Pharmacologic Treatment of Addiction

Dr Andrew Mallon

http://www.nida.nih.gov/scienceofaddiction/health.html

Your Brain on Drugs Today

1-2 Min 3-4 5-6

6-7 7-8 8-9

9-10 10-20 20-30

YELLOW shows places in brain where cocaine goes (striatum)

Front of Brain

Back of Brain

Fowler et al., Synapse, 1989.

Addiction as a Brain Disease

• Key brain pathways involve motivation, salience, memory, and reward

• Prolonged drug use is associated with changes brain function

• Changes are pervasive and persist after drug use stops

• Brain changes demonstrated at molecular, cellular, structural and functional levels

• These studies provide a rationale for medication-assisted treatment of addiction

Drug Addiction Treatment• Scientific studies demonstrate that the right mix of behavioural therapy,

spiritual exploration, medication (when available), medical & social services can help addicted people navigate the road to recovery.

We Need to Treat theWe Need to Treat theWhole Person!Whole Person!

In Social ContextIn Social Context

FDA Approved Treatments for Nicotine Addiction

• Chantix™ (Varenicline)

• Zyban

• Nicotine Replacement

Tobacco use is responsible for an

estimated 5 million deaths worldwide each year

http://www.drugabuse.gov/Infofacts/Tobacco.html

Chantix™ (Varenicline)

• Non-nicotine aid for smoking cessation treatment + counseling

• When smoke is inhaled, nicotine attaches to brain receptors & sends a message to a different part of the brain to release dopamine = pleasure feeling for a short time.

• Chantix works by activating these receptors and blocking nicotine from attaching to them.

Chantix™ (Varenicline)

Dual Mechanism of Action:

• Partial agonist effect through selective receptor binding & stimulates brain receptor-mediated activity, but at significantly lower level than nicotine (agonist effect).

• Blocks the ability of nicotine to activate the receptors & thus, to stimulate the central nervous mesolimbic dopamine sx, the neuronal mechanism underlying reinforcement and reward for smokers (antagonist effect). Use with caution in patients with hx psychosis

Two Trials Comparing Quit Rates* with Chantix, Zyban and Placebo

CHANTIX 1 mg bid Zyban 150 mg bid Placebo

Gonzales et al (n=1025)

44.0%* 29.5%† 17.7%

Jorenby et al (n=1027)

43.9%* 29.8%‡ 17.6%

Quit Rates = Continuous abstinence (not even one puff of a cigarette) during weeks 9-12

JAMA. 2006; 296:47-55 & JAMA. 2006; 296:56-63

Chantix (Varenicline)

• Dose: 0.5 mg q day x 3 days, then 0.5 mg BID on days 4-7, then 1 mg BID x 12  weeks +

• The most frequently reported adverse events (>10%) with CHANTIX were nausea, headache, insomnia and abnormal dreams.

• Nausea was reported by approximately 30% of patients treated with CHANTIX 1 mg bid, with approximately a 3% discontinuation rate during 12 weeks of treatment.

FDA Approved Medications for Treatment of Alcoholism

• Disulfiram (Antabuse)• Acamprosate (Campral)• Naltrexone

NON-FDA Approved Medications • Topiramate (Topamax)• Modafinil• Prazosin (Minipress) - in clincial trials w/patients w/PTSD

• …and many more! www.clinicaltrials.gov

Disulfiram (Antabuse)

• Used to support the treatment of chronic alcohol abuse by producing an acute sensitivity to alcohol

• Disulfiram should not be taken if alcohol has been consumed in the last 12 hours.

• Initial dose is 500 mg for 1 to 2 weeks, followed by a maintenance dose of 250 mg (range 125 mg - 500 mg) per day. The total daily dosage should not exceed 500 mg

• May cause liver toxicity so use w/caution in co-infected patients with chronic HBV and/or HCV

• Alcohol may be a potent cue for cocaine use. Often concurrent use

Acamprosate (Campral)

• Blocks release of glutamate, which is associated with alcohol withdrawal

• Appears to be more helpful in preventing relapse than reducing drinking levels

• Does not prevent withdrawal symptoms

• Dose: .666 mg TID (can use 1/2 strength)

• Side effects: diarrhea, gas, upset stomach, loss of appetite, dry mouth, dizziness, itching, weakness. Monitor for depression. No liver toxicity

Naltrexone• By blocking the µ-opioid receptors, naltrexone weakens the rewarding

effects of alcohol and reduces dopamine release and the inhibitory GABAergic output. Blocks the “high” feeling

• Appears to promote reduction in drinking level

• Dose: 50 mg q day. Side effect nausea is transient and transaminitis rare

• Extended-release naltrexone is the first once-a-month injection medication for alcohol dependence. May cause liver toxicity

Noeline C Latt, Stephen Jurd, Jennie Houseman and Sonia E Wutzke. "Naltrexone in alcoholdependence: a randomised controlled trial of effectiveness in a standard clinical setting.". The Medical Journal of Australia 176

(11): 530-534.

