A 32-year-old man from Mumbai is brought to the psychiatry outpatient clinic by his wife with a 6-month history of escalating cocaine use (intranasal, 2–3 grams per week). He reports intense cravings, failed attempts to cut down, and continued use despite job loss and marital conflict. On examination, he is restless, has a perforated nasal septum, and shows signs of weight loss (BMI 19). Urine drug screen confirms cocaine metabolites. He denies hallucinations or delusions. What is the most appropriate initial pharmacological intervention?

Explanation

## Diagnosis: Cocaine Use Disorder (Severe) **Key Point:** Bupropion is the first-line pharmacological agent for cocaine use disorder because it increases dopamine and norepinephrine, reducing cravings and addressing comorbid depression—a common feature in stimulant withdrawal. **High-Yield:** Cocaine's mechanism of addiction: - Blocks reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) - Produces intense euphoria and reward activation - Chronic use leads to dopamine depletion and anhedonia during withdrawal - Cravings are driven by dopamine deficiency and negative mood states ### Pharmacotherapy for Cocaine Use Disorder | Agent | Mechanism | Efficacy | Adverse Effects | Role | |-------|-----------|---------|-----------------|------| | **Bupropion** | Dopamine/NE reuptake inhibitor; NDRI | Moderate; reduces cravings and depression | Insomnia, agitation, seizure risk (dose-dependent) | **First-line** for cravings + depression | | **Fluoxetine** | SSRI (5-HT reuptake inhibitor) | Weak for cravings; good for comorbid depression/anxiety | Sexual dysfunction, GI upset | Adjunct for mood; not primary | | **Methylphenidate** | Dopamine/NE agonist (stimulant) | Contraindicated; risk of abuse and relapse | Tachycardia, hypertension, addiction potential | **Avoid** — stimulants worsen cravings | | **Disulfiram** | Aldehyde dehydrogenase inhibitor (alcohol aversion) | Weak for cocaine; no proven benefit | Hepatotoxicity, disulfiram-alcohol reaction | Not indicated; designed for alcohol | | **Topiramate** | GABA enhancer, carbonic anhydrase inhibitor | Emerging evidence for cravings | Weight loss, cognitive effects | Adjunct in research | | **Naltrexone** | Opioid antagonist | Weak for cocaine alone | Hepatotoxicity, opioid withdrawal | Better for opioid + cocaine polyuse | **Clinical Pearl:** Bupropion is preferred because: 1. It restores dopamine tone, counteracting the dopamine depletion of cocaine withdrawal 2. It addresses comorbid depression (anhedonia, low mood) common in stimulant users 3. It reduces cravings by 30–50% in clinical trials 4. It is non-addictive and does not carry abuse potential ### Dosing & Safety - **Bupropion XL:** 300 mg once daily (start 150 mg, titrate over 3 days) - **Contraindications:** Seizure disorder, eating disorder, abrupt discontinuation of alcohol/benzodiazepines - **Monitoring:** ECG baseline (QT interval), blood pressure, seizure risk ### Why Bupropion Over Alternatives **vs. Fluoxetine:** SSRIs do not address dopamine deficiency; they are weak for cravings and are best used as adjuncts for comorbid anxiety/depression. **vs. Methylphenidate:** Stimulants are contraindicated because they: - Increase dopamine acutely (mimicking cocaine effect) - Risk triggering relapse and craving escalation - Cause tachycardia and hypertension (cocaine user already at risk) - Have abuse potential in substance-use populations **vs. Disulfiram:** Disulfiram is designed for alcohol use disorder (creates aversion via aldehyde dehydrogenase inhibition); it has no pharmacological mechanism for cocaine and no evidence base in cocaine use disorder. ### Comprehensive Management 1. **Pharmacotherapy:** Bupropion ± fluoxetine (for comorbid anxiety) 2. **Psychotherapy:** Cognitive-behavioral therapy (CBT), contingency management, motivational interviewing 3. **Psychosocial:** Narcotics Anonymous, peer support, family therapy 4. **Monitoring:** Urine drug screens, craving scales, therapeutic alliance 5. **Comorbidity screening:** Depression, anxiety, ADHD, personality disorders **Prognosis:** Relapse rates are high (60–80% within 1 year); long-term engagement in treatment and psychotherapy are essential for sustained recovery.