Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Patient Story Download Section PDF Listen ++ A 26-year-old man is brought into the emergency department in status epilepticus by his “friends,” who promptly flee the scene. His seizures spontaneously cease, and he is noted to have an altered mental status. IV access is obtained and he is stabilized. A urine toxicology screen is positive for cocaine and his creatinine phosphokinase is markedly elevated. He is admitted for cocaine-induced seizures and rhabdomyolysis. He survives the hospitalization and consents to a photograph of his eyes before discharge. Figure 239-1 shows the bilateral subconjunctival hemorrhages that occurred during his seizures. The patient states that he understands the gravity of the situation and will enter a drug rehabilitation program when he leaves the hospital. ++Figure 239-1Graphic Jump LocationView Full Size||Download Slide (.ppt)Bilateral subconjunctival hemorrhages after severe cocaine-induced seizures in a young man. This patient also developed rhabdomyolysis and was hospitalized. (Courtesy of Beau Willison, MD.) + Introduction Download Section PDF Listen ++ Cocaine use is common, and 5% to 6% of users develop dependence within the first year of use. Acutely intoxicated patients have increased heart rates, blood pressures, temperatures, and, initially, respiratory rates; mood changes, involuntary movements; and dilated pupils. Chronic addiction can be treated with a comprehensive program, although only one-third of patients will become and remain abstinent. + Synonyms Download Section PDF Listen ++ Cocaine is also called blow, C, coke, crack, flake, and snow. + Epidemiology Download Section PDF Listen ++ Based on the National Comorbidity Survey Replication (NCS-R) using interviews with a nationally representative sample of 9282 English-speaking respondents ages 18 years and older (conducted in 2001 to 2003), the cumulative incidence of cocaine use was 16%.1Similar numbers were reported from the National Survey on Drug Use and Health in 2005:2Of Americans ages 12 years and older, 13.8% reported lifetime cocaine use in 2005.2A total of 33.7 million Americans ages 12 years and older reported lifetime use of cocaine, and 7.9 million reported using crack cocaine.2An estimated 2.4 million Americans reported current use of cocaine (682,000 of whom reported using crack).2Of the estimated 860,000 new users of cocaine in 2005, most were age 18 years or older, with the average age of first use being 20 years.2The percentage of youth ages 12 to 17 years reporting lifetime use of cocaine was 2.3%, and among young adults ages 18 to 25 years the rate was 15.1%.2For both male and female cocaine users, the estimated risk for developing cocaine dependence, based on data from the NCS-R, was 5% to 6% within the first year after first use.3 Thereafter, the estimated risk decreased from the peak value, with a somewhat faster decline for females in the next 3 years after first use.Females may be more susceptible to crack/cocaine dependence; in a study of 152 individuals (37% female) in a residential substance-use treatment program, females evidenced greater use of crack/cocaine (current and lifetime heaviest) and were significantly more likely to show crack/cocaine dependence than males.4In one study, siblings of cocaine-dependent individuals had an elevated risk of developing cocaine dependence (relative risk [RR] = 1.71).5 + Etiology and Pathophysiology Download Section PDF Listen ++ Cocaine is a stimulant and local anesthetic that causes potent vasoconstriction.It produces its stimulant effects by causing increasing synaptic concentration of monoamine neurotransmitters (i.e., dopamine, norepinephrine, and serotonin).6Similar to other local anesthetics, cocaine blocks the generation and conduction of electrical impulses in excitable tissues (e.g., neurons and cardiac muscle) blocking the voltage-gated fast sodium channels in the cell membrane and abolishing the ability of the tissue to generate an action potential.7Effects are seen following oral, intranasal (as a powder [Figure 239-2]), IV, and inhalation administration (as crack cocaine [Figure 239-3], coca paste, and free-base). ++Figure 239-2Graphic Jump LocationView Full Size||Download Slide (.ppt)Cocaine in a powder form used for snorting and injecting. (Courtesy of the Drug Enforcement Agency.) ++Figure 239-3Graphic Jump LocationView Full Size||Download