A. Scope of Problem [1,5,6]
- Over 1.6 milion persons in USA with opioid dependence or abuse
- About 323,000 abuse heroin in USA
- Diseases Associated with Opioid Abuse
- Overdose: anoxia, anoxic encephalopathy, coma and death
- Complications of needle sharing and unclean needles (see below)
- Heroin Nephropathy
- Spreading infectious disease, including tuberculosis (may be drug resistant)
- Classification of Opiate Associated Syndromes
- Acute Opiate Intoxication (Overdose)
- Chronic Opiate Intoxication (Chronic Abuse)
- Opiate Withdrawal Syndrome (voluntary or involuntary)
- Treatments for Opiate Dependence (Detoxification or Maintenance Therapy)
- Specific Agents
- Heroin: IV injection, snorted or smoked
- Morphine
- OxyContin: long acting oxycodone abused by crushing pill, snorted, dissolved for IV injection
- Hydrocodone abuse increasing as well
- Combination pentazocine (Talwin®) and tripelennamine (antihistamine)
- Other prescription agents may be abused: propoxyphene (Darvon®), meperidine (Demerol®)
- Methadone (Dolophine®) abuse now often reported
- Only ~180,000 opioid dependent persons in USA currently receive opioid-agonist therapy
- National Institute on Drug Abuse Web Site: www.nida.nih.gov
- Substance Abuse and Mental Health Services Administration: www.dpt.samhsa.gov
B. Symptoms of Opiate Abuse and Overdose [2,3]
- Gastrointestinal: nausea, vomiting, constipation, obstipation
- Central Nervous Systemc: confusion, lethargy, stupor, unresponsiveness
- Meiosis
- Hypothermia
- Respiratory Depression and Failure (major cause of death)
- Triad of coma, respiratory depression, and pinpoint pupils
- Opiates may be combined with stimulants (often called a "speedball")
- Cocaine and amphetamines are most commonly used with opiates
- These will obscure depressive effects of opiates
- Complications
- Unclean needles and/or skin: endocarditis, septic arthritis, septic emboli
- Needle sharing: HIV, Hepatitis C virus, Hepatitis B virus, bacteremias
- Post-anoxic sequellae (especially encephalopathy)
- Pulmonary capillary leak syndromes
C. Opiate Withdrawal Syndrome
- Occurs in persons chronically on opiates, particularly using drugs for recreation (abuse)
- Early Symptoms: yawning, rhinorrhea, diaphoresis, lacrimation
- Later symptoms, signs: Nausea, vomiting, tachycardia, diaphoresis, anxiety
- Symptoms peak 2-3 days after cessation of narcotics
- Gradual returning to normal over 5-7 days
D. Treatment of Opiate Intoxication [3,12,15]
- Reversal of suppressive effects with opiate antagonist is called detoxification (detox) [21]
- Several protocols developed using clonidine or buprenorphine or naltrexone for induction
- This is followed by escalating naltrexone doses or general anesthesia [22]
- Other opiate anagonists such as naloxone and nalmefene may be used
- Administration of antagonists induces acute opiate withdrawal
- This withdrawal syndrome is potentially severe
- Intensive supportive management is usually required
- General anesthesia to accelerate detox is not superior to standard drug-only protocols [22]
- Adding clonidine+buprenorphine to naltrexone may be most effective detox method [18]
- Detox is preferred therapeutic modality for severe and most moderate intoxification
- Naloxone (Narcan®) [4]
- Pure opioid antagonist
- Drug half life ~30-45 minutes, given IV is the most commonly used agent
- Administered initially 2mg IV, repeat q2-3 minutes to 10mg total
- IV form is not appropriate for long term use
- Now available in combination with buprenorphine sublingual (Suboxone®)
- Naltrexone
- Opiate antagonist also use for detoxification
- Patients are then usually converted to maintenance therapy on naltrexone
- Dose 50-100mg po daily or three times per week
- Nalmefene (Revex®) [16]
- Half life is significantly longer than naloxone
- Nalmefene may be used for higher dose opiate intoxication
- Treatment of Withdrawal with Non-Opiate Agents [1,12]
- Both elective and non-elective opiate withdrawal syndromes may be treated
- Clonidine, a centrally acting a2-agonist, 0.1-0.3 mg q8-12 hours usually effective
- Clonidine slows heart rate, reduces blood pressure, and can reduce craving
- However, clonidine is more effective for autonomic than for psychiatric symptoms
- Benzodiazepines may be used for sedation, but caution with respiratory suppression
- Blood pressure and heart rate stabilization may require additional agents
- Rapid and ultrarapid methods for opiate detox have been developed
- Rapid detox uses naloxone or nalatrexone
- Ultrarapid detox uses anesthesia or heavy sedation
- Highly effective and nearly ultrarapid detox uses naltrexone+clonidine+buprenorphine [18]
- For severe intoxication, mechanical ventilation is often required
- This may be preferred in setting of ultrarapid detoxification
- Goal of these methods is to reduce the period of opiate withdrawal symptoms
