Progress in Addiction Treatment: From One-Size Fits All to

Medications and Treatment Matching

• George E. Woody, MD• Penn/VA Addiction Treatment & Research

Center• Department of Psychiatry

• Perelman School of Medicine at the University of Pennsylvania

Disclosures• Fidelity Capital provided naltrexone implants

(Prodetoxon®) at reduced cost in Russia• Alkermes provided Vivitrol ® for Iceland study• Reckitt Benckiser provided Suboxone ® for CTN

study and one in Republic of Georgia• Janssen providing Vivitrol ® at reduced cost for

Russian study• Career support provided by VA clinical funds and

NIDA grants for medication & psychotherapy studies, Clinical Trial Network, and K05

Talking Points - Overview

• Beginnings • Emergence of methadone maintenance• How I got involved • Co-morbidities• Treatment Matching • Concluding remarks

– Importance of clinical observations– Working with excellent collaborators– Serendipity– Luck

Beginnings: 1920’s - Mid 1960’sOne Size (pretty much) Fits All

For opioids Abstinence via long-term inpatient rx at prison

hospitals Lexington & Fort WorthAgonist maintenance illegalWithdrawal for opioids & sedatives describedDetoxification strategies developedFollowup studies found high relapseConditioning factors describedFocus on antisocial personality

Beginnings (cont.)

For alcohol 12-Step approach Developed in 1930’s, outside medical

establishment, by recovering physician and stockbroker

Chronic, relapsing nature emphasizedAdvise paying attention to medical developments

- But “no medication” approach emerges Many helped Widely disseminated, mostly by word of mouthAdopted worldwide

Beginnings (cont.)

• Minnesota Model emerges – Blends 12-Step with 28-day inpatient group &

individual rx rehabilitation, or • ” Taking the cure”

– Medications used mostly for detoxification – Emphasis on chronic, relapsing nature of the

problem implicitly de-emphasized– Treatment sort of like a laundry – you enter

dirty and come out clean

Beginnings (cont.)

• TCs emerge • Long-term residential • Emphasis on honesty & personal responsibility• Increasing responsibility and privileges earned

by successful work within the community• Graduates do very well, but many dropout

Beginnings (cont.)

• Psychiatric problems viewed as substance induced

• Little interest in addiction rx by medical profession

• Separated from general healthcare – Separate records– Most rx paid by block grants – not healthcare funds– Emphasis on correcting undisciplined lifestyle using

“reformed addicts” and 12-Step participation

Medication-Assisted Therapy Emerges: Dole & Nyswander Studies

• Originates from clinical observations and followup studies showing high relapse rates, even after long-term residential rx

• And, knowledge of pharmacology• Counter to 40 years of policy • Opposed by many, including law enforcement• But, outcome data strong• Permitted under highly regulated conditions

Methadone Rx Expands: Vietnam War & Work of Jerome Jaffe

• Heroin addiction in troops a focus of public attention • Dr. Jaffe observed positive results from methadone

maintenance while running programs in Chicago• Nixon appoints Dr. Jaffe as first “drug czar”• Methadone treatment expands• Funds approximately equally balanced between demand

reduction & treatment• Patients less highly selected and don’t do as well as in

Dole & Nyswander studies

How I Get Involved

• Join Navy as general medical officer in 1965• Vietnam War escalating • Enter psychiatric residency at Temple in 1997• Had psychotherapy in medical school• Father’s death from alcoholism stimulates interest • Maybe psychoanalysis has the answer

– Enter psychoanalytic institute– Personally helpful– Maybe it can explain why people get addicted– Enter Phila. Psychoanalytic institute

How I Get Involved (cont.)

• With colleague during residency, start individual & group rx with Temple students - most abusing hallucinogens

• 3 students have LSD flashbacks while driving• Write up case reports with help of supervisor (Gerald

Klee) who worked with LSD at Ft. Detrick, MD• Get job at community mental health center in West Phila

after residency ends in 1970 • Flashback paper published in Am. J. Psych (1970) at

same time drug rx in VA expanding

How I Get Involved (cont.)