Slide (.ppt)Crack cocaine used for smoking. (Courtesy of the Drug Enforcement Agency.) + Risk Factors Download Section PDF Listen ++ Family history/genetic predispositionIn a study of inner-city incarcerated male adolescents (23% of whom had used cocaine or crack in the month before arrest and 32% of whom had used cocaine at least once), current cocaine/crack users were more likely to have the following characteristics:8Alcohol, marijuana, and intranasal heroin use.Multiple previous arrests.To be out of school.To be psychologically distressed.To have been sexually molested as a child.To have substance-abusing parents.To have frequent sex with girls, to be gay or bisexual, and to engage in anal intercourse.Among those who died from an accidental drug overdose in New York City, those dying from cocaine-only versus opiates were more likely to be male, black or Hispanic, have alcohol detected at autopsy, and to be of older age.9 + Diagnosis Download Section PDF Listen +++ Clinical Features ++ Acute effects occur within 3 to 5 minutes with intranasal administration (8 to 10 seconds with free base) and last approximately 1 hour, after which there is an abrupt disappearance of the effects.6 When used IV or smoked as crack cocaine, the onset of action is immediate and the peak effect occurs 3 to 5 minutes later, lasting for 20 to 30 minutes.7The acute effects include:6,7Elevated heart rate, increased blood pressure, and usually increased temperature.Increased respiratory rate and/or dyspnea followed by decreased respiratory rate.Mood changes including enhanced mood/euphoria, hyperactivity, irritability and anxiety, excessive talking, and long periods without eating or sleeping.Involuntary movements (e.g., tremors, chorea, and dystonic reactions).Additional findings on physical examination can include: Dilated pupils, nystagmus, and/or retinal hemorrhages.Nasal septum perforation (Figure 239-4), epistaxis, and/or cerebrospinal fluid (CSF) rhinorrhea.Wheezing, rales, and/or pneumothorax.Absent bowel sounds (mesenteric ischemia) and/or right upper quadrant tenderness (hepatic necrosis).Skin tracks from intravenous use (Figure 239-5).Multiple areas of atrophic skin scars are from skin popping—injecting cocaine directly into the skin without finding a vein for intravenous injections (Figure 239-6).Acute effects may be altered by concomitant use of other drugs or alcohol.Adverse effects of cocaine use can include:6Respiratory depression that may result in death.Cardiac arrhythmias, chest pain, and myocardial infarction (MI).Neurologic symptoms, including headache, tonic-clonic seizures, ischemic or hemorrhagic stroke, and subarachnoid hemorrhage.Myalgias and rhabdomyolysis.Severe pulmonary disease (e.g., alveolar hemorrhage and pulmonary edema) and hepatic necrosis caused by crack cocaine.Exacerbation of existing hypertension, cardiac, and cerebrovascular disease.Recurrent diabetic ketoacidosis.10Cutaneous vasculitis secondary to levamisole-adulterated cocaine has been reported many times in the literature.11-15 This type of vasculitis presents with ear purpura (Figure 239-7), retiform (like a net) purpura (Figure 239-8) of the trunk or extremities, neutropenia, and positive tests for perinuclear antineutrophil cytoplasmic antibody (P-ANCA).11 A 2010 U.S. report found that more than 77% of seized cocaine in the United States is contaminated with levamisole.13 This cutaneous vasculitis may also present on the nose or face (Figure 239-9).Chronic cocaine use is associated with decreased libido and impaired reproductive function.1In men, cocaine can cause impotence and gynecomastia.In women, cocaine can cause galactorrhea, amenorrhea, and infertility.In pregnant women, crack cocaine is associated with an increase in placental abruption, miscarriage, and congenital malformation.Protracted use can cause paranoid ideation and visual and auditory hallucinations. Severe depression can follow recovery from cocaine intoxication (called “crashing”).1Withdrawal from chronic cocaine use can cause depression, insomnia, and anorexia. ++Figure 239-4Graphic Jump LocationView Full Size||Download Slide (.ppt)Shining a light through a hole in the nasal septum caused by 10 years of snorting cocaine. (Courtesy of Richard P. Usatine, MD.) ++Figure 239-5Graphic Jump LocationView Full Size||Download Slide (.ppt)An injection track along the vein of a young woman in recovery from IV cocaine use and