Using methadone for opiate dependence: What counselors need to know.

1. Using methadone for opiate dependence: What counselors need to know. Matthew A. Torrington, MD COMP Conference September 11, 2007

2. 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

3. Premise of this Presentation

4. Substance Dependence: A Disease With Many Interacting Causes Substance dependence is a complex disease, including physiological, genetic, psychosocial, and environmental factors. Due to the complexity of substance dependence, a combination of pharmacologic (medication) and psychosocial interventions offers the greatest opportunity for patients to achieve sustained recovery. WHO. Neuroscience of Psychoactive Substance Use And Dependence. 2004.Substance dependence is a complex disease, including physiological, genetic, psychosocial, and environmental factors. Due to the complexity of substance dependence, a combination of pharmacologic (medication) and psychosocial interventions offers the greatest opportunity for patients to achieve sustained recovery. WHO. Neuroscience of Psychoactive Substance Use And Dependence. 2004.

5. Slide 11: The reward pathway Tell your audience that this is a view of the brain cut down the middle. An important part of the reward pathway is shown and the major structures are highlighted: the ventral tegmental area (VTA), the nucleus accumbens and the prefrontal cortex. The VTA is connected to both the nucleus accumbens and the prefrontal cortex via this pathway and it sends information to these structures via its neurons. The neurons of the VTA contain the neurotransmitter dopamine which is released in the nucleus accumbens and in the prefrontal cortex (point to each of these structures). Reiterate that this pathway is activated by a rewarding stimulus. [Note: the pathway shown here is not the only pathway activated by rewards, other structures are involved too, but only this part of the pathway is shown for simplicity.]Slide 11: The reward pathway Tell your audience that this is a view of the brain cut down the middle. An important part of the reward pathway is shown and the major structures are highlighted: the ventral tegmental area (VTA), the nucleus accumbens and the prefrontal cortex. The VTA is connected to both the nucleus accumbens and the prefrontal cortex via this pathway and it sends information to these structures via its neurons. The neurons of the VTA contain the neurotransmitter dopamine which is released in the nucleus accumbens and in the prefrontal cortex (point to each of these structures). Reiterate that this pathway is activated by a rewarding stimulus. [Note: the pathway shown here is not the only pathway activated by rewards, other structures are involved too, but only this part of the pathway is shown for simplicity.]

6. Slide 30: Summary; addictive drugs activate the reward system via increasing dopamine neurotransmission In this last slide, the reward pathway is shown along with several drugs that have addictive potential. Just as heroin (morphine) and cocaine activate the reward pathway in the VTA and nucleus accumbens, other drugs such as nicotine and alcohol activate this pathway as well, although sometimes indirectly (point to the globus pallidus, an area activated by alcohol that connects to the reward pathway). While each drug has a different mechanism of action, each drug increases the activity of the reward pathway by increasing dopamine transmission. Because of the way our brains are designed, and because these drugs activate this particular brain pathway for reward, they have the ability to be abused. Thus, addiction is truely a disease of the brain. As scientists learn more about this disease, they may help to find an effective treatment strategy for the recovering addict.Slide 30: Summary; addictive drugs activate the reward system via increasing dopamine neurotransmission In this last slide, the reward pathway is shown along with several drugs that have addictive potential. Just as heroin (morphine) and cocaine activate the reward pathway in the VTA and nucleus accumbens, other drugs such as nicotine and alcohol activate this pathway as well, although sometimes indirectly (point to the globus pallidus, an area activated by alcohol that connects to the reward pathway). While each drug has a different mechanism of action, each drug increases the activity of the reward pathway by increasing dopamine transmission. Because of the way our brains are designed, and because these drugs activate this particular brain pathway for reward, they have the ability to be abused. Thus, addiction is truely a disease of the brain. As scientists learn more about this disease, they may help to find an effective treatment strategy for the recovering addict.

