should also have a low threshold to consult with poison control. The use of gastrointestinal decontamination and renal replacement therapies for overdoses are covered in Chapter 100 (Suspected Intoxication and Overdose).

If the patient is willing and able, it is important to ascertain what substance(s) were ingested, including dosages and timing. If such information cannot be obtained from the patient, collateral sources for second-hand accounts should be sought, including family and friends, EMS reports, outpatient health care providers and pharmacies. If self-harm is suspected, institute suicide precautions and obtain appropriate psychiatric evaluation to determine a safe disposition. With an unintentional intoxication, counsel the patient regarding medication dosing in order to avoid repeat events.

Complete blood count (CBC), coagulation tests, comprehensive metabolic profile (CMP), serum osmolality and osmolar gap, acetaminophen and salicylate levels, and electrocardiogram (ECG) are routinely performed. Additional blood work may include arterial blood gas analysis, troponin, creatine kinase (CK), serum ethanol levels, drug levels, and an additional red top tube on hold. Urine studies should include a pregnancy test in women if appropriate. Urine toxicology studies are frequently ordered. However, these screens have significant limitations that may mislead the ordering clinician:

• False-positive screens occur for many commonly tested drugs such as amphetamines due to the presence of many other drugs (including ephedrine, pseudoephedrine, ranitidine, trazodone, and chlorpromazine).

• A positive initial screening test may not identify the drug responsible for acute intoxication due to drug detection at levels that produce no clinical effects or due to the persistence of detectable levels following ingestion during the previous days to weeks.

• False-negative screens result from an inability to detect certain drugs such as “designer” amphetamines available over the internet, benzodiazepine metabolites, and phencyclidine (PCP) congeners.

Detection of a particular drug, however, may alter medical management if a positive screen alerts the clinician to:

• Initiate measures to reduce toxicity as in acetaminophen overdose.

• Avoid certain medications such as β-blockers in patients with a positive cocaine screen.

• Consider stimulant-induced psychosis for a patient presenting for the first time with psychosis and a positive drug screen for cocaine or amphetamine.

Clinicians should always consider the possibility of multiple drug toxicity, especially salicylates, acetaminophen, antidepressants, alcohol, and illicit substances. A concise summary of the evaluation and management of these drugs is outlined in Table 250-1.

MEDICATIONS THAT PROLONG THE QT INTERVAL

BACKGROUND

The QT interval (the start of the Q wave and the end of the T wave on the ECG) represents the electrical depolarization and repolarization of the ventricles. Measuring the QT should be performed from leads II, V₅, or V₆ using the longest measurement for highest sensitivity. The heart rate (R-R cycle length) influences the duration of the QT interval (ie, the slower the heart rate, the longer the R-R interval and QT interval). Analysis of the duration of repolarization requires correction of the heart rate. A QTc >450 ms in men and >470 ms in women is considered prolonged. See Chapter 108 (The Resting ECG). Online calculators are available that use a variety of popular methodologies) (http://www.mdcalc.com/corrected-qt-interval-qtc/, http://reference.medscape.com/calculator/qt-interval-correction-ekg, or http://www.medical-calculator.nl/calculator/QTc/).

Medication-induced long QT syndrome (LQTS) increases the risk of the potentially lethal arrhythmia known as torsades de pointes (TdP). Between 1983 and 1999, 761 cases of TdP were reported, causing oversight from the FDA to remove medications from the market that could potentially cause QT prolongation. Antiarrhythmics that prolong the QT interval include amiodarone, disopyramide, dofetilide, ibutilide, mibefradil, procainamide, quinidine, sematilide, and sotalol. Entire classes of medications are well known to prolong QT and have been implicated in acquired LTQS and are still in common use in the United States (Table 250-2). TdP is usually self-limiting; however, it may develop into ventricular fibrillation and sudden cardiac death.

EVALUATION

Patients should be stratified on the basis of risk factors; patients at increased risk for prolonged QT and TdP include female gender, advanced age, prolonged baseline QTc, electrolyte abnormalities (hypokalemia and hypomagnesemia), a history of heart disease (CHF/CAD), hepatic and/or renal dysfunction, and bradycardia. Polypharmacy with multiple medications associated with increased QT interval further increases risk. Initial evaluation should be medication review, ECG and comprehensive metabolic profile.

INPATIENT MANAGEMENT

Once a patient develops TdP, ICU level care is warranted. If TdP does not self-terminate, immediate electrical cardioversion is indicated for all unstable ventricular arrhythmias. In stable patients, the goal is electrolyte stabilization with magnesium and potassium. For refractory cases, induction of tachycardia via chronotropes or direct pacing is sometimes used to shorten the QT interval. After removing all offending agents, the mainstay of management is:

1. IV magnesium

2. IV potassium (goal 4.5-5.0 mEq/L)

3. For refractory cases, direct transvenous overdrive pacing and/or isoproterenol for heart rate goal 90 to 110 beats/min

For patients who develop drug-induced prolonged QT syndrome and TdP, a family history should also be obtained to identify congenital LQTS. This might require ECGs of first-degree relatives and possibly genetic testing (see Chapter 134 [Ventricular Arrhythmias]).

CARDIOVASCULAR MEDICATIONS

B-BLOCKER OVERDOSE

Background

The pleotropic effects of BBs in hypertension, heart failure, coronary artery disease, migraines, and anxiety have increased prescription patterns of these medications, and consequently increased the potential for overdose in the general population despite the increase of safety of newer selective BBs. BBs inhibit either one or a combination of the three types of β-receptors. β-1 is located on mostly cardiac tissue and has chronotropic and ionotropic effect with some effect on juxtaglomerular cells causes release of renin. β-2 receptors regulate smooth muscle tone and are well known to influence bronchial smooth muscle relaxation with some effect on pancreatic islet cells causing release of insulin. BBs affect the β-receptor by preventing G proteins from converting adenosine triphosphate (ATP) to cyclic-adenosine monophosphate (cAMP). Consequently, there is less intracellular calcium available for muscular contraction.

Although BBs have been well studied for effects on each receptor at therapeutic dose, receptor selectivity is lost at overdose plasma levels. Lipid solubility is an important consideration in some BBs as this is associated with more side effects due to crossing the blood-brain barrier and untoward CNS involvement. Some BBs cause quinidine-like sodium channel blockade (ie, acebutolol, propanolol, oxprenolol, and betaxolol), which is exacerbated at toxic doses.

Evaluation

The most typical presentation of patient with BB overdose is bradycardia, first-degree heart block, and hypotension. The standard evaluation for suspected BB overdose includes blood pressure measurement, a 12 lead ECG, CMP for evaluation of end-organ damage or hypoperfusion, serum lactate, finger stick blood sugars, and complete neurological assessment. Propranolol overdose may be associated with QRS prolongation, seizures, and coma. Pindolol, a partial agonist, may cause tachycardia in high doses. Sotolol, a class III antiarrhythmic, may cause QT prolongation, ventricular fibrillation, ventricular tachycardia, or torsades. Some BBs have an increased lipophilic profile with additional CNS effects such as CNS depression and somnolence. Additional unselective beta receptor antagonism can cause bronchospasm and decreased inotropy. A chest x-ray may be indicated to assess for pulmonary edema. Additional symptoms include syncope, chest pain, and seizures. Mild hypoglycemia and hyperkalemia may be seen due to the effect of β-receptor activity on the kidneys and pancreas. At high doses, inadvertent inhibition of the sodium receptor leads to QRS prolongation and an increased susceptibility for arrhythmias.

INPATIENT MANAGEMENT

Treatment of acute BB toxicity is dependent on the severity of the ingestion. Initially, the patient will need supportive care with close cardiac, blood pressure, and electrolyte monitoring. Hypotension and bradycardia require fluid resuscitation; failure to respond may require several agents similar to calcium channel blockers (Table 250-3). More severe cases will require vasopressors with β-1 agonist properties such as dopamine or norepinephrine. Refractory symptomatic bradycardia may require direct cardiac pacing, mechanical intra-aortic balloon pump and cardiology consultation. Dialysis may remove poorly protein bound BBs that are excreted by the kidneys (atenonol, sotalol, nadolol) (see Chapter 133 [Bradycardia]).