addiction. (Courtesy of Richard P. Usatine, MD.) ++Figure 239-6Graphic Jump LocationView Full Size||Download Slide (.ppt)Multiple areas of atrophic skin scarring from skin popping cocaine. Note how the scars are depressed and relatively round. Some cocaine addicts inject the cocaine directly into the skin rather than look for a vein for intravenous injections. (Courtesy of Richard P. Usatine, MD.) ++Figure 239-7Graphic Jump LocationView Full Size||Download Slide (.ppt)Cutaneous vasculitis of the ear caused by levamisole-adulterated cocaine. (Courtesy of Robert T. Gilson, MD.) ++Figure 239-8Graphic Jump LocationView Full Size||Download Slide (.ppt)Cutaneous vasculitis in a retiform (net-like) pattern caused by the use of levamisole-adulterated cocaine. This is also called retiform purpura. (Courtesy of University of Texas Health Science Center San Antonio, Division of Dermatology.) ++Figure 239-9Graphic Jump LocationView Full Size||Download Slide (.ppt)Cutaneous vasculitis of the nose secondary to the use of levamisole-adulterated cocaine. (Courtesy of Robert T. Gilson, MD.) +++ Laboratory Studies ++ Urine toxicology screen (using immunoassays) for commonly abused drugs (e.g., cocaine, marijuana, and opiates) is the gold standard. Cocaine may be detected in the urine for 24 hours after use and the metabolite of cocaine, benzoylecgonine, may be detected as long as 60 hours after a single use.7In chronic cocaine users, benzoylecgonine may be detected for up to 22 days.7A rapid urine test, OnTrak Testcup-5, was reported in a manufacturer-supported study to be accurate and reproducible for marijuana, cocaine, and heroin.16Saliva and hair tests are also available but may not be as accurate for all drugs of interest.All injection-drug users should be screened for human immunodeficiency virus (HIV) (with consent) and hepatitides B and C.If there is a history of multiple sexual partners, unsafe sex and/or sex for drugs, cocaine users should be screened for sexually transmitted diseases (STDs). This might include Chlamydia, gonorrhea, hepatitides B and C, HIV (with consent), and syphilis (Figure 239-10).In an unconscious patient and in patients denying cocaine use, the following laboratory tests can be considered to rule out other diseases with similar symptoms:7Serum glucose, magnesium, and phosphorus.Serum electrolytes.Laboratory tests that can be completed to detect or monitor acute complications of cocaine overdose include:7Arterial blood gas (respiratory acidosis or alkalosis).Blood urea nitrogen (BUN) and/or creatinine (renal infarction).Creatinine kinase (CK) (rhabdomyolysis) and isoenzyme of creatine kinase (CK-MB) (MI).Liver function tests (liver necrosis).Urine dipstick (rhabdomyolysis). ++Figure 239-10Graphic Jump LocationView Full Size||Download Slide (.ppt)Secondary syphilis in a man who was involved in unsafe sex while addicted to cocaine. The papulonodular eruption is an unusual presentation of secondary syphilis that was diagnosed with a skin biopsy and confirmed with an rapid plasma reagin titer of 1:512. The specific treponemal blood test was also positive. (Courtesy of Richard P. Usatine, MD.) +++ Imaging and Other Tests ++ Plain films of the abdomen (supine and upright) can be useful in the diagnosis of body packing or stuffing of cocaine (swallowing or inserting packets of cocaine into a body orifice), but false-negative results may occur. Serial abdominal roentgenograms may be useful in detecting the passage of drug packages.7A chest x-ray and head CT can be considered for respiratory and neurologic symptoms, respectively. + Differential Diagnosis Download Section PDF Listen ++ Adrenal hyperplasia or adenoma—Produces excess cortisol, causing signs and symptoms of Cushing syndrome, including hypertension and emotional changes (ranging from irritability to severe depression and psychosis). Distinguishing features are increased body weight with adipose deposition in the upper face (“moon” facies) and interscapular area (“buffalo” hump), hirsutism, violaceous cutaneous striae, and proximal myopathy. A 24-hour urine test for free cortisol or overnight dexamethasone suppression test is recommended for diagnosis.Hyperthyroidism—In addition to tachycardia and nervousness/agitation, patients can report fatigue, weight loss, and heat intolerance. Exophthalmus and pretibial myxedema may be seen, and laboratory testing reveals a low or undetectable thyroid-stimulating