Example of Medication Impact: Injectable Naltrexone

C o p y r i g h t r e s t r i c t i o n s m a y a p p l y .

G a r b u t t , J . C . e t a l . J A M A 2 0 0 5 ; 2 9 3 : 1 6 1 7 - 1 6 2 5 .

M e d i a n H e a v y D r i n k i n g D a y s p e r M o n t h f o r E a c h T r e a t m e n t G r o u p O v e r a l l a n d b y S e x

Recent Opioid Trends

• Heroin related problems are stable

• Major increases in problems related to prescription opioid use and abuse:– Non-medical use– Emergency department visits– Addiction treatment admissions– Prescription opioid-related death

New Non-medical Users of Pain Relievers Aged 12 or Older

Source: Office of Applied Studies. (2003). Results from the 2002 National Survey on Drug Use and Health: National findings (DHHS Publication No. SMA 03–3836, NHSDA Series H–22). Rockville, MD: Substance Abuse and Mental Health Services Administration. Nonmedical Use of Prescription Pain Relievers May 21, 2004

Mil

lio

ns

Primary Drug at Entry to Opiate Treatment, King County WA

Heroin

94.6

83.2

Rx Opiate

3.0

14.4

0.0

20.0

40.0

60.0

80.0

100.0

1999 2000 2001 2002 2003 2004 2005

%

Drug Caused Deaths, 1997-2005King County, WA

0

10

20

30

40

50

60

70

80

90

1997 1999 2001 2003 2005

# T

imes D

rug

Id

en

tifi

ed

Methadone

Oxycodone (e.g.Percocet,OxyContin)

Hydrocodone (e.g. Vicodin)

Propoxyphene

Fentanyl

Hydromorphone **

Methadone Maintenance:Treatment Outcomes

• Methadone:– Reduces overall and overdose deaths

– Drug use

– Criminal behavior – Spread of infectious diseases (HIV, TB)

• Not a cure

Swedish Methadone StudyBefore

Experimental Group(Methadone)

Control Group(No Methadone)

Gunne & Gronbladh, 1981

Swedish Methadone Study After 2 Years

Experimental Group(Methadone)

Control Group(No Methadone)

Gunne & Gronbladh, 1981

d

a b

c

d d

a Sepsisb Sepsis and Endocarditisc Leg Amputationd In Prison

Adapted from V. Dole (1989) JAMA, 282, p. 1881

Frequency of Heroin Use & Methadone Dose Level

0

10

20

30

40

50

60

70

80

90

10 20 30 40 50 60 70 80 90 100Daily Methadone Dose (in mgs.)

Past month IV drug use (%)

Adapted from: Ball & Ross, 1991.

Reduction of Heroin Use By Duration of Methadone Treatment

8%

23%

97%

67%

0

20

40

60

80

100

120

Percent

Pre-treatment

Admission:< 6 months

stay

AverageStay: 6 to54 months

Long-term:> 54 months

Adapted from: Ball & Ross, 1991.

Return to I.V. Drug Use Following Termination of Methadone Treatment

%

IV

USERS

28.9%

82.1%72.7%

57.6%

45.5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

In Tx. 1 to 3 4 to 6 7 to 9 10 to 12

Months Since Dropout

Methadone Maintenance:How Long?

• Randomized trial of 179 patients

• Maintenance versus 180-day psychosocially enriched detoxification

• Maintenance resulted in greater treatment retention and less heroin use

• No support for diverting resources from maintenance to long-term detoxification

JAMA 2000;283:1303-10

Methadone Maintenance:Summary

• Limitations– Highly structured program (6 days/week)– Limited clinical flexibility and minimal medical

services– Expansion often opposed, stigma

• For patients in Methadone Maintenance– Ask about urine tests and encourage adequate

dose, take-home doses, and treatment retention

Buprenorphine:A New Office-Based Option

• New medication for opioid dependence• Federal legislation (DATA 2000):

– Allows trained MDs to prescribe Schedule III-V drugs approved for addiction treatment

– Initially limited to 30 patients/group practice, but now each MD can treat up to 100 patients