- Unclear whether these methods lead to improved longer term outcomes
- High Clinical Suspicion for Endocarditis
- Blood Cultures should be done routinely on all patients undergoing detoxification
- Baseline electrocardiogram (ECG) is very important
- Cardiac murmers should be evaluated with echocardiography
E. Treatment of Opioid Dependence [1,12,15]
- Treatment Strategies for Dependence and Withdrawal Symptoms [8]
- Detoxification and abstinance is one methodology (uses opiate antagonists)
- Maintenance therapy with monitoring and "legal" opiate agonists is other option
- Detoxification (see above) [1,3]
- Detoxification followed by maintenance with opioid antagonist with psychotherapy
- Permits complete abstinence from opioids after difficult withdrawal period
- Does not require constant methadone or LAAM maintenance therapy
- Clonididine combined with naltrexone was as effective as buprenorphine alone, and more effective than clonidine alone in permitting opioid detoxification
- Patients receiving the mixed agonist-antagonist buprenorphine had less severe withdrawal reactions than the clonidine and/or naltrexone groups
- Benzodiazepines are often used as adjunctive therapies for sedation
- Maintenance to Prevent Relapse [6,9]
- Usually carried out with opioid agonists such as methadone or LAAM
- Naltrexone, an opioid antagonist, is also used (50-100mg po qd or tiw)
- Buprenorphine, a partial agonist, is now available (8-12mg sublingual qd to tiw) [17]
- Buprenorphine was superior to naltrexone as single agent maintenance therapy for 24 weeks in heroin abusers in Malaysia [23]
- In USA, <25% of opioid depdendent persons currently receiving methadone or LAAM
- Combined buprenorphine-naloxone sublingual reduce opioid abuse administered in office- based setting [19]
- With buprenorphine-naloxone, adding brief weekly counseling or once-weekly medication did not differ from extended weekly counseling and 3X weekly medication [20]
- Methadone (Dolophine®) [8,9,11]
- Methadone is a long acting µ-opiate receptor agonist with less abuse potential than heroin
- Methadone prevents opiate withdrawal and reduces subjective effects of illegal opioids
- Methadone must be taken daily, generally in supervised, highly restricted, setting
- Duration of action (prevention of opiate desire) is 24-36 hours
- Methadone maintenance programs are more effective than psychosocial support alone [11]
- Initial dosage is usually 10-40mg/day in opiate dependent persons
- Doses >50mg/d are usually required initially to prevent cravings (and patient drop-out)
- 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]
- There is no maximum dose, and each patient needs to be titrated
- Urinalysis is usually done to monitor compliance and assess other illegal drug abuse
- Reduction rates are 10mg/week for >80mg/d, 5mg/wk for 40-80mg/d, and 2.5mg/wk for <40mg/d
- Opioid dependent patients on stable methadone can be transferred to primary care physicians for continuing treatment [14]
- If transferring from methodone to buprenorphine, reduce methodone dose to <30mg/d
- Schedule II agent (severely restricted, see below)
- Buprenorphine (Subutex®, Suboxone®) [6,7,17]
- Sublingual tablets approved for treatment of opioid dependence
- Mixed opiate agonist/antagonist (partial agonist at mu receptors)
- Clearly reduces opioid self-administration (opiate abuse)
- Dose is 12-16mg/day (usually begun at 2mg/day, dose doubled to 16-32mg/d)
- Can also be given as 8-24mg sublingually, daily or three times per week
- Maximum dose sublingual is 24-32mg daily
- Use in primary care setting is at least as effective as in drug-dependence centers
- As effective as high dose methadone and LAAM [13]
- One year retention in buprenorphine group 100% versus 0% with placebo in Sweden [7]
- Buprenorphine superior to naltrexone as single agent maintenance therapy for 24 weeks in heroin abusers in Malaysia [23]
- Also available in combination with naloxone (Suboxone®)
- Schedule III agent (less severely restricted than methadone)
- Office based treatment with buprenorphine-naloxone combination may be most effective [6]
- See prescription guidelines at www.suboxone.com
- Levo-Alpha-Acetylmethadol (LAAM) [12,13]
- Opioid agonist longer acting than methadone, may be used on alternate days (qod)
- LAAM is effective in a dose dependent fashion
- Recommended dose is 50/50/70mg or 100/100/140mg (thrice weekly)
- Treatment Regulations [17]
- Schedule III, IV, V drug prescriptions allowed in specific office-based settings
- Physicians must be certified in addiction medicine or addiction psychiatry, OR have at least 8 hours authorized training, OR participated in clinical trial
- Prescribers must register with Substance Abuse and Mental Health Services Admin
- Each physician or group practice may treat up to 30 patients with buprenorphine at once
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