CALCIUM CHANNEL OVERDOSE

Background

CCBs inhibit transmembrane flow of calcium ions through voltage-gated L-type channels. These medications cause vascular smooth muscle relaxation leading to vasodilation which lowers blood pressure and have negative inotropic and chronotropic myocardial effects. CCBs also restrict pancreatic beta cell insulin secretion causing hyperglycemia. There are two major categories, the dihydropyridines (preferentially inhibit channels in the vasculature) and the nondihydropyridines (selectively block channels in the myocardium and delay atrioventricular conduction and sinus node function). For example, amlodipine, felodipine, nicardipine, and nifedipine are categorized as dihydropyridines, while verapamil and diltiazem belong to the nondihydropyridine category. There are numerous CCBs in both immediate and extended release preparations with widely variable half-lives from 1 to 50 hours. Bioavailability depends on first pass metabolism and all are metabolized by P-450 enzymes (CYP3A). High serum concentrations due to overdose overwhelm first-pass metabolism leading to increased circulating drug concentrations with even longer half-lives. CCB toxicity can be seen with ingestions of more than five times the usual dose.

Evaluation

Typically, dihydropyridine overdose leads to vasodilation with hypotension and reflex tachycardia, whereas nondihydropyridine overdose leads to decreased cardiac contractility and bradycardia. With higher drug concentrations, however, the L-type channel selectivity is often lost so that bradycardia, hypotension, and decreased cardiac contractility may occur due to overdoses from either CCB category. Negative inotropic effects may be associated with heart failure. Ventricular dysrhythmias and mental status changes are usually not seen; however, CNS depression with confusion may be progressing to coma in isolated cases or in patients with refractory hypotension. β-blocker (BB), clonidine and digoxin ingestions may present similarly and should be considered in the differential diagnosis. Unlike CCB, clonidine tends to cause miosis and sinus bradycardia rather than high-degree AV block. BBs may cause hypoglycemia whereas CCB may cause hyperglycemia.

Basic laboratory data testing begins with the ECG, CBC, CMP, calcium, and cardiac enzymes to exclude cardiac ischemia as a possible etiology of the hypotension or arrhythmia. ECG may reveal bradycardia, PR prolongation, or escape rhythms with advanced AV blocks. Chest x-ray may be obtained to evaluate for pulmonary edema. Digoxin levels should be obtained if concomitant ingestion is suspected. CCB assays are not routinely available and not be part of standard evaluation.

INPATIENT MANAGEMENT

Asymptomatic, stable patients require monitoring for hypotension, bradycardia, and hyperglycemia as these patients may quickly decompensate. Depending on whether the ingested formulation was immediate-release, standard-release or extended release, a recommended length of observation is 6, 6 to 12, and 24 to 36 hours, respectively. When hypotension does not respond to aggressive fluid resuscitation, a combination of IV calcium, glucagon, high dose insulin, vasopressors, and IV lipid emulsions should be administered. Atropine and glucagon may be administered for symptomatic bradycardia. In patients with mild symptoms, these treatments may be implemented sequentially (every 15 minutes with interval reassessment) whereas multiple therapies should be implemented simultaneously in hemodynamically unstable patients (Table 250-3). Calcium chloride administration requires a central line.

More aggressive and invasive therapies are needed, including transvenous pacemaker, intra-aortic balloon pump, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO) if the patient remains hemodynamically unstable despite the aforementioned therapies. Hemodialysis is not effective since CCBs have large distribution volumes and are highly protein bound.

ANTIDEPRESSANTS AND ANTIPSYCHOTICS

LITHIUM

Background

Despite its narrow therapeutic window, lithium remains widely utilized; in 2010 the AAPCC was notified of over 6000 cases of lithium toxicity. Lithium is rapidly and completely absorbed from the digestive tract, with a half-life of 18 to 36 hours. Time to peak concentration varies based on the formulation, ranging from 0.5 to 3 hours for immediate release to 2 to 6 hours for extended release. Lithium is nearly exclusively eliminated by the kidneys so renal compromise readily lends itself to toxicity.

Evaluation

Clinically, lithium intoxication presents differently depending on whether it is acute, acute on chronic, or chronic. Acute or acute on chronic lithium toxicity typically presents with gastrointestinal complaints including nausea, vomiting, and diarrhea. Later in the course of acute poisoning, patients develop neurologic complaints including sluggishness, ataxia, confusion/agitation, and neuromuscular excitability (myoclonic jerks, coarse tremor or seizure). Acute kidney injury may be the cause or the result of acute lithium toxicity. Chronic toxicity will often present as nephrogenic diabetes insipidus with accompanying hypernatremia, polyuria, and polydipsia. Chronic toxicity can demonstrate the same neurologic effects as acute toxicity. Chronic toxicity may also present with a spectrum of pathology including hypothyroidism, hyperparathyroidism with accompanying hypercalcemia. Lithium overdose should be differentiated from neuroleptic malignant syndrome, the latter is more likely to cause rigidity. Laboratory evaluation should include serum lithium level, basic metabolic profile to address renal function, sodium and calcium levels, and ECG. Lithium levels do not accurately predict toxicity due to slow absorption into the central nervous system. A slight elevation in levels may be associated with lithium toxicity, especially in chronic users.

INPATIENT MANAGEMENT

IVFs (typically normal saline) should be administered, up to a 2 L bolus followed by 200 mL/h as tolerated. Patients should be monitored for the development of hypernatremia due to diabetes insipidus. Avoid using phenytoin for seizure treatment as it can decrease renal clearance of lithium. Hemodialysis effectively removes lithium from the serum and therefore is the primary treatment for significant toxicity. However, serial dialysis may be required due to inability to remove intracellular lithium; in some cases lithium levels may increase despite effective dialysis. Most experts recommend hemodialysis for serum lithium levels > 2.5 mEq/L with serious manifestations (eg, seizure or altered mental status) or levels > 4 mEq/L regardless of clinical status. Therapeutic goal is to reduce levels to < 1 mEq/L. Lithium levels should be monitored for 8 to 12 hours after dialysis to exclude rebound of lithium reentering the serum from the intracellular space. Additionally, dialysis may be considered for patients that cannot tolerate fluid resuscitation (renal compromise, volume overload, heart failure). Nephrogenic diabetes insipidus may respond to indomethacin (more effective in inhibiting renal prostaglandin synthesis than other nonsteroidal drugs and works within a few hours), thiazide diuretics (acting by mild volume depletion), and amiloride (enhances action of thiazide natriuresis and partially blocks potassium elimination from concurrent thiazide administration).

NONCYCLIC ANTIDEPRESSANT OVERDOSE

Background

Noncyclic antidepressants include:

• Selective serotonin reuptake inhibitors (SSRIs): fluoxetine, sertraline, citalopram, escitalopram, paroxetine, and fluvoxamine

• Serotonin-norepinephrine reuptake inhibitors (SNRIs): venlafaxine, desvenlafaxine, and duloxetine

• Norepinephrine-dopamine reuptake inhibitors (NDRIs): bupropion, trazodone and mirtazapine

These medications are widely prescribed for depression and anxiety disorders. Bupropion is also prescribed for smoking cessation. In general, they are safe and well-tolerated, especially when compared to TCAs and monoamine oxidase inhibitors (MAOIs). Despite more than 46,000 SSRI overdoses reported in 2011, only two deaths resulted.