• Chuck O’Brien finishing 2-years in Navy as psychiatrist at Phila. Naval Hospital

• Dept. Chair at Penn (Mickey Stunkard) recruits Chuck to lead substance abuse program at VA

• Stunkard looking for person to do clinical work– Reads the flashback paper– Invites me to meet with Chuck– I’m hired and start at the Phila. VA in 1971– Know very little about drug treatment

VA Research Begins

• Most vets applying for rx in Phila. are heroin addicts• VA starts a methadone program• Observe that many pts. anxious & depressed• Prescribe antidepressants or antianxiety medications for

some & they seem to help• Chuck says let’s study it & introduces me to Karl Rickels • Do first randomized, placebo controlled trial of

antidepressant medication rx (Sinequan) for depressed methadone pts. & find evidence of effect

What About Talking Therapy?(Does it help to talk to psychopaths?)

• Psychoanalysts working in methadone programs observe a lot of psychiatric problems

• Khantzian publishes self-medication theory iin 1974• Observes that methadone patients being rxed by staff

with little or no psychiatric training get NIDA’s attention• NIDA organizes workshops to develop testable

hypotheses & puts out RFA• Research question formulated: would professional

psychorx improve outcomes?• Jim Mintz & I write proposal to study psychorx with help

of Drs. Beck & Luborsky

Study Design

• After stabilization on methadone:– Did structured interview to assess

psychopathology– Random assignment to:

• Counseling alone• Counseling + SE therapy• Counseling + CB therapy

• Therapies available for 6 months• Mintz leaves; Tom McLellan arrives

Summary of Findings• High levels of anxiety, depression & antisocial

personality• Psychiatrically-focused rx’s usually reduce psychiatric

symptoms• Sometimes reduce drug use • Benefits of psychiatric rx mostly in patients with more

psychiatric symptoms (duh!)• No evidence that treating psychiatric disorders cures

substance use disorders• Conclusion: psychiatric and substance use

disorders, influence each other, each needs attention

Treatment Implications

Not all opioid addicts are psychopaths Talking therapy can magnify effect of methadone

Dole & Nyswander thought the same Treatment matching probably helpful

Patients with high levels of psychiatric problems do better if psych rx combined with drug-focused rx

Principle similar to antidepressant studies Many other studies of psychiatric co-morbidities done Asked to review grants on Joe Brady’s study section

Opportunity to learn more about research

Collectively, the Field Begins to Move Away from One Size Fits All

• Comorbidity, antidepressant & psychotherapy studies showed:– Patients heterogeneous– Heterogeneity results in different rx needs– Effect of drug-focused rx’s can be magnified by

targeting co-morbidities– Drug-focused therapies, pharmacotherapies and

psychotherapies can be combined– Contributed to development of ASI to assess outcome

and use in treatment matching

On a Personal Level: What Serendipity! What Luck!

• Had personal interest in addiction• Had psychorx experience and training• First publication happened to be read by

Department Chair who was looking for someone to treat patients in a new VA program that:– Was likely to be stable over the long-term – Directed by an outstanding leader– Affiliated with a university – Great collaborators

Prevalence of Co-morbidity Explored in Large Epidemiological Studies

• Epidemiologic Catchment Study• National Co-Morbidity Study

– Alcohol use disorders lifetime prevalence = 14%– Drug use disorders lifetime prevalence = 6%

• Overlap between SUDs & other psychiatric disorders examined via odds ratios

• Depression, anxiety, bipolar, schizophrenia, personality disorders all have elevated odds ratios

• Example from study by Grant et al

Co-occurrence of 12-Month Alcohol & Drug

Use Disorders and Personality Disorders

Grant et al, 2004

43,093 persons interviewed Alcohol Disorder: 28.6% had PD

- ASP: OR 4.8 - Histrionic: OR 4.7

- Dependent: OR 3.0

Drug Disorder: 47.7% had PD- ASP: OR 11.8

- Histrionic: OR 8.0 - Dependent: OR 11.6

Led to Interest in Differentiating Substance-Induced from Independent

Disorders

• Depression & anxiety in alcohol dependent patients showed clearing with abstinence– Schuckit; Mendelson; others

