1. Pharmacological Treatment of Addiction
David A. Fiellin, M.D.
Professor of Medicine
Yale University School of Medicine

2. Overview Epidemiology of opioid dependence
Treatment of opioid dependence
Buprenoprhine
Office-based treatment
Epidemiology of alcohol problems
Treatment of alcohol problems
Naltrexone, acamprosate, disulfiram

3. Opioid Dependence (DSM-IV, 3 or more within one year)
Physical Dependence
Tolerance
Withdrawal
Loss of control (addiction)
Larger amounts/longer period than intended
Inability to/persistent desire to cut down or control
Increased amount of time spent in activities necessary to obtain opioids
Social, occupational and recreational activities given up or reduced
Opioid use is continued despite adverse consequences

4. Epidemiology Prescription opioids Heroin
National Survey on Drug Use and Health, 2006
> 12 million reported non-medical use of prescription opioids
Estimated 1.6 million met criteria for prescription opioid abuse or dependence
Heroin
National Household Survey on Drug Abuse, 2006
> 500,000 reported past year heroin use
Approximately 323,000 individuals met criteria for heroin abuse or dependence
Combined, 2 million opioid dependent in U.S.
In 2005 only 331,000 individuals entered treatment for opioid dependence 4

5. Prescription of Opioids
Between 1994 & 2003, prescriptions for:
Non-controlled drugs increased by 57%
Controlled substances increased by 154%.
With increased attention to the treatment of pain, there has been a significant increase in perscriptions.
Between 1994 and 2003, prescriptions for noncontrolled drugs increased by 57%, while prescriptions for controlled substances increased by 154%.
Data from the DEA presented on this graph demonstrates grams of therapeutic opioid use in the United States per 100,000 people between 1997 and Notable that all show dramatic increase in use; oxycodone with less than 3000 grams/100,000 to more than 12,000 over this time period.
Trescot et al. Pain Physician, 2008; 11: S5-62. 5

6. Nonmedical Use of Prescription Drugs
Past Month Users, Ages 12 and Older (in Millions)
Marijuana
14.6
Prescription Drugs
6.2
Cocaine
2.0
(incl. crack)
Crack
0.6
Ecstasy
0.7
Meth
0.6
Inhalants
0.6
Heroin
0.2
LSD
0.1 1 3 5 7 9 11 13 15
Source: SAMHSA, 2002 National Survey on Drug Use and Health.

8. Annual sales of prescription opioids and unintentional overdose death 1990 - 2006
Sources: unintentional drug poisoning mortality is from the National Vital Statistics System.. The drug poisoning mortality category is defined by E850-E858 in 1990 through 1998 and by X40-X44 in 1999 through The rate for 2005 is estimated as 95% of the unintentional poisoning death rate.
Total sales are from DEA ARCOS. Opioid sales are in total morphine equivalents for all major opioids combined except codeine. The conversions are the same as those used in Paulozzi and Budnitz, Pharmacoepidemiology and Drug Safety, Sales data for 2006 is estimated from the first 3 quarters of 2006.
Source: Paulozzi, CDC, Congressional testimony, 2007 8

9. Brain’s Reward pathways
The ubiquity of the mu opioid receptor in the central nervous system has a double-edged sword if you will because opioids agonists are not only potent analgesics but because of the mu receptor’s presence in the midbrain, opioids are very effective and efficient stimulators of reward pathways. What do I mean by reward pathways? Typically, endogenous opioids are released when we engage in pleasurable activities and these endogenous opioids stimulate the production of dopamine in the so-called reward center of the midbrain. Dopaminergic neurons project to the cortex to stimulate repeated behavior and then recurrent pleasurable feelings that the brain perceives as linked to and caused by the original activity. In the case of opioid analgesics, these medications directly agonize the mu receptors that cause the dopamine release that project to the cortex. So, the pleasurable activity that the brain begins to crave is taking the medication itself and this is how addiction arises. The seeking of and taking of opioids supercedes virtually every other activity for the patient including even eating. Now to be clear I am in no way saying that addiction is an inevitable consequence of opioid-taking. In fact, we know that it is a small minority of patients, probably with a genetic susceptibility related to mu receptor polymorphisms and other genetic variability that contributes to the risk of addiction.