• Safer than methadone• With naloxone, reduced abuse potential

-10 -9 -8 -7 -6 -5 -40

10

20

30

40

50

60

70

80

90

100

Activity

Log Dose of Opioid

Full Agonist

Partial Agonist

Antagonist

Full Agonist vs Partial Agonist

Zubieta et al., 2000

Buprenorphine Maintenance versus Detoxification

• Randomized trial of 40 Swedish patients ineligible for methadone but >1 year of dependence

• Control group given buprenorphine taper (1 week)

• Both groups given weekly Cognitive Behavioral Therapy, individual counseling and assistance with social services

Treatment duration (days)

Rem

aini

ng in

tre

atm

ent

(nr

)

0

5

10

15

20

0 50 100 150 200 250 300 350

Control

Buprenorphine

Buprenorphine Maintenance/Withdrawal: Retention

(Kakko et al., 2003)

Placebo Buprenorphine Cox regression

Dead 4/20 (20%) 0/20 (0%) 2=5.9; p=0.015

Buprenorphine Maintenance/Withdrawal: Mortality

(Kakko et al., 2003)

• Buprenorphine, methadone, LAAM comparison:

– 17 week outpatient randomized, double-blind clinical trial, single site (n=220)

– Four conditions with flexible dosing for three of the four: high dose methadone, LAAM (3x per week), buprenorphine (3x per week), and low dose methadone

Maintenance Treatment Using Buprenorphine

Buprenorphine, Methadone, LAAM: Treatment Retention

Per

cent

Ret

aine

d

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

20% Lo Meth

58% Bup

73% Hi Meth

53% LAAM

Study Week (Johnson et al., 2000)

Buprenorphine, Methadone, LAAM:Opioid Urine Results

Mea

n %

Neg

ativ

e

Study Week

All Subjects

Lo Meth

BupHi Meth

LAAM

1 3 5 7 9 11 13 15 170

20

40

60

80

100

19%

40%

39%

49%

(Johnson et al., 2000)

Suboxone and HAART

• Buprenorphine is metabolized through CYP3A4

• Protease Inhibitors: RTV, but not NFV or LPV/R, increases buprenorphine AUC, but no opioid excess seen

• NNRTI: DLV increases and EFV decreases the buprenorphine AUC, but no clinically significant consequences

• Naloxone has no CYP3A4 metabolism, so no HAART interactions expected

Buprenorphine Implementation

• Major efforts by CSAT to train physicians, provide mentoring, help patients find help

• Slow adoption by physicians• Difficulty integrating office-based treatment

and psychosocial services• Insurance coverage inconsistent and

generally not available for publicly funded patients

Buprenorphine: Who Gets It?• CSAT Waiver Evaluation Results:

– 31% new to addiction treatment (60% new to medication assisted treatment)

– 60% addicted to non-heroin opioid – No reduction in patients seeking methadone

• Compared with a methadone treatment sample:– Younger, more white (92% vs 53%)– More employed (50% vs 29%) – More post-secondary education (56% vs 18%)– More non-heroin only users (40% vs 10%)

Buprenorphine in Washington State

• Facilitate and evaluate the development and implementation of a pilot office-based buprenorphine program within the Washington State Medicaid program

• Funded by the RWJ Substance Abuse Policy Research Program

WA State Buprenorphine Policy

• Medicaid Eligibility Limitations – CNP/GAX coupons only (“dual eligible” and

parents)– Not GAU, ADATSA (exception for special project)

• Clinical Requirements– Patients must be enrolled in addiction program– Limited to 6 months with one 6-month extension– Limited to two-week supply of medication

Buprenorphine in WA State:Program Features

• Physician Recruitment– HMC clinics (AMC, FMC, Madison, PSC)– Community clinics

• Psychosocial Services– Evergreen Treatment Services– King County funding for CNP/GAX patients– Approximately 2 hours/month– RCKC for ADATSA patients

Buprenorphine in WA State:Limitations

• Physician Issues – Many clinic directors not interested– Appointment scheduling difficult, especially induction

• Psychosocial Treatment Issues– Off site services cumbersome

• Patient Recruitment Issues– Many patients had wrong/no medical coupon– Access to methadone increased– Multiple steps prior to medication

HMC Addictions Program: Suboxone Track

• Focus on HMC patients– Expedited access to assessment, induction– Still restricted to CNP/GAX patients

• Centralized Induction Services– Devoted physician FTE– Refer to primary care physicians once stabilized

• Collaborate with HMC Addictions Program– On site psychosocial services– Referrals: 744-9657 or call me

Summary

• Buprenorphine has potential to expand treatment access and physician involvement in addiction treatment

• Substantial limitations exist, especially regulatory restrictions and cost

• Methadone maintenance remains an effective treatment option