Evaluation

Unlike tricyclics none of these drugs have significant anticholinergic effects. Most drugs cause central nervous system depression. Bupropion, a stimulant, may cause seizures due to inhibition or reuptake of norepinephrine and dopamine. Trazodone and mirtazapine can cause hypotension due to peripheral α-adrenergic blockade. SSRI intoxication may lead to seizures and/or serotonin syndrome. SSRIs are well absorbed in the gastrointestinal tract and reach peak levels in 1 to 8 hours. SSRIs inhibit neurotransmitter-specific pumps that transfer serotonin from the synapse (where they have their activity) into the cytoplasm of the afferent neuron. They are eliminated by the liver. The half-life for the majority of the SSRIs is in the range of 20 to 30 hours, with exceptions being fluoxetine (24-72 hours) and fluvoxamine (15 hours). A significant number of substances effect serotonergic pathways and can precipitate serotonin syndrome in a patient taking SSRIs (eg, tramadol, cocaine, carbamazepine, St. John’s wort, linezolid, MAOIs, meperidine). This syndrome may develop during hospitalization so must be considered both for newly presenting patients and as a complication arising during the treatment of another disorder.

Diagnosis is based on clinical criteria. In order to meet Hunter criteria, the patient must have a history of ingestion of a serotonergic drug and one of the following: spontaneous clonus; inducible clonus or ocular clonus and diaphoresis or agitation; tremor and hyperreflexia; hypertonia and temperature greater than 38°C and ocular clonus or inducible clonus.

Laboratory evaluation should include CBC, CMP, and CK. An ECG should be obtained to look for QTc prolongation (fluoxetine, citalopram, escitalopram, venlafaxine). SSRI drug levels are not recommended. There are also many false positives in urine assays.

INPATIENT MANAGEMENT OF THE SEROTONIN SYNDROME

Benzodiazepines are the mainstay of therapy to ease agitation and address mild hypertension and tachycardia. A typical starting dose is diazepam 5 to 10 mg IV with titration to effect; patients may require repeat dosing q10min. Supportive therapy is aimed at normalizing vital signs. Patients may exhibit severe hypertension or tachycardia, which should be treated with short acting agents (eg, esmolol, nitroprusside). Hyperthermia should be aggressively treated according to the severity. Physical restraints and butyraphones (haloperidol) are not recommended given concern for worsening hyperthermia. Additional supportive care should include IVFs, oxygen and cardiac monitoring. The antihistamine, cyproheptadine, also has serotonergic antagonism although quality evidence is lacking for its efficacy.

See Chapter 92 (Hyperthermia and Fever).

TRICYCLIC ANTIDEPRESSANT OVERDOSE

Background

Though tricyclic antidepressants (TCAs) remain the 12th most common substance associated with fatalities from ingestion despite having been largely supplanted by SSRI’s in the treatment of depression. The therapeutic window is narrow, and TCAs have a half-life ranging from 7 to 58 hours. The drug is rapidly absorbed in the gastrointestinal tract at therapeutic doses and undergoes conversion in the liver to the active metabolite, nortriptyline. Peak levels in the serum for amitriptyline at normal doses are observed at 2 to 5 hours. In the setting of overdose, however, anticholinergic effects may slow gastrointestinal absorption and delay peak levels. TCAs have wide ranging effects including: antagonism of cardiac fast sodium channels, anticholinergic and antiadrenergic effects, antagonism of histamine-1 receptors, and antagonism of central nervous system GABA-A receptors.

Evaluation

TCAs cause cardiac and neurologic effects at toxic doses. Cardiac effects include sinus tachycardia, worsening cardiac dysrhythmias, and hypotension which can be difficult to control. ECG findings vary from widened QRS to QT segment prolongation and ventricular fibrillation. TCAs also may cause a range of neurologic symptoms, including seizures related to GABA-A antagonism. Anticholinergics effects may lead to delirium, urinary retention, hyperthermia, and dilated, poorly responsive pupils. Antihistaminic activity may cause decreased level of consciousness and even coma.

Laboratory evaluation includes ECG, chemistry panel, and troponin. An ABG may be necessary to evaluate acidosis. The 12-lead ECG guides therapy and provides prognostic information. The most sensitive predictor of seizures and ventricular arrhythmias is QRS duration (>0.16 seconds). Serum and urine TCA testing does not reliably guide management or provide prognostic information. Multiple drugs cause false positive results, significant toxicity may occur at nontoxic levels, especially with chronic TCA use, and results are usually not available at the time of clinical decision-making.

INPATIENT MANAGEMENT

Close cardiac and neurologic monitoring should be in place for admitted patients. Telemetry and serial 12-lead ECG monitoring is recommended for patients with sinus tachycardia. ICU admission should be considered if ECG changes (including QRS prolongation, prolonged QTc, tall R waves in AVR or AVR R/S >0.7, arrhythmias), hypotension, respiratory depression, or altered mental status.

Treatment agents should be targeted by indication (Table 250-4).

SEDATIVE AND ALCOHOL

SEDATIVE AND ALCOHOL INTOXICATION

Background

Sedatives constitute a diverse group of agents, including alcohol, benzodiazepines, nonbenzodiazepine hypnotic medications (so-called Z-drugs such as zolpidem [Ambien]), barbiturates, and several other compounds, including chloral hydrate and meprobamate. All sedatives dose-dependently depress neuronal function, and most of these agents can produce fatal respiratory depression.

Evaluation

Both alcohol intoxication and sedative overdose present with uncoordinated motor functioning (gait ataxia, finger to nose incoordination, positive Romberg sign), nystagmus, slurred speech, and various aberrant behaviors, including behavioral disinhibition, impairment of consciousness, reduced respirations, and drowsiness or sleep. Memory disturbances and frank amnesia, frequently referred to as blackouts, are more likely with short-acting sedatives, alcohol, or a combination of the two. The history, either directly from the patient or from his or her associates, usually provides sufficient evidence to confirm intoxication with alcohol or sedatives. Laboratory testing in these patients should include a blood alcohol level (Table 250-5) obtained directly from a serum sample or indirectly by measurement of the breath alcohol content with a breathalyzer.

A metabolic profile should be obtained to check blood glucose (malnourished patients may have hypoglycemia) and to calculate the anion gap. Other toxic alcohols (ethylene glycol [antifreeze], methanol [wood alcohol]) will cause a high anion gap acidosis and osmolar gap. Isopropyl alcohol is associated with an elevated osmolar gap but not with an elevated anion gap acidosis (see Chapter 238 [Acid Base Disorders]).

Urine testing for benzodiazepines and barbiturates is widely available. Standard assays for benzodiazepines do not detect benzodiazepines but rather metabolites of 1,4-benzodiazepines. Therefore, they vary in their sensitivity to detect some benzodiazepines (clonazepam, lorazepam, midazolam, or alprazolam). Urine tests for other sedatives, including the Z-drugs and older sedatives (eg, meprobamate, chloral hydrate, ethchlorvynol), are not widely available, although may be requested from outside laboratories. Serum benzodiazepine levels do not correlate with clinical findings and are not readily available during emergent management.

INPATIENT MANAGEMENT

With alcohol intoxication, neurologic symptoms should clear within 4 hours unless due to coingestions, head trauma, or other causes. With any sedative overdose, the management is supportive and may require a period of artificial ventilation until the sedative level falls and spontaneous respiration resumes. A benzodiazepine antagonist, flumazenil, competitively binds but does not activate the gamma-aminobutyric acid (GABA) benzodiazepine receptor. The use of flumazenil may precipitate seizures in individuals who have developed physiologic dependence on benzodiazepines; therefore, this drug should only be used in consultation with a toxicologist (eg, Poison Control).

SEDATIVE AND ALCOHOL WITHDRAWAL

Background

Use of a sedative or alcohol on a daily basis for more than 2 weeks may result in withdrawal upon cessation of use. The likelihood increases with longer periods and heavier use. Withdrawal can also occur with nondaily, binge pattern use (more days of the week than not). The common signs and symptoms of alcohol withdrawal are shown in Table 250-6 and delirium tremens (DTs) are shown in Table 250-7. In general, withdrawal from sedatives produces similar signs and symptoms as withdrawal from alcohol. Barbiturates and other, older sedatives may be more likely to produce seizures and/or delirium during withdrawal. The syndromes differ principally in their time course, which is directly correlated with the elimination half-life of the agent. Long-acting sedatives, such as diazepam or phenobarbital would typically present more gradually than alcohol withdrawal, and with a later onset of withdrawal seizures and peak symptoms.