hormone (TSH) and an elevated free thyroxin level (T4) (see Chapter 227, Graves Disease and Goiter).Delirium—Defined as a state of confusion accompanied by agitation, hallucinations, tremor, and illusions, delirium can be caused by drug toxicity or withdrawal, seizure, head injury, systemic infections, metabolic disorders, or a chronic dementing condition. The history, physical examination, and laboratory tests (many noted above) can help to identify the etiology.Hypoglycemia—Low blood sugar most commonly caused by taking insulin or oral drugs used to treat diabetes mellitus. Symptoms include confusion, fatigue, seizures, and loss of consciousness. Autonomic responses to hypoglycemia include palpitations, sweating, tremor, and anxiety. Laboratory testing for serum glucose will document the condition, and symptoms resolve with administration of oral or IV glucose.Meningitis—Acute infection within the subarachnoid space presenting within hours or days with fever, headache, and stiff neck (more than 90% of patients); additional potential signs are change in mental status (e.g., confusion and decreased consciousness), seizures, increased intracranial pressure, and stroke. The appearance of a rash/petechiae can aid in the diagnosis (meningococcemia). Diagnosis is made with examination of the CSF following lumbar puncture (LP).Encephalitis—Acute infection of the central nervous system that involves the brain parenchyma usually caused by viruses. The clinical features include fever, altered level of consciousness, and focal (e.g., aphasia, ataxia, hemiparesis, and involuntary movements) or diffuse (e.g., agitation, hallucinations, and personality change) symptoms. Diagnosis is established with examination of the CSF following LP. + Management Download Section PDF Listen +++ Management of Acute Overdose ++ Acute overdose is a medical emergency best managed in the intensive care unit because of the hyperadrenergic state and seizures. Hyperthermia and severe psychomotor agitation are the most immediately life-threatening complications of cocaine poisoning.7 Temperatures as high as 45.6°C (114°F) have been recorded. Rapid physical cooling with sponging, fans, ice baths, and cooling blankets can be used and gastric or peritoneal lavage with iced saline is considered if persistent.IV diazepam up to 0.5 mg/kg given over 8 hours is used to control psychomotor agitation and seizures. Hypertension may also respond to benzodiazepines. β-Blockers should not be used in the setting of cocaine toxicity (except to control ventricular arrhythmia, as below) because they may result in unopposed alpha effects of cocaine.7Avoid the use of neuroleptic agents because they can interfere with heat dissipation and, perhaps, lower the seizure threshold.7Avoid physical restraints if possible. Benzodiazepines are safe to use as a pharmacologic restraint.7Propranolol (0.5 to 1 mg IV) can be used to control ventricular arrhythmia. Perform defibrillation in all patients with pulseless ventricular tachycardia.7Consider electrical cardioversion in all unstable patients.7Beta-blockers should not be used in cocaine-induced cardiac ischemia.17 Nitroglycerin may be used for cocaine-induced cardiac ischemia or infarct. 7Monitor for rhabdomyolysis and provide rapid fluid resuscitation as needed.7Check a pregnancy test on women of childbearing years as 6% of emergency room patients may have an unrecognized pregnancy.7Administer activated charcoal to alert patients with oral ingestions of cocaine (i.e., body stuffers and body packers) to reduce absorption. Whole-bowel irrigation may be used to reduce transit time in these patients.7Medical providers should be prepared to manage multiple drug effects, especially heroin. +++ Management of Chronic Addiction ++ Cognitive-behavioral therapy is effective in the treatment of cocaine-dependent outpatients.18There is no current evidence supporting the clinical use of carbamazepine, antidepressants, dopamine agonists, disulfiram, mazindol, phenytoin, nimodipine, lithium, and NeuRecover-SA in the treatment of cocaine dependence.19Antidepressant medication exerts a modest beneficial effect for patients with combined depressive and substance-use disorders, but should be used as part of a program to directly target the addiction.20The cocaine vaccine elicits an immune response that binds cocaine, creating an immune complex that is too large to cross the blood-brain barrier. In