Buprenorphine and the Office-Based Treatment of Opiate Dependence

1. Buprenorphine and the Office-Based Treatment of Opiate Dependence • Matthew A. Torrington, MD AAFP ASAM • Medical Director Matrix Institute, Narcotic Treatment Program

2. What are opiates? • a.) Inducing sleep; somniferous; narcotic; hence, anodyne; causing rest, dullness, or inaction; as, the opiate rod of Hermes. • (n.) Originally, a medicine of a thicker consistence than syrup, prepared with opium. • (n.) Any medicine that contains opium, and has the quality of inducing sleep or repose; a narcotic. • (n.) Anything which induces rest or inaction; that which quiets uneasiness.

3. Opiates • Oxycodone • (oxycontin) • Propoxyphene • (Darvon) • Hydrocodone • (Vicodin) • Hydromorphone • (Dilaudid) • Meperidine • (Demerol), • Diphenoxylate (Lomotil) • Codeine http://www.chemheritage.org/EducationalServices/pharm/asp/images/heroin.gif

4. Heroin • Heroin is processed from morphine (diacetylmorphine) • Morphine is a naturally occurring substance extracted from the seedpod of the Asian poppy plant. • Heroin usually appears as a white or brown powder. • Street names • "smack," "H," “horse,” "skag," and "junk" "Mexican black tar,” “China White” • Originally produced by Bayer as a “non addictive” analgesic www.thinkbigdesigns.com/ justin/Heroin.jpg

5. Opiate EFFECTS • Desirable • Pain relief • Euphoria - heroin produces greater ‘rush’ than morphine due to  lipophilicity • Prolonged sense of contentment and well-being • Undesirable • Nausea and vomiting • Respiratory depression –  in sensitivity of respiratory center to PCO2 • Constipation -  tone +  motility in GI tract • DON’T RX OPIATES WITHOUT CONSIDERING THIS • Pupillary constriction - stimulation of oculomotor nucleus

6. PATHOPHYSIOLOGY • Opiate metabolites act on  receptors on GABA neurons to uninhibit the firing of dopaminergic neurons in VTA. • This results in  DE release in Nacc.

7. Tolerance, Addiction, and Withdrawal • With regular opiate use, tolerance develops. • As higher doses are used over time, physical dependence develops. • Withdrawal, which in regular abusers may occur as early as a few hours after the last administration • drug craving, restlessness, muscle and bone pain, insomnia, diarrhea and vomiting, cold flashes with goose bumps ("cold turkey"), kicking movements ("kicking the habit"), etc. www.naplesnews.com/cgi-bin/ sendto.pl?location=specials

8. Major withdrawal symptoms peak between 48 and 72 hours after the last dose Duration and intensity dependent on quantity and half live of opiates being used Heroin WD usually subsides after about a week. Methadone WD can last weeks RX OPIATES CAUSE WITHDRAWAL TOO Opiate withdrawal http://www.heroinaddiction.com/Pictures/withdrawal.jpg

9. MOA Withdrawal • On cessation of heroin excessive cAMP production occurs causing withdrawal symptoms

10. DSM 4 criteria for opiate abuse • Significant impairment or distress resulting from use • Failure to fulfill roles at work, home, or school • Persistent use in physically hazardous situations • Recurrent legal problems related to use • Continued use despite interpersonal problems

11. DSM 4 criteria for Opiate Depend.≥ 3 of the following occurring in the same 12- month period 1. Desire or unsuccessful efforts to cut down on opiate use 2. Large amount of time spent obtaining opiates, using opiates, or recovering from opiate effects 3. Social, occupational, or recreational activities reduced because of opiate use 4. Opiate use continued despite knowledge that a physical or psychological problem is being caused or exacerbated by use

12. 5. Tolerance • Need for increased amounts of opiates to achieve desired effect; or • Diminished effect with continued use of the same amount of opiate • Tolerance develops normally with repeated use • Tolerance to sedating effect develops quickly • Tolerance to respiratory depression can be marked

13. 6. Withdrawal withdrawal syndrome with cessation of use, reduction of use, or use of opiate antagonist Opiates or related substance taken to relieve or avoid withdrawal symptoms

14. Biological Dysregulation Cultural Social Environmental Psychological Genetic Substance Dependence A Multifactorial Brain Disease Substance Dependence WHO. Neuroscience of Psychoactive Substance Use and Dependence. 2004.