Alcohol withdrawal typically progresses through stages due to central nervous system hyperactivity:

• 6 to 12 hours after last drink: tremulousness (in up to 100% of individuals) and other minor symptoms (insomnia, anxiety, gastrointestinal upset, headache)

• 12 to 48 hours after last drink: withdrawal seizures occurring predominantly in patients with a long history of heavy alcohol use or prior withdrawal seizures

• 12 to 48 hours after last drink: alcoholic visual hallucinations without mental status changes or hemodynamic instability (in up to 25% of individuals)

• 2 to 4 days after last drink: delirium tremens (in 4%-5% of patients)

Other causes of symptoms suggesting DTs that do not respond to high doses of benzodiazepines or last more than a week include intoxication due to benzodiazepines, gamma hydroxybutyrate (GHB) or baclofen withdrawal.

Evaluation

Laboratory evaluation should include complete blood count with differential and platelet count, coagulation tests, comprehensive metabolic profile, liver biochemical tests, amylase or lipase, ECG, urinalysis, and in selected patients cultures. The ECG should be examined to determine QTc interval (prior to initiating possible treatment with haloperidol) and to identify possible ischemia. Ethanol levels are usually low or undetectable and do not influence management. Patients may experience withdrawal signs and symptoms with an elevated blood alcohol level.

INPATIENT MANAGEMENT

All patients should receive thiamine before glucose administration to avoid causing Wernicke’s encephalopathy (encephalopathy, oculomotor dysfunction, gait ataxia), folate, multivitamins, intravenous hydration, correction of electrolyte disorders (especially magnesium and potassium depletion). For alcohol withdrawal, the most important element of management is prevention of seizures and DTs. Management of DTs commonly requires admission to an intensive care unit, for very close monitoring of vital signs and administration of high doses of benzodiazepines or barbiturates with or without adjunctive haloperidol. The general approach is to substitute an adequate dosage of a long-acting benzodiazepine (eg, diazepam, chlordiazepoxide, or clonazepam) to alleviate withdrawal symptoms. Some experts favor the use of lorazepam because it is not metabolized in the liver and would therefore not accumulate in patients with severe liver disease; however, metabolic function is usually well preserved until severe end-stage liver disease is present. Lorazepam’s principal advantages are that it is available as a parenteral agent, and its short half-life allows rapid titration. Administering more than one benzodiazepine will complicate management due to different half-lives and should be avoided.

Table 250-8 provides a range of suggested doses of several common benzodiazepines and phenobarbital for use in mild to moderate alcohol withdrawal.

A fixed dose regimen or a symptom-triggered approach is used to establish the benzodiazepine taper. The symptom-triggered approach can minimize the total dosage of benzodiazepines utilized, but may be too labor intensive to be practical in some settings. As such, a fixed-flexible dose regimen may be preferred. Clinical Institute Withdrawal Assessment for Alcohol (CIWA) is a widely used scoring system that may be used at the bedside with set protocol forms or online (http://www.reseaufranco.com/en/assessment_and_treatment_information/assessment_tools/clinical_institute_withdrawal_assessment_for_alcohol_ciwa.pdf). A score <8 supports a clinical impression that the patient has not yet developed alcohol withdrawal and withdrawal prophylaxis is appropriate. An increasing score > 8 supports withdrawal and need for intervention with an aim to achieve a score less than 8 by inducing a light sleep with benzodiazepines.

Once stabilized, most patients can be tapered off benzodiazepines in approximately 10 days, with dosage reductions of approximately 10% of the total daily dosage each day over the course of those 10 days (which can be completed as an outpatient). Withdrawal from alcohol may also be managed very effectively with a long-acting barbiturate (phenobarbital), again with the need first to stabilize the patient’s vital signs and eliminate other withdrawal signs and symptoms, followed by a taper schedule over approximately 10 days. There is some evidence that alcohol withdrawal may also be managed with anticonvulsants (carbamazepine, gabapentin, valproic acid, and others), either in conjunction with benzodiazepines or as a standalone therapy, although the evidence thus far for anticonvulsants in alcohol withdrawal is insufficient to support their use over benzodiazepines.

Withdrawal from sedatives is more complicated than withdrawal from alcohol. Long-term use (for more than 6 months) of benzodiazepines and Z-drugs, even at modest dosages, may be associated with a greater risk of seizures for days to weeks following cessation. As a result, many physicians recommend a sedative taper over several months under the supervision of a psychiatrist or addiction specialist. This may best be accomplished by switching a patient to phenobarbital and tapering it gradually over several months. Adjunctive use of anticonvulsants may play a role to reduce the seizure risk, but the evidence for this is limited. Withdrawal from barbiturates and other sedatives cannot safely be safely managed using benzodiazepines, because benzodiazepines do not adequately reduce the risk of seizures or withdrawal delirium. As such, phenobarbital is the agent of choice for managing withdrawal from barbiturates and other sedatives. Mixed sedative dependence syndromes, in which individuals regularly ingest multiple agents and possibly alcohol, should be managed with phenobarbital because it will safely cover withdrawal symptoms from all sedatives and alcohol.

ANALGESICS

ACETAMINOPHEN OVERDOSE

Acetaminophen is an analgesic drug, commonly used in combination with other drugs. The active ingredient is acetyl-para-aminophenol (APAP). The amount of acetaminophen ingested and the time to presentation are the most important prognostic indicators of hepatotoxicity. The APAP level guides therapy. The biggest benefit of N-acetylcysteine is within 12 hours of ingestion; however, treatment should be initiated for any toxic APAP level (see Chapter 100 [Suspected Intoxication and Overdose], Chapter 109 [Elevated Liver Biochemical and Function Tests], and Chapter 159 [Acute Liver Disease]).

SALICYLATE OVERDOSE

Salicylates are found in a number of medications, including aspirin products, bismuth subsalicylate (Pepto-Bismol) and herbal medications. Salicylate poisoning should be considered in any patient with an elevated anion gap acidosis. Serum salicylate levels may not correlate with clinical presentation due to a number of factors, including delayed absorption of enteric-coated formulations, altered absorption and elimination following overdose, and salicylate redistribution in body tissues rather than excretion by the kidneys. Available through poison control, a medical toxicologist should be consulted in any patient suspected of salicylate poisoning. Consider consultation with a nephrologist for guidance on alkalinization to promote elimination of salicylate and for recommendations and timing of possible hemodialysis.

OPIATE OVERDOSE

Background

Opioids are now among the most commonly prescribed medications in the United States. Over 5 million people use opioids for nonmedical purposes each year, and there are over 100,000 new users of heroin each year.

Evaluation

Fever, dyspnea, and acute pain are common presenting complaints of opioid-using patients. Underlying infection is often the cause of these complaints, particularly among injection drug users (IDUs). Endocarditis, skin, and soft-tissue infections, bone and joint infections, epidural abscess, and even pneumonia are more common among IDUs than in general medicine patients. When an opioid user is identified, a key part of the evaluation is to determine if the individual is physically dependent on opioids.

The role of urine drug testing in the diagnosis of opioid use is fairly limited. Providers need to be aware of general test characteristics as well as what tests are locally available. Specific (and separate) urine radioimmunoassay screening tests can be used to screen for opiates, oxycodone, meperidine, propoxyphene, and methadone metabolites. A “negative” screening test never rules out opioid use, and a “positive” screening test can only be used to support a clinical diagnosis. Definitive testing can be performed with gas chromatography/mass spectroscopy, but such testing is expensive and results are not immediately available.

Patients may present with symptoms of overdose (lethargy, pinpoint pupils, respiratory depression) or withdrawal (sweating, tremor, tachycardia, anxiety, pupillary dilation). Withdrawal symptoms typically begin 6 to 12 hours after the last use and will peak at 24 to 48 hours, but vary based on agent (Table 250-9).