early phase II trials, 57% of subjects remained abstinent at 6 months. The immunologic treatment of substance use disorders is an exciting new approach that needs further study.21 +++ Referral ++ Referral to specialists may be needed to assist patients with upper respiratory tract (e.g., CSF rhinorrhea and nasal septum perforation) or ophthalmologic complications (e.g., central retinal artery occlusion).Following withdrawal from chronic cocaine use, patients may benefit from individual, group, and/or family therapy and peer assistance.6 + Prognosis Download Section PDF Listen ++ Cocaine addiction is difficult to treat.Of patients enrolled in cocaine addiction programs, 42% do not complete treatment.22One-third of patients treated for cocaine addiction remain abstinent.22 Some comprehensive therapy programs have demonstrated abstinence rates at 1 year of up to 58%.23Of 131 persons addicted to crack cocaine, 107 were able to be followed for 12-years: 43 (33%) were crack-free for at least 12 months, 22 (17%) continued to use, 13 (10%) were imprisoned, 2 (1.5%) were lost to follow-up, and 27 (20.5%) were deceased.24 + Follow-Up Download Section PDF Listen ++ Patients and their families may need ongoing support, home healthcare, and physical and occupational therapy to address long-term neurologic and cardiovascular complications of cocaine including anoxic encephalopathy, stroke, intracerebral hemorrhage, congestive heart failure, and cardiomyopathy.Physicians should closely monitor and assist patients in managing depression, insomnia, and anorexia that may follow cessation of chronic cocaine use.6Among individuals leaving residential detoxification, chronic pain is a common problem and is associated independently with long-term substance use after detoxification; management of pain may improve long-term outcomes.25 + Patient Education Download Section PDF Listen ++ Encourage patients to quit cocaine use and offer assistance.Recommend 12-step programs including cocaine anonymous.Patients should be made aware of the potential complications associated with use of cocaine, including its powerful psychologically addictive properties.Instruct patients about seeking help in the emergency department for any of the following:26A brisk nosebleed that does not stop after 10 minutes of direct pressure.Facial pain or headache with a fever.Severe chest pain, difficulty breathing, or shortness of breath.If pregnant, vaginal bleeding or premature labor pains.Significant swelling, pain, redness, and red lines leading from the injection site and accompanied by fever.Severe abdominal pain, persistent vomiting, and vomiting blood.If you think that one of your packets you have swallowed or stuffed in a body orifice (vagina and rectum) is leaking or has broken.Instruct IV drug users who continue to use not to reuse or share needles or syringes; cleaning the skin before injection can also decrease risk of infection. Harm reduction programs exist that help addicts obtain and maintain clean needles and syringes. +++ Patient Resources ++ eMedicineHealth. Cocaine Abuse—http://www.emedicinehealth.com/cocaine_abuse/article_em.htm.The Substance Abuse and Mental Health Services Administration (SAMHSA) provides an on-line resource for locating drug and alcohol abuse treatment programs—http://findtreatment.samhsa.gov/TreatmentLocator/faces/quickSearch.jspx.The SAMHSA referral helpline in English and Spanish is: 1-800-662-HELP.National Institute on Drug Abuse. Preventing Drug Abuse among Children and Adolescents (In Brief) [for parents]—http://www.drugabuse.gov/prevention/prevopen.html.Cocaine Anonymous (CA). Meetings are free. “Hope, Faith and Courage: Stories from the Fellowship of Cocaine Anonymous” now has a new second volume to go with the first volume - both can be ordered online—http://www.ca.org/. +++ Provider Resources ++ National Institute on Drug Abuse. Cocaine—http://www.nida.nih.gov/drugpages/cocaine.html.MedlinePlus. Cocaine—http://www.nlm.nih.gov/medlineplus/cocaine.html.U.S. Drug Enforcement Administration. Cocaine—http://www.usdoj.gov/dea/concern/cocaine.html. + References Download Section PDF Listen ++1. Degenhardt L, Chiu WT, Sampson N, et al. Epidemiological patterns of extra-medical drug use in the United States: evidence from the National Comorbidity Survey Replication, 2001-2003. Drug Alcohol Depend. 