11. Changes in Neurobiology
Repeated exposure to short acting opioids leads to neuronal adaptations
Mesolimbic dopaminergic system
adaptations in G protein-coupled receptors
up regulation of cyclic cAMP second messenger pathway
changes in transcription and translation
Adaptations
Mediate tolerance, withdrawal, craving, self-adminstration
Provide insight into the chronic and relapsing nature of opioid dependence
Form basis of pharmacotherapies to stabilize neuronal circuits

12. Opioid Treatment

13. Pharmacologic Treatment of Opioid Dependence
Pharmacologic withdrawal - “detoxification”
Opioid antagonist treatment
Naltrexone
Opioid agonist treatment
Methadone
Buprenorphine

14. Poor results with detoxification Kakko, Lancet 200315
Remaining in treatment (nr) 10 5
Detoxification
Maintenance 50
100
150
200
250
300
350
Treatment duration (days)

15. Opioid Agonist Treatment
Rationale
Cross-tolerance
prevent withdrawal
relieve craving for opioids
Narcotic blockade
block or attenuate euphoric effect of exogenous opioids

16. How effective is opioid agonist treatment?

17. Buprenorphine, Methadone, LAAM: Treatment Retention
100 80
73% Hi Meth 60
58% Bup
Percent Retained
53% LAAM 40 20
20% Lo Meth 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Study Week

21. HIV Seroconversion Metzger, 1993: 2 cohorts of patients
103 out-of-treatment intravenous opiate users
152 subjects receiving methadone treatment
HIV antibody conversion, 18-months
22% of those out-of-treatment
3.5% of those receiving methadone treatment

22. Treatment vs. Addiction
Marked
Absent
Euphoria
3-6 hours
24-36 hours
Duration
Immediate
30 minutes
Onset
IV, IN
Oral, sublingual
Route
Heroin
Methadone or buprenorphine

23. Buprenorphine Partial agonist at mu receptor
Low abuse and diversion potential, especially when combined with naloxone
Can be prescribed from the office by a physician
Sub-lingual tablet
Daily or thrice weekly dosing

24. Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone)
100 90
Full Agonist
(Methadone, oxycodone) 80 70
Intrinsic Activity 60
Partial Agonist 50
(Buprenorphine) 40 30 20 10
Antagonist (Naltrexone)
-10 -9 -8 -7 -6 -5 -4
Log Dose of Opioid

25. Effects of Buprenorphine Dose on µ-Opioid Receptor Availability in a Representative Subject
MRI
Bup 00 mg
Binding
Potential
(Bmax/Kd)
Bup 02 mg
4 -
Bup 16 mg
Bup 32 mg
0 -

26. Federal Efforts to Increase Access Fiellin and O’Connor, NEJM 2002
Congress (2000)
Drug Addiction Treatment Act
Allows qualifying physicians to use approved schedule III-V medications
Qualifying physician either certified in Addiction Medicine/Psychiatry or complete 8 hour training
FDA and DEA (2002)
Approves buprenorphine and buprenorphine/naloxone for treatment of opioid dependence, schedule III

27. How effective is office-based buprenorphine treatment?

28. Self-Reported Frequency of Illicit Opioid Use in Opioid-Dependent Patients Receiving Buprenorphine-Naloxone in Primary Care
Fiellin D et al. N Engl J Med 2006;355:

29. Retention among Opioid-Dependent Patients Receiving Buprenorphine-Naloxone in Primary Care
Fiellin D et al. N Engl J Med 2006;355:

30. 6 Weeks of Opioid Abstinence
Moore, JGIM, 2007

31. 66 Physicians and 31 Treatment Programs listed in Minnesota

32. Trained, Registered and Prescribing Physicians U.S. January 2009
8295 32

33. Alcohol Treatment

34. Patterns of Alcohol Use: Epidemiology

35. Terminology For Alcohol Use Behaviors

36. What is a drink? 14 grams of alcohol 12 ounces of beer
14 grams of alcohol
12 ounces of beer
5 ounces of wine
1.5 ounces of distilled spirits

37. Alcohol Treatment Pharmacotherapy

38. Disulfiram Disulfiram ADH ALDH Ethanol Acetaldehyde Acetate
Build up of acetaldehyde causes:
-Flushing
-Headache
-Nausea
-Dizziness
-Palpitations
An old standby for alcoholism treatment since the 1940s has been disulfiram, an inhibitor of aldehyde dehydrogenase, ALDH, that results in increased levels of acetaldehyde and an unpleasant reaction after consumption of ethanol. In one of the largest studies of this medication, disulfiram was no better than placebo in achieving abstinence. But it is not clear that a placebo controlled trial is the best way to test a drug whose efficacy depends on the patient knowing that they may experience a very unpleasant reaction. Of note, in post hoc analyses, the drug was more effective in those who were adherent to it.
In controlled studies, 4 trials (conducted in the 1970s and early 1980s) have shown significantly improved abstinence rates when disulfiram is taken under direct monitoring by a concerned other.