INPATIENT MANAGEMENT

Overdose may occur in new opioid users, as part of a suicide attempt, when drug purity is unexpectedly high, or during induction on a long-acting opioid (eg, methadone). Injection drug users are particularly vulnerable to overdose when getting opioids from a new source where drug purity is not known and there is a mixture multiple drugs such as fentanyl and heroin. Initial treatment includes the use of the short-acting injectable opioid antagonist naloxone and supportive care. In the opioid-naïve individual, full-­agonist reversal generally occurs when 0.4 mg of naloxone is given (IV/IM/SQ/ET) every 2 to 3 minutes. The intravenous route provides the most predictable response. For opioid-dependent patients, smaller doses should be used and titrated to reverse respiratory depression (giving full-reversal doses of naloxone to opioid-­dependent individuals may result in a severe withdrawal syndrome); doses of 0.1 to 0.2 mg of naloxone can be used in incremental fashion to reverse respiratory depression. Patients who have overdosed with a long-acting or high-affinity agent (eg, methadone, buprenorphine) will generally need admission for oxygen, close monitoring, and an intravenous naloxone infusion.

OPIATE WITHDRAWAL

Inpatient Management

Management of the opioid withdrawal syndrome (OWS) should be based on patient characteristics, goals of treatment, and local resources. Always verify methodone dosage prior to administration of large doses in patients who chronically take methadone. Patient characteristics include determination of the presence or absence of pain (acute and chronic), the presence or absence of pathologic opioid use (abuse and addiction), the type and amount of opioid being used, and the cause and severity of withdrawal. The goal of treatment will be either stabilization on an opioid, or complete cessation of all opioids. For opioid-addicted patients who are not currently receiving addiction treatment, the presence or absence of pain is the primary determinant of medication selection. Patients with pain will require agonist treatment with buprenorphine, methadone, or other opioid agonists. Patients without pain (other than withdrawal pain) can be managed with clonidine or buprenorphine. Medications most commonly used for the treatment and symptom management of OWS are outlined in Table 250-10 and Table 250-11.

STIMULANTS

STIMULANT OVERDOSE

Background

There are many types of abused stimulants in the United States, including cocaine, amphetamines, ecstasy, and over-the-counter and prescription stimulants. Table 250-12 outlines the most commonly abused stimulants. Prescription stimulants include methylphenidate, methamphetamine, dextroamphetamine, mazindol, phenmetrazine, and phentermine. Prescribed stimulants may be used therapeutically for multiple conditions, including attention-deficit disorder, narcolepsy, fatigue in multiple sclerosis, and refractory depression, as well as in palliative care. Nicotine and caffeine are mild stimulants that are also in widespread use.

Evaluation

Stimulant overdose usually presents with symptoms due to overstimulation of the sympathetic nervous system leading to peripheral vasoconstriction, increased heart rate, and lowered seizure threshold. Psychological effects result from stimulation of corticomesolimbic dopamine circuits in the brain, leading to desired effects (increased energy and alertness, euphoria, decreased appetite and need for sleep) as well as negative effects (anxiety, grandiosity, impaired judgment, psychosis, paranoid delusions and hallucinations, and addiction). Adrenergic poisoning syndromes have similar presentations to neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, intracranial hemorrhage, and pheochromocytoma. Laboratory evaluation includes urine drug screen, CBC, CMP, creatine kinase, urinalysis, coagulation tests, liver biochemical tests, troponins, ECG, and CXR. Additional testing may include thyroid function tests and neuroimaging.

Stimulant overdose symptoms are outlined in Table 250-13.

INPATIENT MANAGEMENT

Treatment for acute overdose of stimulants includes stabilization of airway, breathing, and circulation, administration of activated charcoal, seizure control with benzodiazepines, aggressive management of hypertension, and management of hyperthermia. The acutely intoxicated stimulant user should be approached in a subdued manner. Specific management for cocaine-associated complications is outlined in Table 250-14.

Designer drugs, especially MDMA (ecstasy), are stimulants with some hallucinogen-like effects, so acute physiological effects include more pronounced hypertension and hyperthermia as compared to other hallucinogens. MDMA also has serotonergic effects. Peak effects occur within 2 hours following ingestion and effects last approximately 4 to 6 hours. Ecstasy often contains adulterants. Urine drug screen will be positive for amphetamines but a negative screen does not exclusion ingestions of this drug. Hyperthermia is the main cause of death.

Toxicity of designer drugs may be related to additives such as ketamine or LSD. There are numerous case reports of MDMA use resulting in hyperthermia, rhadomyolysis, serotonin syndrome, hyponatremia with cerebral edema, fulminant hepatic failure, and stroke. Other stimulant-derived hallucinogens may cause cardiac arrhythmias.

STIMULANT WITHDRAWAL

The severity and duration of withdrawal from stimulants depends upon the intensity of the preceding months of chronic abuse and the presence of predisposing psychiatric disorders. In general, the “crash,” or drastic reduction in mood and energy, can start within minutes after the last use. The user experiences craving, depression, irritability, anxiety, and paranoia. The craving for stimulants decreases over several hours and is replaced by a need for sleep and food. Hypersomnolence lasts between 8 hours and 4 days. Sleep is interrupted by brief awakenings during which the user experiences hyperphagia (“the munchies”). This phase is followed by a protracted dysphoric syndrome consisting of anhedonia, boredom, anxiety, panic attacks, generalized malaise, problems with memory and concentration, and occasional suicidal ideation. This induces severe craving that may lead to resumption of stimulant use and a vicious cycle of recurrent binges. Withdrawal syndromes for stimulants require only supportive care.

OTHER DRUGS OF ABUSE

BACKGROUND

Patients may be admitted to a hospital with an overdose, intoxication, or withdrawal syndrome from drugs of abuse, including marijuana, hallucinogens, “club drugs,” and/or inhalants. Marijuana is the most frequently abused drug in the United States, with a prevalence of around 4% of the adult population. The most widely used hallucinogen is LSD, with a lifetime prevalence of use of 14% among young adults. Among club-going young adults, use of hallucinogens is up to 70%. Common “club drugs” are listed in Table 250-15.

EVALUATION

Indicators that would raise the suspicion of the use of these drugs are outlined in Tables 250-16 and 250-17.

INPATIENT MANAGEMENT

Treatment tips for the management of acute overdose of marijuana and hallucinogens are outlined in Table 250-18.

For PCP, hypertension should be treated vigorously with intravenous antihypertensives, since it may cause hypertensive encephalopathy or intracerebral bleeding. PCP can also cause life-threatening hyperthermia with temperatures over 106°F; rapid cooling measures (ice packs, cooling blanket, etc) may be required. Psychotic behavior can be treated with haloperidol. If the patient is severely agitated and poses a potential threat to self or others, haloperidol or lorazepam is effective for control of agitation; barbiturates may be even more useful in this setting with this drug, according to some reports.

GHB overdose may cause severe central nervous system and respiratory depression that abates over several hours. For acute GHB intoxication, supportive care includes oxygen supplementation, intravenous access, and comprehensive physiologic and cardiac monitoring. Providers should attempt to keep the patient stimulated and awake. Atropine may be used for persistent symptomatic bradycardia. Naloxone and flumazenil are ineffective, and activated charcoal is contraindicated due to the risk of aspiration and the short half-life of GHB. The most dangerous effects of GHB use often occur with the use of other drugs. Concurrent use of sedatives or alcohol may increase the risk of vomiting, aspiration, or cardiopulmonary depression; the use of GHB and stimulants may increase the risk of seizure.

WITHDRAWAL

Heavy marijuana use for more than 3 weeks results in a withdrawal syndrome after abrupt cessation and consists of irritability, agitation, depression, insomnia, nausea, anorexia, and tremor that can last for weeks. Marijuana withdrawal is uncomfortable but not life threatening; treatment is entirely supportive and rarely requires adjunctive medications.

Withdrawal from GHB is similar to withdrawal from sedatives such as benzodiazepines and alcohol; symptoms start within 6 hours of the last use, then increase in intensity over several hours to days and may persist for 2 weeks. Physiologic signs include diaphoresis, tremor, tachycardia, and hypertension. Other symptoms are nausea with vomiting, anxiety, restlessness, insomnia, and “feelings of doom.” Severe withdrawal involves agitation, delirium, and psychosis. GHB withdrawal may not respond to benzodiazepines despite very high doses. Antipsychotics or pentobarbital may have some utility in treatment of severe GHB withdrawal, although antipsychotics may lower the seizure threshold, especially when used without a sedative.