7. Slide 23: Addiction vs dependence As you have just explained, different parts of the brain are responsible for the addiction and dependence to heroin and opiates. Review the areas in the brain underlying the addiction to morphine (reward pathway) and those underlying the dependence to morphine (thalamus and brainstem). Thus, it is possible to be dependent on morphine, without being addicted to morphine. (Although, if one is addicted, they are most likely dependent as well.) This is especially true for people being treated chronically with morphine for pain, for example associated with terminal cancer. They may be dependent--if the drug is stopped, they suffer a withdrawal syndrome. But, they are not compulsive users of the morphine, and they are not addicted. Finally, people treated with morphine in the hospital for pain control after surgery are unlikely to become addicted; although they may feel some of the euphoria, the analgesic and sedating effects predominate. There is no compulsive use and the prescribed use is short-lived.Slide 23: Addiction vs dependence As you have just explained, different parts of the brain are responsible for the addiction and dependence to heroin and opiates. Review the areas in the brain underlying the addiction to morphine (reward pathway) and those underlying the dependence to morphine (thalamus and brainstem). Thus, it is possible to be dependent on morphine, without being addicted to morphine. (Although, if one is addicted, they are most likely dependent as well.) This is especially true for people being treated chronically with morphine for pain, for example associated with terminal cancer. They may be dependent--if the drug is stopped, they suffer a withdrawal syndrome. But, they are not compulsive users of the morphine, and they are not addicted. Finally, people treated with morphine in the hospital for pain control after surgery are unlikely to become addicted; although they may feel some of the euphoria, the analgesic and sedating effects predominate. There is no compulsive use and the prescribed use is short-lived.

8. 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

9. Addiction is NOT: Physical dependence - characteristic withdrawal syndrome emerges upon decreased blood levels of substance or antagonist administration Tolerance - increasing amount of drug needed over time to induce the same effect Both are neuroadaptive states resulting from chronic drug administration

10. 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.

11. Schematic of Opiate Receptor Comparison of the amino acid sequences of the cloned mouse deta and kapa and rat mu receptor. The blue indicated common amino acid sequences. G protein couple receptors.Comparison of the amino acid sequences of the cloned mouse deta and kapa and rat mu receptor. The blue indicated common amino acid sequences. G protein couple receptors.

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

13. A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period: 1. This and the following slides list the DSM-IV criteria for dependence on a psychoactive substance. The criteria are generic � that is, they apply to all substances, including opioids. [Reference: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington, D.C., 1994.] 1. This and the following slides list the DSM-IV criteria for dependence on a psychoactive substance. The criteria are generic � that is, they apply to all substances, including opioids. [Reference: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington, D.C., 1994.]

14. Physiologic Criteria: 1. Tolerance, as defined by either of the following: a) a need for markedly increased amounts of the substance to achieve intoxication or the desired effect, or b) markedly diminished effect with continued use of the same amount of the substance 2. Withdrawal, as manifested by either of the following: a) the characteristic withdrawal syndrome for the substance, or b) the same (or closely related) substance is taken to relieve or avoid withdrawal symptoms 1. This and the following slides list the DSM-IV criteria for dependence on a psychoactive substance. The criteria are generic � that is, they apply to all substances, including opioids. [Reference: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington, D.C., 1994.] 1. This and the following slides list the DSM-IV criteria for dependence on a psychoactive substance. The criteria are generic � that is, they apply to all substances, including opioids. [Reference: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington, D.C., 1994.]

15. Behavioral Criteria: 3. The substance is often taken in larger amounts or over a longer period than was intended 4. There is a persistent desire or unsuccessful efforts to cut down or control substance use 5. A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects 1. 1.

16. Behavioral Criteria: (Cont�d) 6. Important social, occupational, or recreational activities are given up or reduced because of substance use 7. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance

17. Prevalence 3,744,000 persons in US reported using heroin at least once in their lifetime (2003 NSDUH) 149,000 new users (1999) 980,000 persons using heroin at least weekly (1998) 810,000 to 1,000,000 chronic users of heroin (ONDCP 2003) 1. According to the National Household Survey on Drug Use and Health (NSDUH), in 2003, 3,744,000 persons reported ever using heroin, and in 1999, 149,000 reported initiating use. Among the latter, 42,000 were between the ages of 12-17 years, and 73,000 between the ages of 18-25 years. 2. It is also estimated, based on the National Household Survey on Drug Abuse and the Drug Use Forecasting program, that there were 980,000 people who use heroin at least once per week, and 253,000 people who use heroin less than once per week in the United States in 1998. 3. The Office of National Drug Control Policy reports that there are 810,000 chronic opioid users in the United States, and that this is the highest number since the late 1970s. [References: National Drug Control Strategy: 2000 Annual Report. Office of National Drug Control Policy, page 116. National Household Survey on Drug Abuse, Population Estimates 1998. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, Rockville, Maryland, 1999. Office of National Drug Control Policy. What America's Users Spend on Illegal Drugs: 1988-1995. Washington, DC: Office of National Drug Control Policy 1997. Summary of Findings from the 1999 National Household Survey on Drug Abuse. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, Rockville, Maryland, 2000. Web sites: Substance Abuse and Mental Health Services Administration (www.samhsa.gov); National Institute on Drug Abuse (www.nida.nih.gov)] 1. According to the National Household Survey on Drug Use and Health (NSDUH), in 2003, 3,744,000 persons reported ever using heroin, and in 1999, 149,000 reported initiating use. Among the latter, 42,000 were between the ages of 12-17 years, and 73,000 between the ages of 18-25 years. 2. It is also estimated, based on the National Household Survey on Drug Abuse and the Drug Use Forecasting program, that there were 980,000 people who use heroin at least once per week, and 253,000 people who use heroin less than once per week in the United States in 1998. 3. The Office of National Drug Control Policy reports that there are 810,000 chronic opioid users in the United States, and that this is the highest number since the late 1970s. [References: National Drug Control Strategy: 2000 Annual Report. Office of National Drug Control Policy, page 116. National Household Survey on Drug Abuse, Population Estimates 1998. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, Rockville, Maryland, 1999. Office of National Drug Control Policy. What America's Users Spend on Illegal Drugs: 1988-1995. Washington, DC: Office of National Drug Control Policy 1997. Summary of Findings from the 1999 National Household Survey on Drug Abuse. Substance Abuse and Mental Health Services Administration, Office of Applied Studies, Rockville, Maryland, 2000. Web sites: Substance Abuse and Mental Health Services Administration (www.samhsa.gov); National Institute on Drug Abuse (www.nida.nih.gov)]