2007;90(2-3):210-223. ++2. National Survey on Drug Use and Health. Substance Abuse and Mental Health Services Administration. http://www.samhsa.gov, accessed May 14, 2012. ++3. Wagner FA, Anthony JC. Male-female differences in the risk of progression from first use to dependence upon cannabis, cocaine, and alcohol. Drug Alcohol Depend. 2007;86(2-3):191-198. ++4. Lejuez CW, Bornovalova MA, Reynolds EK, et al. Risk factors in the relationship between gender and crack/cocaine. Exp Clin Psychopharmacol. 2007;15(2):165-175. [PubMed: 17469940] ++5. Bierut LJ, Dinwiddie SH, Begleiter H, et al. Familial transmission of substance dependence: Alcohol, marijuana, cocaine, and habitual smoking: a report from the Collaborative Study on the Genetics of Alcoholism. Arch Gen Psychiatry. 1998;55(11):982-988. [PubMed: 9819066] ++6. Mendelson JH, Mello NK. Cocaine and other commonly abused drugs. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL eds. Harrison's Principles of Internal Medicine, 16th ed. New York, NY: McGraw-Hill; 2005:2570-2573. ++7. Burnett LB. Cocaine Toxicity in Emergency Medicine Treatment and Management. http://emedicine.medscape.com/article/813959, updated Mar 19, 2010, accessed May 14, 2012. ++8. Kang SY, Magura S, Shapiro JL. Correlates of cocaine/crack use among inner-city incarcerated adolescents. Am J Drug Alcohol Abuse. 1994;20(4):413-429. [PubMed: 7832177] ++9. Bernstein KT, Bucciarelli A, Piper TM, et al. Cocaine- and opiate-related fatal overdose in New York City, 1990-2000. BMC Public Health. 2007;7:31. [PubMed: 17349051] ++10. Nyenwe EA, Loganathan RS, Blum S, et al. Active use of cocaine: an independent risk factor for recurrent diabetic ketoacidosis in a city hospital. Endocr Pract. 2007;13(1):22-29. [PubMed: 17360297] ++11. Chung C, Tumeh PC, Birnbaum R, et al. Characteristic purpura of the ears, vasculitis, and neutropenia—a potential public health epidemic associated with levamisole-adulterated cocaine. J Am Acad Dermatol. 2011;65:722-725. [PubMed: 21658797] ++12. Gross RL, Brucker J, Bahce-Altuntas A, et al. A novel cutaneous vasculitis syndrome induced by levamisole-contaminated cocaine. Clin Rheumatol. 2011;30:1385-1392. [PubMed: 21706168] ++13. Gulati S, Donato AA. Lupus anticoagulant and ANCA associated thrombotic vasculopathy due to cocaine contaminated with levamisole: a case report and review of the literature. J Thromb Thrombolysis. 2012;34(1):7-10. [PubMed: 22437653] ++14. Jenkins J, Babu K, Hsu-Hung E, et al. ANCA-positive necrotizing vasculitis and thrombotic vasculopathy induced by levamisole-adulterated cocaine: a distinctive clinicopathologic presentation. J Am Acad Dermatol. 2011;65:e14-e16. ++15. Larocque A, Hoffman RS. Levamisole in cocaine: unexpected news from an old acquaintance. Clin Toxicol (Phila). 2012;50:231-241. [PubMed: 22455354] ++16. Yacoubian GS Jr, Wish ED, Choyka JD. A comparison of the OnTrak Testcup-5 to laboratory urinalysis among arrestees. J Psychoactive Drugs. 2002;34(3):325-329. [PubMed: 12422945] ++17. Sen A, Fairbairn T, Levy F. Best evidence topic report. Beta-blockers in cocaine induced acute coronary syndrome. Emerg Med J. 2006;23(5):401-402. [PubMed: 16627850] ++18. Carroll KM, Onken LS. Behavioral therapies for drug abuse. Am J Psychiatry. 2005;162(8):1452-1460. [PubMed: 16055766] ++19. de Lima MS, de Oliveira Soares BG, Reisser AA, Farrell M. Pharmacological treatment of cocaine dependence: a systematic review. Addiction. 2002;97(8):931-949. ++20. Nunes EX, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896. [PubMed: 15100209] ++21. Shorter D, Kosten TR. Novel pharmacotherapeutic treatments for cocaine addiction. BMC Med. 2001,9:119. ++22. Dutra L, Stathopoulou G, Basden SL, et al. A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry. 2008;165:179-187. [PubMed: 18198270] ++23. Secades-Villa R, García-Rodríguez O, García-Fernández G, et al. Community reinforcement approach plus vouchers among cocaine-dependent outpatients: twelve-month outcomes. Psychol Addict Behav. 2011;25(1):174-179. [PubMed: 21261406] ++24. Dias AC, Araujo MR, Laranjeira R. Evolution of drug use in a cohort of treated crack cocaine users. Rev Saude Publica. 2011;45(5):938-948. [PubMed: 21808833] ++25. Larson MJ, Paasche-Orlow M, Cheng DM, et al. Persistent pain is associated with substance use after detoxification: A prospective cohort analysis. Addiction. 2007;102(5):752-760. [PubMed: 17506152] ++26. Dryden-Edwards R. http://www.emedicinehealth.com/cocaine_abuse/article_em.htm, accessed May 14, 2012.