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INTRODUCTION

Patients with addiction can baffle and overwhelm even the most compassionate physicians, and these patients sometimes even deceive themselves into believing there is no problem. The symptoms of drug and alcohol use can mimic or co-occur with mental illness and chronic pain, complicating the diagnosis. Families can play a role in the development of addiction and also in its treatment. Fortunately, addiction is a treatable disease of the brain. Physicians have a unique opportunity to intervene in the addictive process and shepherd our patients—and our colleagues—into treatment when needed.

The brain is hardwired to reward behaviors that enhance survival of the individual or the species. The reward is pleasure, and it happens when dopamine levels rise in the limbic system. For example, eating when you are hungry, drinking water when you are thirsty, or having sex releases dopamine, which is subjectively experienced as pleasurable. People are motivated to seek pleasure and avoid pain in order to survive. Every behavior you perform is related to pain avoidance or short- or long-term pleasure reward.

Drugs of abuse—including alcohol, nicotine, illicit drugs, and some prescription medications—are potentially dangerous because they raise the dopamine in the limbic system faster, longer, and much higher than any natural reward (such as food, sex, or seeing your family). The brain, which is motivated to seek immediate reward, drives an individual’s behavior to repeat the intense pleasure as much as possible. Dopamine also enhances learning and classical conditioning, so a person with an addiction unconsciously learns the pleasurable “survival value” of the drug. If the drug use continues, it essentially hijacks the brain’s motivational dopamine system, tricking the brain into behaving as though the individual needs the drug to survive. At this point, the individual becomes dominated by seeking and repeating drug use. Changes take place in the brain that make it extremely uncomfortable to be without the drug. Natural dopamine production downregulates, and the brain becomes less responsive to dopamine presence. This is known as tolerance, meaning more of the drug is needed to produce a pleasurable sensation. It also means that previously pleasurable activities are no longer gratifying. The relative absence of dopamine leads to dysphoria in the absence of reinforcing drugs. Taking the drug is the fastest and easiest way for an addicted person in withdrawal to feel “normal” again. Eventually, continuing drug use overwhelms voluntary control and crowds out other relationships, becoming more important than an individual’s family, values, even food and sex. At this point, drug and alcohol users isolate from other people to focus more obsessively on drug use. When addiction progresses to this level, people may use any means necessary—including manipulation, deceit, sometimes even violence—to obtain the drug of choice. Survival instincts can override judgment and moral values. This is why “drug seeking” patients can seem so difficult. The brain is motivated to survive, and following the brain changes of chronic drug use, survival equals continued use.

In late-stage addiction, a patient’s body has usually become so used to the presence of the drug that the patient reports needing the drug to feel “normal.” Without the drug, the patient will become increasingly uncomfortable and anxious until nothing in the environment can prevent the person from using. At that point, asking an addicted person to stop drinking or using is like asking you to stop breathing. If you were to voluntarily stop breathing, your hypoxic drive would make you increasingly anxious and uncomfortable until nothing in your environment could prevent you from taking a breath. And with the first breath you would begin to feel relief, begin to return to “normal.” After derangement of multiple brain systems, stopping breathing is what it feels like for an addicted person to stop using. That is why the relapse rate is so high if the disease of addiction is not treated properly.

RECOGNIZING ADDICTION

Substance use occurs on a continuum from sporadic use to abuse to dependence and addiction. Rather than being defined by frequency of use, the hallmark of addiction is continued use despite consequences. Consequences may be social (damaged relationships), financial (money spent on drugs, or lost pay due to work absence), legal (driving under the influence or disorderly conduct), or medical (infections, overdoses, injuries while intoxicated, pancreatitis). In general, “if you’ve had problems because of drinking or using drugs, then you have a problem with alcohol or drugs.” This means that some alcoholic and addicted individuals use episodically, or in a “binge” pattern—not necessarily every day. The natural history of addiction is progressive, with a variable rate: some patients progress rapidly from abuse to severe addiction; others smolder for years with less severe consequences. Few are able to stop permanently on their own. With each relapse to substance abuse, the addiction usually returns immediately to its worst point and progresses further. Depending on the substance(s) of choice, there can be a “shotgun effect” of end-organ damage involving every organ system. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) contains specific criteria for diagnosing mild, moderate, and severe substance use disorders.

“I DON’T HAVE A PROBLEM”

Alcoholic and addicted patients are frequently in denial, meaning they honestly believe they do not have a problem; or they may desire very strongly to stop, but find they cannot stop because the biological motivation to use has become so strong. In addition, patients may not even remember some of the consequences of their use if they were intoxicated to amnesia (“blackouts”)—­particularly with alcohol. They can also misinterpret the causal relationships with their drinking, for example, believing, “I drink a lot because my wife nags me,” when in fact the opposite is true (conflict arises because of the patient’s drinking). Addicted patients in denial frequently cannot fully see the effects their use has on the lives around them.

SUBSTANCE USE AFFECTS DECISION MAKING

Cognitive changes occur with chronic drug use, particularly with loss of ability to make decisions and weigh future consequences against immediate gratification—this is why addicted patients sometimes baffle us by leaving the hospital against medical advice. Addicted people do not make decisions the way nonaddicted people do. When the neurochemistry of the limbic system is altered in long-term drug use, decisions about drug use are driven by craving rather than by reason. In addition, many addicted people begin using during adolescence, around age 12 to 14. Individuals who rely on drug use as their primary coping mechanism do not learn any further coping skills that foster maturity. This means that a ­46-year-old patient who has been using continuously since adolescence may have the emotional maturity and coping skills of a 13-year-old.

DIFFERENTIAL DIAGNOSIS

Tolerance refers to homeostatic adaptations due to the repeated presence of a drug over an extended period. It is defined by emergence of physical symptoms (a withdrawal syndrome) when the substance is stopped. The body adapts in this way to many prescription medications, such as antihypertensives, SSRIs, and opioid pain medications; this is why clonidine, beta-blockers, and some SSRIs need to be tapered slowly rather than stopped abruptly. Both tolerance and withdrawal are expected in patients with chronic pain on long-term opioid therapy, but neither defines addiction. That is why substance use disorders (SUDs) are diagnosed based on behaviors and consequences, not just physical tolerance and withdrawal.

Pseudoaddiction: Imagine for a moment that a person has chronic or acute pain from, say, a femoral fracture. Imagine that the pain was not adequately treated with the medication prescribed at discharge. What strategies could the person employ to get the pain treated? The person might take larger doses of the prescribed pain medication, refill it early, leave repeated messages for the prescribing physician, even resort to an emergency department visit for pain medication. She might borrow a few hydrocodone from a friend. Based on her behavior, she might correctly be labeled a “drug seeker.” This is pseudoaddiction, when untreated pain motivates a desperate patient to seek relief in ways that resemble addictive behaviors. It can be difficult to unravel whether pain or addiction, or both, are causing the behaviors; thus, pseudoaddiction should always be in the differential diagnosis list.

Mental illness: Acute intoxication can mimic the symptoms of anxiety, depression, mania, paranoia, psychosis, and even schizophrenia. Drug rebound and withdrawal can also imitate psychiatric conditions. Only a careful history with strict attention to the timing of onset of psychiatric symptoms and drug use can begin to elucidate the diagnosis. There is a strong association between substance use disorders and major depression, dysthymia, hypomania, social phobia, panic, and generalized anxiety; close to half of substance users may have some degree of concurrent personality disorder. Sometimes people with mental illness resort to illicit drug use in order to avoid unpleasant psychiatric symptoms; mental illness and drug use can then produce new psychiatric symptoms that result in more drug use. Drugs can precipitate new psychotic breaks that persist after intoxication in previously unaffected individuals. The two can be intimately entwined and fuel each other. Dual diagnosis or co-occurring disorder refers to a coexisting psychiatric diagnosis as well as a substance use disorder.