18. 810,000 to 1,000,000 chronic users of heroin 200,000� patients receiving methadone maintenance treatment 1998 NIH Consensus Statement on Appropriate Treatment of Opiate Dependence called for increased access to pharmacotherapy. 1. A survey conducted by the American Methadone Treatment Association (AMTA) now AATOD, the American Association for Treatment of Opioid Dependence, at the end of 1998 found there were 179,329 patients in methadone treatment. AATOD estimates in 2003 were 200,000 in treatment in Opioid Treatment Programs (OTPs) or methadone maintenance treatment programs. 2. According to the National Survey of Substance Abuse Treatment Services (N-SSATS), there were 994 methadone/LAAM programs in the U.S. treating 215,667 patients as of March, 2002. 3. Treatment with methadone is essentially restricted to licensed and accredited treatment programs. There are over 900 methadone maintenance programs registered with the DEA. In 5 states and in some counties in other states, OTPs are not allowed (by public policy). In many other locations it has been difficult for new programs to start or for existing programs to expand. 4. This difference between the number of patients in treatment and the number of persons who chronically use opioids highlights the need to expand treatment capacity. [Reference:American Methadone Treatment Association: News Report (sixth edition). American Methadone Treatment Association, New York, December, 1999.] 1. A survey conducted by the American Methadone Treatment Association (AMTA) now AATOD, the American Association for Treatment of Opioid Dependence, at the end of 1998 found there were 179,329 patients in methadone treatment. AATOD estimates in 2003 were 200,000 in treatment in Opioid Treatment Programs (OTPs) or methadone maintenance treatment programs. 2. According to the National Survey of Substance Abuse Treatment Services (N-SSATS), there were 994 methadone/LAAM programs in the U.S. treating 215,667 patients as of March, 2002. 3. Treatment with methadone is essentially restricted to licensed and accredited treatment programs. There are over 900 methadone maintenance programs registered with the DEA. In 5 states and in some counties in other states, OTPs are not allowed (by public policy). In many other locations it has been difficult for new programs to start or for existing programs to expand. 4. This difference between the number of patients in treatment and the number of persons who chronically use opioids highlights the need to expand treatment capacity. [Reference:American Methadone Treatment Association: News Report (sixth edition). American Methadone Treatment Association, New York, December, 1999.]

19. Number of new non-medical users of therapeutics 1. This figure is taken from the NSDUH, and shows the annual number of persons who have non-medical use of different substances. As can be seen in the figure, during the 1970s and most of the 1980s there was a relative stable number of new users for each class, and this did not really differ between drug classes. However, starting in the 1990s, the number of new users of pain relievers (opioids) has increased dramatically, and is markedly higher than the other classes of substances. 1. This figure is taken from the NSDUH, and shows the annual number of persons who have non-medical use of different substances. As can be seen in the figure, during the 1970s and most of the 1980s there was a relative stable number of new users for each class, and this did not really differ between drug classes. However, starting in the 1990s, the number of new users of pain relievers (opioids) has increased dramatically, and is markedly higher than the other classes of substances.

20. Diacetylmorphine (Heroin) Hydromorphone (Dilaudid) Oxycodone (OxyContin, Percodan, Percocet, Tylox) Meperidine (Demerol) Hydrocodone (Lortab, Vicodin) 1. While most patients abuse heroin, there are several other opioids that can be abused. This list is continued on the next slide, and it is not meant to be exhaustive. Note that all of these opioids exert a mu agonist effect. 1. While most patients abuse heroin, there are several other opioids that can be abused. This list is continued on the next slide, and it is not meant to be exhaustive. Note that all of these opioids exert a mu agonist effect.