15. Substance Dependence Is a Disease • Disease • An interruption, cessation, or disorder of bodily function, system, or organ; When something is wrong with a bodily function.1 • Determinants include environment and genetics (nature and nurture). • Substance Dependence • Adisorder of the normal biological regulation of brain chemicals, specifically the GABA system in the brain. • Determinants include environment and genetics 1. Stedman’s Medical Dictionary. Baltimore, Md: Williams & Wilkins; 2000.

16. Substance-related disorders • Intoxication • use of substance resulting in maladaptive behavior • Withdrawal • negative reactions that occur when use is discontinued or drastically reduced • Delirium • Dementia • Psychosis • Mood disorder • Anxiety • Sexual dysfunction • Sleep disorder

17. AAPainMed,APainS, ASAMdefined ADDICTON in 2001 • Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving • Savage et al., 2001

18. RX Opiate Abuse • The use of pain relievers for nonmedicinal purposes has been steadily increasing since the mid-1980s. • The number of initiates leapt from an estimated 400,000 annually in the mid-1980s to two million by 2000 (SAMHSA, 2002a).

19. RX Opiate Abuse • Abuse of prescription narcotics shows a concurrent increase in prevalence over the past decade, increasing 123% since 1994. • In 1999, it was estimated that 2.9 million Americans had abused pain relievers in the past month (SAMHSA, 1999).

20. Pseudoaddiction • operationally defined as aberrant drug-related behaviors that make patients with chronic pain look like addicts. • these behaviors stop if opioid doses are increased and pain improves (Weissman and Haddox, 1989). • This indicates that the aberrant drug-related behaviors were actually a search for relief • Little data on the subject, but evidence in rats

21. Treatment: Opiate Overdose • Respiratory depression, CNS depression, Myosis, signs of drug abuse, history • R/O hypoglycemia, acidemia, fluid and electrolyte abnormalities • Support: airway, ventilation, cardiac function, • Naloxone HCL 0.4-0.8mg initially; • repeat PRN

22. Treatment of opiate dependence • Comprehensive treatment gives best chance of long lasting remission • Opiate replacement or pharmacologic support of withdraw symptoms • Cognitive Behavioral Treatment: matrix, counseling, etc. • 12 step work • Faith

23. “Supportive Detoxification” • Alpha Blockers • clonidine • Anxiolytics • Benzodiazepines, barbituates • Analgesics • Ibuprofen, acetaminophen, • Sleep Aids • Ambien, trazadone • GI drugs • bentyl, compazine, phenergan

24. Agonist Opens door Partial Agonist Opens door with safety chain Antagonists Dummy key Morphine like effect Weak morphine like effects with strong receptor affinity No effect in absence of an opiate or opiate dependence Receptor Binding at Mu receptor

25. Agonist Therapy • Methadone is the gold standard • Must be administerd in setting of OTP, Opiate Treatment Program • Highly regulated • Can be used for pain • Legislation prevents the use of agonists specifically for the treatment of opiate dependence outside the setting of OTP

26. Agonist Therapy continued • Methadone • Long acting opiate agonist • Combats withdraw and craving • must be dosed in NTPs, daily dosing mandatory until patient stable…months • Outpatient treatment after patient considered very low risk….years • LAAM even longer acting (dose 3 X a week) • potential for increased QT intervals • Of historical interest only, NO LONGER Available

27. Opiate Antagonist therapy • Naltrexone, REVIA • Start 25mg po q d, repeat in 1 hour if no WD • Must be opiate free 7-10 days and pass naloxone challenge test prior to dosing • T/C Check LFTs @ baseline and q 3 months

28. Schematic of Opiate Receptor Source: Goodman and Gillman 9th ed, p. 526

29. Heroin, morphine, methadone Buprenorphine Naltrexone (Revia, Vixo) Nalmefene naloxone Agonist Partial Agonist Antagonist Effect of Common Opiates at mu receptor