Substance-induced mood disorder refers to new mood symptoms experienced after the onset of substance use. Some sober time may be required to disentangle drug effects from underlying mental illness. Symptoms or diagnosis of mental illness prior to introduction of drugs and alcohol can be a clue. Outcomes are generally poorer for dually diagnosed patients, and once concurrent mental illness is established, addiction and mental illness must be treated concurrently, rather than waiting for the SUD to “clear.” Your patient may never achieve sobriety if the mental illness is not treated.

Chaotic social situation: A patient who is homeless or has an abusive or unstable social situation may present with behaviors mimicking addiction, such as missed appointments, multiple admissions (including admissions for pain control), early refills on medications, multiple phone calls, and the like. The person may meet criteria for problem opioid use or problem prescription drug use based on behaviors that are troubling to health care personnel rather than behaviors driven by addiction.

EPIDEMIOLOGY AND RISK FACTORS

Excluding nicotine addiction (which in itself causes 485,000 deaths in this country each year), substance use disorders have a 16% lifetime prevalence in the United States. Death rates are 50 to 100 times higher among substance users. Four out of every 10 families are affected by addiction. Given the 50% genetic contribution to the etiology of addiction, an affected family member is a powerful risk factor. The 50% environmental contribution has to do with cultural and family norms that value or stigmatize drugs and alcohol, exposure at an early age, and availability of mind-altering substances. We know that perception of drugs and alcohol as dangerous and socially unacceptable is protective against experimentation and development of addiction. Point prevalence is highest among males 15 to 19, but addiction cuts across gender, race, and socioeconomic status. In women, there is a strong association between sexual/physical violence, including childhood sexual abuse, and starting to drink. As a profession, physicians have among the highest rates of substance abuse and addiction.

Impulsivity and an orientation toward immediate gratification are risk factors for SUDs. Thus, adolescents are at high risk: they can be impulsive, rebellious, and novelty seeking with poorly developed judgment. Early exposure to substances in adolescence may lead to permanent brain changes; one-third of adolescent drinkers develop alcohol abuse or dependence in adulthood, and the younger the age at first use, the greater risk of subsequent SUD. Early diagnosis makes treatment more effective, so failing to screen for substance use is like not checking blood sugar in a new diabetic, or not checking for HIV disease with suspicious infections. It is important to ask adolescents about substance use and to check urine toxicologies to confirm the history.

TWELVE-STEP PARTICIPATION SUPPORTS SOBRIETY

Alcoholics Anonymous (AA) started in 1935 when two self-­proclaimed “hopeless alcoholics”—one of them a physician—came together to help each other stop drinking. They published a guide, formally titled Alcoholics Anonymous but better known as the “Big Book” in 1939, whereby others could retrace their steps in supporting each other to sobriety. AA is free and available in nearly every locale, currently with more than 2 million members in 105,000 groups across 182 countries. The only requirement to attend meetings is a desire to stop drinking. The 12 Steps refer to a “higher power,” which some members interpret as God; however, AA is spiritual—not religious—and members may interpret “higher power” as any wisdom stronger than their own. For example, a group of people can be a higher power. AA specifically refutes any connection to organized religion, and the “Big Book” discusses its compatibility with atheism and agnosticism in Appendix II, “Spiritual Experience.” Many patients are able to stop drinking or using with only 12-Step participation in the absence of professional treatment. Statistically, AA with physician visits works as well as professional therapy (cognitive behavioral therapy and/or motivational enhancement therapy), but it is impossible to know which patients will respond best to which treatment; thus it is recommended that patients start with professional treatment to learn a new bedrock of coping skills, and then continue with lifelong 12-Step participation.

Unfortunately, patients are unlikely to follow-up with an AA telephone number provided by physicians; however, putting the patient directly in touch with an AA member while they are in the office can be tremendously effective. A sponsor is an individual with several years of successful recovery who can shepherd a new member, or newcomer, through the 12 Steps and be available to the newcomer 24 hours a day, 7 days a week should a crisis or craving emerge. The sponsor serves as a mentor and positive role model, accompanying the newcomer to meetings, and maintaining frequent contact between meetings. A newcomer can always ask the group to assign an appropriate sponsor. Physicians can demonstrate support for a patient’s 12-Step “program” by inquiring what step she is working on, whether she has a sponsor, and how much “sober time” she has. It is important for the physician to listen to the patient’s concerns (and complaints) about 12-Step participation, then encourage the patient to continue attending. Because every AA group is autonomous, each group develops its own personality and flavor; a patient who does not like one group should try another. The 12-Step mutual-help model has been modified to help compulsive behaviors from drug use (Narcotics Anonymous, Pills ­Anonymous, Marijuana Anonymous, Cocaine Anonymous, and others) to compulsive sex to hoarding and cluttering. There are also groups for alcoholics with special interests such as musicians, professionals, gay and lesbian people, nonsmokers, and various ethnic groups. AA groups for physicians include Caduceus and International Doctors in AA (IDAA).

ADDICTION IS A FAMILY DISEASE

Codependence describes a loved one’s misguided attempts to protect an addicted or alcoholic individual from the consequences of his or her consumption of drugs or alcohol. It is a natural instinct to shelter loved ones from negative consequences, but in the case of addiction, this can be very harmful by allowing the addiction to continue and progress to greater severity. Unwittingly acting as an accomplice to an addiction is known as enabling. Enabling ranges from making excuses and explaining away behaviors to bailing an addicted individual out of jail, to providing a place to use drugs or alcohol, to joining in the use of alcohol and drugs. Codependents tend to focus on helping the addicted person manage short-term crises rather than focusing on long-term recovery from drugs and alcohol. The addicted person and the family may derive some unconscious secondary benefit from the addictive behavior that makes it difficult to stop (eg, the codependent individuals may be distracted from addressing their own problems by helping the addicted person instead). Codependents may even ally with the addicted person against physicians or others encouraging treatment and recovery. The stress of codependence, and involvement with an addicted person can be the root of somatic complaints. Thus, drug and alcohol abuse should be part of the family history obtained of every patient.

Just as codependents can have a large role in enabling a person’s addiction, they also can have an important role in recognizing the disease and ushering the patient into treatment. Some addicts will not stop using until they feel harm and perceive that they must stop to survive; thus, the best way to expedite treatment is for codependents to stop sheltering their loved one from the consequences of their use of alcohol or drugs. The consequences can then move an alcoholic or addicted person toward accepting treatment. When families are involved in treatment with the addicted individual, outcomes improve significantly. Sometimes, codependents need therapy or treatment to gain perspective before they are able to support their addicted family member toward treatment. Family members learn they only control their own behavior, and quitting their codependent roles can ease their anxiety and may be helpful in influencing the addicted family member to seek treatment. “Love with detachment” is a goal for family members. Professional group therapy, with a focus on codependency, is often available to family members at treatment centers. Al-Anon is a mutual support group for people whose lives have been affected by another person’s addiction. It is based on the 12 Steps, although its central philosophy is that members should start to focus on themselves rather than continuing to focus on their loved one’s addiction. Ala-Teen, Families Anonymous, and Tough Love are other mutual support groups for families.

PROCESS ADDICTIONS

Rather than abusing chemical substances, some people continue certain behaviors—such as overeating, gambling, or high-risk sex—despite disastrous consequences. Many behaviors are classified among the spectrum of impulse control disorders, such as trichotillomania (obsessive hair-pulling), kleptomania (decreased ability to overcome impulses to steal unwanted items), intermittent explosive disorder (failure to inhibit aggressive impulses that are disproportionate to the precipitating stressor), and obsessive-compulsive disorders. However, the compulsive nature of these behaviors is not mutually exclusive with addiction. These behaviors raise dopamine in the limbic system, although much less than substances of abuse, and are repeated in order to decrease anxiety. Some research indicates a shared genetic vulnerability between substance abuse and impulse control disorders. Because process addictions share common threads with substance use disorders, it follows that some of the same treatments might be useful. 12-Step groups have been modified to address hundreds of different behaviors, from binge eating (Overeaters Anonymous) to compulsive shopping (Overspenders Anonymous), pornography overuse, Internet overuse, pathological gambling (Gamblers Anonymous), hoarding, pathological cluttering, and many others.