21. Morphine (MS Contin, Oramorph) Fentanyl (Sublimaze) Propoxyphene (Darvon) Methadone (Dolophine) Codeine Opium 1. 1.

23. Mortality Caused by IV Drug Use Methods: 1,769 not in Tx IDUs in Portland, OR interviewed in 1989-1991. Search of death certificates in 1992. Results: 33 (1.87%) died 39% OD 15% trauma 12% infection 12% Intracranial hemorrhage 9% cirrhosis Interpretation: Age-adjusted relative risk of death=8.3

25. MEDICAL COMPLICATIONS OF HEROIN ADDICTION FROM DIRECT DRUG EFFECT Coma Pulmonary Edema Respiratory Arrest FROM UNSTERILE NEEDLE USE AND SHARING AIDS Hepatitis Sepsis FROM LIFESTYLE STDs TB

28. Talking to patients about addiction treatment models

29. ADDICTION AS A CHRONIC ILLNESS

30. ADDICTION AS CHRONIC DISEASE: IMPLICATIONS It is treatable but not curable. Adjustment to diagnosis is part of patient�s task. There is a wide spectrum of severity. Retention in treatment is key. Best treatment is integrated.

31. Four questions patients ask: How is methadone better for me than heroin? What is the right dose of methadone for me? How long should I stay on methadone? What are the side effects of methadone?

32.

33. How is methadone better than heroin? Legal Avoids needles Known amount ingested

37. What is the right dose? Eliminate physical withdrawal Eliminate �craving� Comfort/function: usually trough is 400-600 ng/ml, peak no more than twice the trough. Not over-sedated Blocking dose

42. Relapse to IV drug use after MMT105 male patients who left treatment

45. Opiate effects, physical Predictable physical effects of administering opiates: Tolerance: the body becomes efficient in processing the drug and requires ever higher doses to produce the desired effect. Dependence: when the drug is discontinued there are typical withdrawal signs and symptoms.

46. Side effects of methadone: General opiate effects: Sedation/stimulation Maintained phys. dependence (stable) hypogonadism (not as severe as with heroin, may be dose dependent) Constipation Slight QTc prolongation on ECG (Martell etal) Sweating Methadone treatment tied to regulated clinic

47. Treatment Outcome Data 4-5 fold reduction in death rate reduction of drug use reduction of criminal activity engagement in socially productive roles reduced spread of HIV excellent retention (see: Joseph et al, 2000, Mt. Sinai J.Med., vol67, # 5, 6)

48. Crime among 491 patients before and during MMT at 6 programs

49. HIV CONVERSION IN TREATMENT

50. Other drugs of abuse: how do they affect MMT? Stimulants: patients do poorly Alcohol: additive sedation, complicate Hep C. Benzodiazepines: synergistic sedation THC: no effect on major outcomes Opioids: usually blocked, tolerance

51. Pregnancy MMT treatment of choice for pregnant, opioid-abusing women. Efforts to avoid intra-uterine fetal withdrawal, including split dose. Neonatal withdrawal occurs within 72 hours, at least 45% need treatment. Breastfeeding recommended if not HIV positive.

52. Pain in patients on MMT Methadone is prescribed for pain treatment in twice or three times daily doses. Up to 60% of MMT patients have chronic pain (Jamison 2000, Rosenblum 2003) Split doses may be indicated.

53. Pharmacotherapy in context: correct glossary Abstinence includes pharmacotherapy Maintenance, not substitution or replacement (new term also: MAT) Tapering from maintenance, not detoxification, (also �medically supervised withdrawal�, or MSW) Discontinuation, not discharge Toxicology screens: pos/neg, not clean/dirty)

54. Buprenorphine

55. A FEW WORDS ABOUT BUPRENORPHINE �Ceiling effect� and safety Displaced other opiates: withdrawal on induction Sublingual tablet Schedule 3(methadone is 2) One form combined with naloxone Office � based use available

56. Comparison of Activity Levels

59. Buprenorphine, Methadone, LAAM: Treatment Retention

60. Buprenorphine, Methadone, LAAM:Opioid Urine Results

61. Effect of counseling in buprenorphine treatment (Fiellin, 2002)

62. Retention in treatment

63. Opioid pharmacotherapy, summary: Methadone, buprenorphine and LAAM all approved by the FDA for treatment of opiate dependence. (LAAM not currently available from any drug company) Best evidence so far supports maintenance. Detoxification attempts should have maintenance as a back up in case of relapse.