30. Buprenorphine

31. Buprenorphine for Opiate Dependence: • Suppresses withdrawal • Substitutes for street opiates • Blocks subsequently administered opiates • Safety in long term use

32. Buprenorphine pharmacology contd. • “Less bounce to the ounce” • Ceiling effect on respiratory depression • Less physical dependence capacity • Blocks withdrawal in mildly dependent people • Precipitates withdrawal in moderate to severely dependent people

33. Buprenorphine: Clinical Pharmacology Partial Agonist • high safety profile/ceiling effect • low dependence • partial substitution for highly addicted patients • precipitates withdrawal in highly dependent patients Tight Receptor Binding • long duration of action • slow onset mild abstinence

35. Good Effect

36. Respiration

37. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Intensity of abstinence Buprenorphine Morphine 60 50 40 30 20 10 0 Himmelsbach scores Days after drug withdrawal

38. Buprenorphine/Naloxone combo SUBOXONE 4 part buprenorphine: 1 part naloxone Sublingual: Opiate agonist effect from buprenorphine Intravenous: Opiate antagonist effect from naloxone

39. Addition of Naloxone Reduces Abuse Potential • Naloxone will block buprenorphine’s effects by the IV but not the sublingual route • Sublingual absorption of buprenorphine @ 70%; naloxone @ 10% • If injected, BUP/NX will precipitate withdrawal in a moderately to severely dependent addict

40. A Sequential Pharmacological Intervention Model for Opiate Dependence Naltrexone Buprenorphine 3 x/Week Successful Medication-free Street Addict Daily Buprenorphine Unsuccessful Methadone

41. Buprenorphine: Potent Analgesic • 20-50 times potency of morphine • Available worldwide for pain treatment • Injectable formulation available in U.S. • Usual analgesic dose: .2-.4 mg sl • Higher dose for opiate dependence

42. Buprenorphine and Pain • Animal data don’t predict human data • Good potent analgesic • Mild CVS effect, mild G-I effect • Ceiling effect on respiratory depression • Analgesia not compromised by ceiling. • Effective for long term use mos. to yrs.

43. Buprenorphine: Analgesic Profile Rapid onset of action Long duration of peak effect (60-120 min) Long half life (3.5 hrs) Analgesic action up to 8 hrs. No apparent analgesic ceiling effect at doses below 300 mg Ms equivalent; no inverted U Ceiling effect on respiratory depression Low physical dependence profile

45. Buprenorphine: Analgesic Use • Surgical pain • Intra-operative, peri-operative, post-operative • Labor pain • Back pain • Phantom pain • Post-herpetic neuralgia • Cancer pain

46. Buprenorphine in Acute Pain • 30 x potency of Ms by intramuscular injection • 8-12 x by epidural route (effect: 12-24 hrs) • Long duration of action (8-12 hrs) • Better analgesia cf. meperidine; comparable to morphine, hydromorphone, fentanyl • Low incidence of respiratory depression (up to 7 mg iv given post-op) • Nausea, vomiting, dizziness common

47. Buprenorphine for Chronic Pain • Cancer and non-cancer pain • 0.15-0.8 mg/dose q 6-8 hrs • 0.3 mg=10 mg morphine • Given SL, epidural, subcut, subarachnoid • Comparable to Ms; less resp dep • Given up to 12 wks. • Experience not extensive

48. Buprenorphine for Chronic Pain • Good for trans-dermal application • Lipophilic, High level analgesia Low adverse effects • Transdermal patch (35-52.5 micro gm/hr) • Consistent delivery, desirable time course • Flexible dosing and compliance • Effective up to 7 days, used up to 18 mos • Used in neuropathic pain (.3 mg=methadone 10 mg; usual dose 0.6 mg (20 mg methadone)

49. Thanks for your attention! • DO NOT HESITIATE TO CONTACT ME WITH QUESTIONS • matorringtonmd@yahoo.com • 310 207 4322 office • 310 207 6511 fax • 310 487 2488 mobile