ADDICTION TREATMENT WORKS

The brain changes of addiction set the stage for a chronic, recurring illness requiring long-term ongoing treatment. Just as providers care for chronic diseases like diabetes, hypertension, and asthma, they can help manage and coordinate care for the chronic disease of addiction. The first step is recognizing and diagnosing, then referring for treatment, and following up each time you see the patient. Detoxifying an addicted person in the hospital has no more effect on the disease of addiction than treating diabetic ketoacidosis (DKA) affects the course of diabetes. Both require long-term, ongoing management and treatment. Significant research demonstrates that, with proper treatment, addiction has recovery and outcomes nearly identical to the other chronic diseases.

Detoxification means poison exiting the body—in this case, alcohol or drugs of abuse clearing from the brain and blood. When a person is physically dependent on substances, detoxification can result in symptoms known as withdrawal. Some withdrawal syndromes are exquisitely uncomfortable; others are life threatening. Withdrawal can be medically supervised, which means symptoms are managed to keep patients as safe and comfortable as possible during withdrawal. This is only the first step in what will become lifelong treatment. Just as successfully managing a diabetic patient through DKA does not change the course of the disease, a detoxification episode will not alter the natural history of addiction unless the patient is treated. Just as the person with diabetes will need ongoing hypoglycemics, statins, and blood sugar monitoring, the person with addiction will need ongoing counseling, group participation (to defeat the isolation of addiction), and urine toxicology monitoring. Long-term management of stressors and re-emergent cravings, even after sustained abstinence, is crucial to relapse prevention. If the treatment for diabetes or hypertension is stopped, the symptoms again manifest in full force. The same is true for addiction and alcoholism.

Treatment means interventions delivered by licensed professionals; mutual help refers to community support groups such as AA, Rational Recovery, and Secular Organizations for Sobriety. Most recovery models employ both treatment and mutual help, engaging patients and their families in education and therapy whenever possible. Because multiple brain systems are disrupted with long-term substance abuse (and multiple areas of a patient’s life are damaged by addiction), multiple modalities are required to strengthen impulse control, overcome learned responses, support decision making, teach new coping skills, and focus on rewards that compete with substance use. It is clear that skilled, empathic therapy styles achieve better outcomes than confrontational approaches. Many treatment programs also incorporate the use of medications to help maintain sobriety—such medications have a small but measurable benefit and should be routinely offered to patients (information on such medications is in subsequent chapters). Thus the best treatment programs have specialized physician involvement; without physician involvement, programs may not be able to offer medications or diagnose or treat comorbid psychiatric or medical disorders.

Abstinence-based means that a treatment program expects abstinence from all mind-altering substances, not just the patient’s drug of choice; for example, a patient in treatment for alcohol dependence is expected not to use heroin or cocaine; a person in treatment for methamphetamine dependence is expected not to use cannabis or recreational vicodin. A patient is considered to be abstinent and sober when taking medications as prescribed by a physician—including methadone or buprenorphine (suboxone) for relapse prevention; all major 12-Step groups are in agreement. Sobriety (abstaining from mind-altering chemicals) is the bedrock to recovery, but recovery from addiction is more than just abstinence. It is learning new honesty and coping skills, and many times involves a spiritual transformation that can result in a new citizenship in society. Recovery is not something that is ever complete; it is evolving, never-ending growth.

No significant outcome advantage has been proven for residential over outpatient treatment. The treatment venue is less important than the duration of engagement in treatment. Some patients, due to the severity of their disease or the chaos of their social situation, may benefit from more highly structured treatment (residential or partial hospitalization vs outpatient). In general, more intense treatment is offered during the newly sober period, tapering off to less frequently as the patient gains stability and experience. Research shows that a minimum of 3 months of treatment is required for sustained benefit, with continued progress after 3 months. It is important for the patient to maintain some continuous connection to mutual help and/or treatment for life—otherwise relapse can occur even after years of abstinence.

When do substance users seek treatment? Some addiction experts believe that spiraling consequences and distress related to substance use, compounded by pressure from family, friends, and others can catalyze change following a specific “trigger event,” when an individual realizes that she cannot manage her addiction without help. In many cases, an intervention staged by family and friends can be helpful in moving a patient toward treatment. It is important to take advantage of such opportunities, when a substance user is ready to accept help; patients can be lost if treatment is not easily available to them.

MONITORING

Patients with chronic disease underreport damaging health behaviors that may reflect poorly on them. For example, patients with diabetes may underreport dietary indiscretion, and patients with congestive heart failure may underreport their salt intake; thus, it is important to check hemoglobin A1Cs and daily weights to be certain that the medical treatments are working, and to provide an objective measure of compliance with those treatments. Substance use disorders are no exception, and monitoring, usually with urine toxicology screening or breath-alcohol testing, is an important part of addiction treatment. Urine tests for Ethylene Glycol (ETG), an ethanol metabolite, detect alcohol intake during the previous 80 hours. Because relapse is a part of chronic disease, positive toxicology results (meaning the sample was positive for the presence of illicit substances), in concert with the patient’s history, should be addressed with empathy and support, not with confrontational accusation.

BRIEF INTERVENTION IMPROVES OUTCOMES

Hospitalists have a unique opportunity to help motivate someone toward treatment. The admission provides a “teachable moment,” and, as already mentioned, intervention outcomes are better for physicians who use an empathic approach rather than a confrontational one—this means being accepting, not approving of drug use. Overt persuasion results in patients’ working hard to resist the persuasion; they do not want to acknowledge painful realities to themselves or others. Motivational interviewing (MI) is an evidence-based process that encourages patients to voice their own reasons for stopping or cutting back. Most substance users have some degree of ambivalence (strong feelings both ways) about continuing their use, and MI is a way to identify and amplify the desire to stop using. In its simplest form, motivational interviewing queries the patients on the benefits of continuing substance use, the disadvantages of stopping, the disadvantages of continuing, and the advantages of sobriety. Asking nonjudgmentally about all four, without criticizing or blaming, helps patients to articulate their own reasons for quitting and does not create resistance.

Another model for brief intervention is the four A’s: ask, advise, assist, arrange. For any substance, including nicotine, the physician asks about length of use and consequences (family, job, financial, legal, health, injuries, blackouts, withdrawal, diminished self-care, etc) and then gives brief, specific, personalized advice about the health effects of the patient’s use: “As your physician, I must advise you that smoking cigarettes is bad for your liver. Because of your elevated liver function tests, it is important that you stop smoking now. If you stop smoking cigarettes, the damage may not progress further.” The physician can assist the patient with a referral to an addiction medicine specialist, 12-Step groups (such as Nicotine Anonymous), or a treatment center specializing in addictions; sometimes this might include prescriptions for nicotine replacement or other medications. Remember that just giving a phone number to a patient results in poor follow-up; but putting the person in touch with a 12-Step member or treatment center while in the hospital or office can have excellent results. Finally, arrange for patients to follow-up with primary care to review any action they have taken. Some patients will not be ready to stop using immediately; physicians must remain patient, empathic, and supportive at every admission when inquiring about substance use.

CONCLUSION: ADDICTION IS A TREATABLE BRAIN DISEASE

Addiction is a multifactorial chronic brain disease with social and behavioral dimensions. The brain’s limbic system is the seat of the disease, but addiction can result in end-organ damage to every system. The natural history of addiction is generally chronic relapsing-remitting with progression over time. New discoveries in brain imaging, genetics, and neurobiology shed light on the multiple brain systems affected in addiction. While psychobehavioral treatment remains the cornerstone of treatment, medications to modulate brain functions involved with cravings are emerging to buttress patients’ recovery. With proper treatment, patients with the disease of addiction have outcomes equivalent to those with other chronic diseases such as asthma, diabetes, and hypertension. The hospitalist physician can have a pivotal role in recognizing disease and directing these patients toward treatment and recovery.

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