• Specific symptoms vary according to drug class, and according to intoxication, withdrawal, persistent

• DSM-IV and 5 provide details in text and summary table that is in DSM-V with slight modifications

Diagnoses Associated with Class of Substances

Reprinted with permission from the Diagsnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association

More Medications Development: Naltrexone & Alcohol

• Tried ntx tablets with opioid addicts at VA but never worked well due to low interest and high dropout

• Animal data showed that ntx might reduce alcohol craving and use

Non-relapse “Survival”

Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880

No. of Weeks Receiving Medication

10 2 3 4 5 6 7 8 9 10 11 12

0.0

0.1

0.2

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.3Naltrexone HCL (N=35)Placebo (N=35)

Cu

mm

ula

tive

Pro

po

rtio

n w

ith

No

Rel

apse

Rates of Never Relapsing According to Treatment Group (n=97)

O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992

Naltrexone/coping skillsNaltrexone/supportive therapyPlacebo/coping skillsPlacebo/supportive therapy

Days

0

20

40

60

80

100

n=97

0 20 40 80 60

Emergence of HIV Expands Focus on Addressing Co-Morbidity

• Participate in reviews of first AIDS Centers• Zili Sloboda (fellow reviewer) and I write grant to

study methadone rx as HIV risk reduction• Study HIV risk and HIV incidence among

methadone patients and in persons that are “just like you”, but not on methadone.

• Dave Metzger joins team• Find big differences between groups

21%

13%

18%

51%

21%

39%

0%

10%

20%

30%

40%

50%

60%

B 6 12 18 24 30 36 42 48 60 72

Months

In Treatment Out of Treatment

Six year HIV infection rates by treatment status at time of enrollment

(Metzger et al. 1993)

Percent Infected After 18 Months by Treatment

Participation

4.50%

22%

3.50%

0%

5%

10%

15%

20%

25%

Tx Partial Tx No Tx

(Metzger et al. 1993)

Emergence of NIDA International HIV-Related Studies

• In early 1990’s, invited to participate in NIDA meeting in Brazil to develop addiction studies– Meet Flavio Pechansky– Receives Humphrey Fellowship– Spends time at Penn/VA addiction program– ASI translated into Brazilian Portuguese– Develop a study of HIV incidence in cocaine users– Find 5% annual incidence– Addiction work continues and Flavio recently funded

for Center focused on crack cocaine rx & research

Invited to NIDA/Pavlov Meeting in St. Petersburg, Russia

• Aimed at developing studies to reduce spread of HIV• Meet Drs. Zvartau & Krupitsky• Idea exchanges showed prominent role of heroin

addiction in spreading HIV • Agonist rx illegal; naltrexone only effective medication• Research infrastructure but little funding• Tradition of prospective, randomized, double-blind,

double-dummy trials• Develop series of naltrexone studies• Lead to Alkermes study with approval of Vivitrol for

opioid addiction

Kaplan-Meier Survival Functions

Weeks

302724211815129630

Cu

m S

urv

ival

1,1

1,0

,9

,8

,7

,6

,5

,4

,3

,2

F+NP

N+F

NP+FP

N+FP

N+F>NP+FPN+F>F+NPN+FP>NP+FPN+FP>F+NP

F+NP=NP+FPN+F=N+FP

HIV Risk Assessment Battery

Drug risk Sex risk

remissionrelapse

2,00

4,00

6,00

8,00

Sco

re

]

]

remissionrelapse

]

]

Log Rank (Mantel-Cox) Sig.