39. Disulfiram Efficacy
• In a large double-blinded study, disulfiram was no better than placebo in helping patients remain abstinent
• A subset of relapsed patients, who were older and more socially stable, drank less frequently when given disulfiram
• Greater efficacy has been shown with supervised disulfiram administration
Fuller PK, et al. JAMA 1986;256:

40. Prescribing Disulfiram
Start at 250mg daily and titrate to 500mg daily
Contraindications:
Recent alcohol use
Pregnancy
Cognitive impairment
Side effects:
Hepatotoxicity
Neuropathy
Of all of the approved, efficacious medications, disulfiram may be the most difficult to use since it is an aversive therapy that works best when its administration is monitored.
Disulfiram should be started at 250 mg a day, up to a dose of 500 mg. The drug can be used daily or just prior to risky situations, and it lasts 4-7, and up to 14 days. Tell the monitor and the patient they are to take the medication as prescribed. The monitor should observe the patient as he or she takes the pill and call you if the patient is non-adherent.
The main contraindications are recent alcohol use, pregnancy, rubber, nickel cobalt allergy, cognitive impairment (since awareness of the risk of the reaction is essential), and as a relative contraindication, conditions that would increase the risk of harm from the disulfiram ethanol reaction, for example, coronary artery disease, esophageal varices. Disulfiram also has numerous drug interactions, including warfarin and anticonvulsants. The main side effect is an idiosyncratic sometimes fulminant hepatitis, and neuropathy seen at higher doses. Regular monitoring of liver enzymes is advised, as is a clear recommendation to avoid alcohol even in over-the-counter medications.

41. Naltrexone 1. Mechanism of Action: opioid receptor blockade
2. Effects: decreased craving and alcohol consumption
3. Dose: 50 mg/day
4. Side Effects: nausea (10%), headache
5. Contraindications: opioid dependence
severe liver disease

42. Combined Analysis of Yale and U Penn Studies of Naltrexone
• 12 week, double-blind, placebo controlled
• Concurrent Psychotherapy:
– Once weekly individual therapy (Yale)
– Day Hospital (1 month), twice weekly
group (2 months) (U Penn)
• Abstinence rates:
 Naltrexone: 54%
 Placebo: %
O’Malley et al., Psychiatric Annals 1995;25:

43. Naltrexone: Efficacy Meta-analysis of 14 studies*
Relapse to heavy drinking
Naltrexone 428/1142 (37%), control 445/930 (48%)
Odds ratio for relapse
0.62 (95% CI 0.52,0.75)
COMBINE Study† (Naltrexone X 16 w, n=302)
Increased abstinence over placebo (81% vs. 75%)
Reduced risk of a heavy drinking day (HR 0.72, p<0.02)
This meta-analysis included 14 clinical trials, in which relapse was decreased significantly, from 48% to 37%. The odds ratio favored naltrexone, 0.62, suggesting a 38% decrease in heavy drinking. In one study, patients were not abstinent before beginning naltrexone. In another study, the drug was effective in a primary care setting. In a third study, naltrexone was effective for reducing heavy drinking in nondependent heavy drinkers. In a fourth study, the combination of naltrexone and acamprosate was as safe and more effective than either alone.
COMBINE study 1383 participants from 11 academic sites with EtOH dependence and at least 4 days of abstinence
Naltrexone only arm vs. placebo 302
*Carmen B, Addiction 2004; † Anton RF, JAMA, 2004

