A. Scope of Problem [1,5,6]

1. Over 1.6 milion persons in USA with opioid dependence or abuse
2. About 323,000 abuse heroin in USA
3. Diseases Associated with Opioid Abuse
   1. Overdose: anoxia, anoxic encephalopathy, coma and death
   2. Complications of needle sharing and unclean needles (see below)
   3. Heroin Nephropathy
   4. Spreading infectious disease, including tuberculosis (may be drug resistant)
4. Classification of Opiate Associated Syndromes
   1. Acute Opiate Intoxication (Overdose)
   2. Chronic Opiate Intoxication (Chronic Abuse)
   3. Opiate Withdrawal Syndrome (voluntary or involuntary)
   4. Treatments for Opiate Dependence (Detoxification or Maintenance Therapy)
5. Specific Agents
   1. Heroin: IV injection, snorted or smoked
   2. Morphine
   3. OxyContin: long acting oxycodone abused by crushing pill, snorted, dissolved for IV injection
   4. Hydrocodone abuse increasing as well
   5. Combination pentazocine (Talwin®) and tripelennamine (antihistamine)
   6. Other prescription agents may be abused: propoxyphene (Darvon®), meperidine (Demerol®)
   7. Methadone (Dolophine®) abuse now often reported
6. Only ~180,000 opioid dependent persons in USA currently receive opioid-agonist therapy
7. National Institute on Drug Abuse Web Site: www.nida.nih.gov
8. Substance Abuse and Mental Health Services Administration: www.dpt.samhsa.gov

B. Symptoms of Opiate Abuse and Overdose [2,3]

1. Gastrointestinal: nausea, vomiting, constipation, obstipation
2. Central Nervous Systemc: confusion, lethargy, stupor, unresponsiveness
3. Meiosis
4. Hypothermia
5. Respiratory Depression and Failure (major cause of death)
6. Triad of coma, respiratory depression, and pinpoint pupils
7. Opiates may be combined with stimulants (often called a "speedball")
   1. Cocaine and amphetamines are most commonly used with opiates
   2. These will obscure depressive effects of opiates
8. Complications
   1. Unclean needles and/or skin: endocarditis, septic arthritis, septic emboli
   2. Needle sharing: HIV, Hepatitis C virus, Hepatitis B virus, bacteremias
   3. Post-anoxic sequellae (especially encephalopathy)
   4. Pulmonary capillary leak syndromes

C. Opiate Withdrawal Syndrome

1. Occurs in persons chronically on opiates, particularly using drugs for recreation (abuse)
2. Early Symptoms: yawning, rhinorrhea, diaphoresis, lacrimation
3. Later symptoms, signs: Nausea, vomiting, tachycardia, diaphoresis, anxiety
4. Symptoms peak 2-3 days after cessation of narcotics
5. Gradual returning to normal over 5-7 days

D. Treatment of Opiate Intoxication [3,12,15]

1. Reversal of suppressive effects with opiate antagonist is called detoxification (detox) [21]
   1. Several protocols developed using clonidine or buprenorphine or naltrexone for induction
   2. This is followed by escalating naltrexone doses or general anesthesia [22]
   3. Other opiate anagonists such as naloxone and nalmefene may be used
   4. Administration of antagonists induces acute opiate withdrawal
   5. This withdrawal syndrome is potentially severe
   6. Intensive supportive management is usually required
   7. General anesthesia to accelerate detox is not superior to standard drug-only protocols [22]
   8. Adding clonidine+buprenorphine to naltrexone may be most effective detox method [18]
   9. Detox is preferred therapeutic modality for severe and most moderate intoxification
2. Naloxone (Narcan®) [4]
   1. Pure opioid antagonist
   2. Drug half life ~30-45 minutes, given IV is the most commonly used agent
   3. Administered initially 2mg IV, repeat q2-3 minutes to 10mg total
   4. IV form is not appropriate for long term use
   5. Now available in combination with buprenorphine sublingual (Suboxone®)
3. Naltrexone
   1. Opiate antagonist also use for detoxification
   2. Patients are then usually converted to maintenance therapy on naltrexone
   3. Dose 50-100mg po daily or three times per week
4. Nalmefene (Revex®) [16]
   1. Half life is significantly longer than naloxone
   2. Nalmefene may be used for higher dose opiate intoxication
5. Treatment of Withdrawal with Non-Opiate Agents [1,12]
   1. Both elective and non-elective opiate withdrawal syndromes may be treated
   2. Clonidine, a centrally acting a2-agonist, 0.1-0.3 mg q8-12 hours usually effective
   3. Clonidine slows heart rate, reduces blood pressure, and can reduce craving
   4. However, clonidine is more effective for autonomic than for psychiatric symptoms
   5. Benzodiazepines may be used for sedation, but caution with respiratory suppression
   6. Blood pressure and heart rate stabilization may require additional agents
6. Rapid and ultrarapid methods for opiate detox have been developed
   1. Rapid detox uses naloxone or nalatrexone
   2. Ultrarapid detox uses anesthesia or heavy sedation
   3. Highly effective and nearly ultrarapid detox uses naltrexone+clonidine+buprenorphine [18]
   4. For severe intoxication, mechanical ventilation is often required
   5. This may be preferred in setting of ultrarapid detoxification
   6. Goal of these methods is to reduce the period of opiate withdrawal symptoms
   7. Unclear whether these methods lead to improved longer term outcomes
7. High Clinical Suspicion for Endocarditis
   1. Blood Cultures should be done routinely on all patients undergoing detoxification
   2. Baseline electrocardiogram (ECG) is very important
   3. Cardiac murmers should be evaluated with echocardiography