P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,069

Kaplan-Meier Survival Functions: Drop out

Response ProfileCumulative % of Participants at Each Rate of WeeklyConfirmed Abstinence: XR-NTX 380 mg vs. Placebo

Total abstinence (100% opioid-free weeks) during Weeks 5-24 was reported in 45 (35.7%) of subjects in the XR-NTX group versus 28 (22.6%) subjects in placebo group (P=0.0224).

Kiev, Ukraine

• Fastest growing HIV problem in Europe• Opioid IDU main driver • Buprenorphine started rx in 2007; methadone in

2008; little outcome data• Sergey Dvoryak does rotation at Penn during

Humphrey program• Get R21 to test acceptability& outcome of 12-

week trial of methadone for 25 HIV+ and 25 HIV negative IDUs

Kiev, Continued

• Excellent adherence (though TH’s not allowed)• All pts. chose to continue methadone in city

program after 12 weeks• Marked reduction in drug use and HIV risk• Focus groups show marked fear of police, and

vice-versa• Government changes; methadone expansion

halted• Will our data will help restart methadone work?

Tbilisi, Republic of Georgia

• Subutex ® not approved but smuggled in from France & Germany

• David Otiashvili does rotation at Penn during Humphrey program

• CTN fellowship for Gvantsa Piralishvili • R21 study developed & randomized 80

Subutex ® injectors to 12-week course of daily observed methadone or Suboxone ®

Results

• Only 3 females; average age 34• 75% HCV+, NONE HIV+• Excellent adherence, less than 5% drug

use confirmed by urine testing• No significant outcome differences

between groups• As in Kiev, most pts continue methadone

in city program after study ends

Others

• Vivitrol for amphetamine addiction in Iceland• 100 ss randomized to Vivitrol or placebo• Excellent rx in Iceland • Very little drug use in ss who stay in rx• No evidence that Vivitrol adds to usual rx outcome

• Regular vs sporadic counseling for methadone patients in Jakarta

• 80%+ followup• Study completed but data not analyzed

All of the Above Facilitated by CTN:

Begins in 1998 after IOM recommended more studies in community treatment programs to “bridge the gap” between research and practice

Funded 16 “Nodes” including “Delaware Valley Node”

CTN infrastructure helps apply for & obtain: International studies & fellowships Demonstration study of SBIRT on medical units at

Christina Medical Ctr in Delaware DVN participates in CTN studies

Short or longer-term buprenorphine-naloxone treatment of opioid addicted youth

• Usual care is detoxification and counseling• Clinicians observed relapse is common• Tested impact of usual vs longer-term rx• Made possible by collaborative network within

CTN• Difficult to find sites - opposition to using longer-

term agonist rx for opioid addicted youth• Findings published in JAMA (2008)

Screening Assent/Consent

Not EligibleEligible End of process

Randomization: (within clinics)

DETOX Detox over 2 wks

BUPNAL for 12 wksTaper starts wk 9;

Ends wk 12

Evaluations: weekly X 12 wks Comprehensive @ 4, 8, 12, 24, 36 and 52 wks

All Get Psycho/Soc Rx2x weekly for 12 Wks

Opioid Positive Urines: Missing excluded (N=90)

Baseline Week 4 Week 8 Week 120

10

20

30

40

50

60

70

80

90

100

DTX

BUP

Group Effect = p<.001Time Effect = NSTime X Group = p<.07

Recent Move Toward Studies In Medical Settings

• Idea from observations and studies showing that untreated SUDs interfere with rx for other medical problems

• Examples:– SBIRT in ER’s– HIV testing with or without counseling– Facilitating HIV and addiction rx adherence in

hospitalized HIV+ pts.– Integrating addiction & HIV treatment

Concluding Remarks

• Gradual shift away from one size fits all and no-medication ideology

• Multiple reasons for this change – Clinical observations– Research findings– Vietnam War– HIV epidemic

In My Case

• Have been very lucky to participate and contribute to these developments

• Good fortune made possible by:– Clinical observations/serendipity– Persistence & Luck – Leadership of Chuck O’Brien – Collaboration with Tom McLellan– VA and NIDA support

• Thank you very much for this award!