44. Prescribing Naltrexone
25 to 50 mg daily taken after a meal for at least 3-4 months
Depot form available doses studied mg
25% reduction in heavy drinking days
Contraindications:
Opioid use
Pregnancy
Side Effects:
Nausea
Naltrexone can be started at 12.5 or 25 mg a day and advanced to 50 mg a day. Its main contraindication is opiate dependence or need for opioids. The main side effects are nausea and dizziness, which can be avoided by starting at a low dose and increasing it to the therapeutic dose of 50 mg per day over time as tolerated, usually after a few days. Liver enzymes should be monitored because of hepatitis seen at much higher than the doses recommended for alcoholism (for example, >300 mg a day). The main difficulty with the use of naltrexone is that it can complicate pain management, leading to a need to give very high dose opioids in the event of acute pain, or stopping and restarting therapy perioperatively.
DEPOT:
Naltrexone has modest efficacy for treating alcohol dependence. So why focus on
a single clinical trial of naltrexone? This trial was well done: it employed advanced
statistical techniques and had excellent external validity, enrolling 70% of the eligible
population and not requiring abstinence for study entry. The study found efficacy for
a novel injectable preparation that may have adherence advantages over oral tablets.
How do we interpret the results? The higher dose of extended-release naltrexone
combined with psychosocial therapy was associated with a 25% greater decrease in
heavy drinking than was the combination of placebo and psychosocial therapy. Although
the relative effects are of interest, absolute numbers (as displayed in Figure 3 of the
original article, for example) are of greater interest. This figure suggests (by rough
inspection) that after treatment, the 380-mg naltrexone group drank heavily on a median
of about 3 days per month compared with about 6 days per month for the placebo group.
In a subgroup analysis, naltrexone had a more impressive effect in those with a week
of abstinence prior to study entry—the 190-mg and 380-mg subgroups, however, had
only 17 patients each. In another subgroup analysis, the drug had efficacy in men but
not women. Subgroup analyses such as these should be interpreted with caution. My
take is that extended-release naltrexone has efficacy, but that future research with this
drug should address improving outcomes in women and in those who do not initially
establish abstinence.
A more significant consideration is whether the drinking decreases were clinically
important. Clearly, on each additional heavy drinking day, people are at risk for acute
adverse consequences, and over time, the more heavy drinking days, the more negative
health consequences. So the effects are likely meaningful, though trials that look at
health outcomes beyond surrogate measures (consumption) would certainly be welcome.
Unlike most other chronic diseases, alcohol dependence is characterized by loss of
control and impaired motivation, which make adherence to treatment particularly
difficult. Does the new injectable preparation represent an advance over oral naltrexone?
A monthly injection might be easier to adhere to than a daily pill, but this is not yet
known to be the case in alcohol dependence. Many people may prefer pills to avoid
injections and/or the office visits to receive them. And it will be a challenge for the
healthcare system to get these injections to where people with alcohol dependence
can receive them from qualified personnel. So the adherence advantages remain to be
seen. The niche for injectable extended-release naltrexone also remains to be seen. It
will likely make sense for those who prefer it or find it easier to adhere to. But for most
people with alcohol dependence, the key issue is not which preparation of a medication
they choose. The issue for them is getting as many known efficacious therapies as
possible: pharmacotherapy (eg, naltrexone or acamprosate), psychosocial therapy
including support for treatment adherence, and mutual help.
BRENDA (Biopsychosocial, Report, Empathy, Needs, Direct advice, and
Assessment)
Garbutt JC, JAMA, 2005, Anton R, NEJM, 2008

45. Project Combine: Design
Anton, R. F. et al. JAMA 2006;295:

46. Project Combine: Effect Size Estimates and Hazard Ratios for Primary Outcomes
Anton, R. F. et al. JAMA 2006;295:
Copyright restrictions may apply.

47. Injectable Naltrexone: Mean Heavy Drinking Event Rate
Garbutt, J. C. et al. JAMA 2005;293:

48. Acamprosate
Alcohol is an agonist at the inhibitory GABA receptors and antagonist at excitatory glutamate receptors
Acamprosate modulates alcohol effects:
GABA-analogue
Modulates action at NMDA receptor

49. Acamprosate: Efficacy
Meta-analysis of 7 placebo controlled trials*
Acamprosate (n=1195), placebo (n=1027)
Proportion of patients continually abstinent at one year 23% for acamprosate group, 15% for placebo group
COMBINE study† (Acamprosate arm, n=300)
No significant effect on drinking over placebo
COMBINE study 1383 participants from 11 academic sites with EtOH dependence and at least 4 days of abstinence
Why was combine not positive for acamprosate?
Required only 4 days abstinence while other trials required longer pretreatment abstinence
*Carmen B, Addiction 2004; †Anton, RF, JAMA 2004

50. Prescribing Acamprosate
666 mg po TID; start after a period of abstinence
Contraindications
CrCl < 30 cc/min
Pregnancy
Side effects
Diarrhea
Acamprosate is dosed three times a day, 666 mg. The main issue with Acamprosate is that it is contraindicated in renal insufficiency (Cr CL <30 ml/min, half dose for ml/min) and its main side effect is diarrhea. Acamprosate and all other alcohol dependence pharmacotherapies are pregnancy category C, meaning that there are no controlled studies in pregnant women, and that they should be prescribed during pregnancy only if clearly needed and the benefits are likely to outweigh the risks.

51. Topiramate Reduces corticomesolimbic dopamine release Not FDA approved
Agonist at GABA
Antagonist at glutamate
Not FDA approved

52. Topiramate: Efficacy
N=371, double blind randomized placebo controlled trial
Intention-to-treat analysis
Topiramate
Placebo p
Reduction in number of heavy drinking days
44%
52%
0.002
Increase in abstinence days (baselinewk 14)
10% to 38%
9% to 29%
Johnson BA, JAMA 2007

53. Summary Opioid and alcohol problems are common
Effective therapies for opioid dependence and alcohol use disorders exist
Office-based treatment of addictive disorders may help increase access to treatment and decrease stigma