E. Treatment of Opioid Dependence [1,12,15]

1. Treatment Strategies for Dependence and Withdrawal Symptoms [8]
   1. Detoxification and abstinance is one methodology (uses opiate antagonists)
   2. Maintenance therapy with monitoring and "legal" opiate agonists is other option
2. Detoxification (see above) [1,3]
   1. Detoxification followed by maintenance with opioid antagonist with psychotherapy
   2. Permits complete abstinence from opioids after difficult withdrawal period
   3. Does not require constant methadone or LAAM maintenance therapy
   4. Clonididine combined with naltrexone was as effective as buprenorphine alone, and more effective than clonidine alone in permitting opioid detoxification
   5. Patients receiving the mixed agonist-antagonist buprenorphine had less severe withdrawal reactions than the clonidine and/or naltrexone groups
   6. Benzodiazepines are often used as adjunctive therapies for sedation
3. Maintenance to Prevent Relapse [6,9]
   1. Usually carried out with opioid agonists such as methadone or LAAM
   2. Naltrexone, an opioid antagonist, is also used (50-100mg po qd or tiw)
   3. Buprenorphine, a partial agonist, is now available (8-12mg sublingual qd to tiw) [17]
   4. Buprenorphine was superior to naltrexone as single agent maintenance therapy for 24 weeks in heroin abusers in Malaysia [23]
   5. In USA, <25% of opioid depdendent persons currently receiving methadone or LAAM
   6. Combined buprenorphine-naloxone sublingual reduce opioid abuse administered in office- based setting [19]
   7. With buprenorphine-naloxone, adding brief weekly counseling or once-weekly medication did not differ from extended weekly counseling and 3X weekly medication [20]
4. Methadone (Dolophine®) [8,9,11]
   1. Methadone is a long acting µ-opiate receptor agonist with less abuse potential than heroin
   2. Methadone prevents opiate withdrawal and reduces subjective effects of illegal opioids
   3. Methadone must be taken daily, generally in supervised, highly restricted, setting
   4. Duration of action (prevention of opiate desire) is 24-36 hours
   5. Methadone maintenance programs are more effective than psychosocial support alone [11]
   6. Initial dosage is usually 10-40mg/day in opiate dependent persons
   7. Doses >50mg/d are usually required initially to prevent cravings (and patient drop-out)
   8. Daily high dose (80-100mg) more effective than moderate (40-50mg) and low (20mg) methadone dose for opioid abstinance and completion of detoxification program [10,13]
   9. There is no maximum dose, and each patient needs to be titrated
   10. Urinalysis is usually done to monitor compliance and assess other illegal drug abuse
   11. Reduction rates are 10mg/week for >80mg/d, 5mg/wk for 40-80mg/d, and 2.5mg/wk for <40mg/d
   12. Opioid dependent patients on stable methadone can be transferred to primary care physicians for continuing treatment [14]
   13. If transferring from methodone to buprenorphine, reduce methodone dose to <30mg/d
   14. Schedule II agent (severely restricted, see below)
5. Buprenorphine (Subutex®, Suboxone®) [6,7,17]
   1. Sublingual tablets approved for treatment of opioid dependence
   2. Mixed opiate agonist/antagonist (partial agonist at mu receptors)
   3. Clearly reduces opioid self-administration (opiate abuse)
   4. Dose is 12-16mg/day (usually begun at 2mg/day, dose doubled to 16-32mg/d)
   5. Can also be given as 8-24mg sublingually, daily or three times per week
   6. Maximum dose sublingual is 24-32mg daily
   7. Use in primary care setting is at least as effective as in drug-dependence centers
   8. As effective as high dose methadone and LAAM [13]
   9. One year retention in buprenorphine group 100% versus 0% with placebo in Sweden [7]
   10. Buprenorphine superior to naltrexone as single agent maintenance therapy for 24 weeks in heroin abusers in Malaysia [23]
   11. Also available in combination with naloxone (Suboxone®)
   12. Schedule III agent (less severely restricted than methadone)
   13. Office based treatment with buprenorphine-naloxone combination may be most effective [6]
   14. See prescription guidelines at www.suboxone.com
6. Levo-Alpha-Acetylmethadol (LAAM) [12,13]
   1. Opioid agonist longer acting than methadone, may be used on alternate days (qod)
   2. LAAM is effective in a dose dependent fashion
   3. Recommended dose is 50/50/70mg or 100/100/140mg (thrice weekly)
7. Treatment Regulations [17]
   1. Schedule III, IV, V drug prescriptions allowed in specific office-based settings
   2. Physicians must be certified in addiction medicine or addiction psychiatry, OR have at least 8 hours authorized training, OR participated in clinical trial
   3. Prescribers must register with Substance Abuse and Mental Health Services Admin
   4. Each physician or group practice may treat up to 30 patients with buprenorphine at once

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