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’s One Size (pretty much) Fits All For opioids Abstinence via long-term inpatient rx at prison hospitals Lexington & Fort Worth Agonist maintenance illegal Withdrawal for opioids & sedatives described Detoxification strategies developed Followup studies found high relapse Conditioning factors described Focus 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 emphasized Advise paying attention to medical developments - But “no medication” approach emerges Many helped Widely disseminated, mostly by word of mouth Adopted 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 Cummulative Proportion with No Relapse Non-relapse “Survival” 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 Naltrexone HCL (N=35) Placebo (N=35) 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 No. of Weeks Receiving Medication Volpicelli et al, Arch Gen Psychiatry, 1992; 49: 876-880 Rates of Never Relapsing According to Treatment Group (n=97) Naltrexone/coping skills Naltrexone/supportive therapy Placebo/coping skills Placebo/supportive therapy 100 80 60 40 n=97 20 0 0 20 40 60 80 Days O’Malley et al, Arch of Gen Psychiatry, Vol 49, Nov 1992 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 Six year HIV infection rates by treatment status at time of enrollment In Treatment 60% Out of Treatment 51% 50% 39% 40% 30% 18% 21% 20% 21% 13% 10% 0% B 6 12 18 24 30 36 42 48 60 72 Months (Metzger et al. 1993) Percent Infected After 18 Months by Treatment Participation 25% 22% 20% 15% 10% 5% 4.50% 3.50% 0% Tx (Metzger et al. 1993) Partial Tx No Tx 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 1,1 1,0 N+F N+FP ,9 F+NP NP+FP ,8 ,7 N+F>NP+ N+F>F+NP FP N+FP>NP N+FP>F+NP +FP F+NP=NP+FP N+F=N+FP ,6 Cum Survival ,5 ,4 ,3 ,2 0 3 6 9 12 Weeks 15 18 21 24 27 30 HIV Risk Assessment Battery Sex risk Drug risk 8,00 ] 6,00 ] ] 4,00 2,00 ] remissionrelapse remissionrelapse Kaplan-Meier Survival Functions: Drop out Log Rank (Mantel-Cox) Sig. P(PO+IN)- (PO+PI)<0,001 P(ON+PI)- (PO+PI)=0,069 Response Profile Cumulative % of Participants at Each Rate of Weekly Confirmed 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 12week 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 longerterm agonist rx for opioid addicted youth • Findings published in JAMA (2008) Screening Assent/Consent Eligible Not Eligible End of process Randomization: (within clinics) DETOX Detox over 2 wks All Get Psycho/Soc Rx 2x weekly for 12 Wks BUPNAL for 12 wks Taper starts wk 9; Ends wk 12 Evaluations: weekly X 12 wks Comprehensive @ 4, 8, 12, 24, 36 and 52 wks Opioid Positive Urines: Missing excluded (N=90) 100 90 DTX 80 BUP 70 60 50 40 30 20 10 0 Group Effect = p<.001 Time Effect = NS Time X Group = p<.07 Baseline Week 4 Week 8 Week 12 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!