Prescription opioid abuse

Prescription opioid abuse Stacey Sigmon, Ph.D. College of Medicine University of Vermont Burlington, VT

Class of drug that is derived from nature (poppy) or man-made Opium Heroin Morphine (IR morphine, MS-Contin) Codeine (Tylenol-3) Hydromorphone (Dilaudid ) Oxycodone (OxyContin, Percodan ) Hydrocodone (Vicodin ) Propoxyphene (Darvon ) Meriperidine (Demerol ) Produce analgesia, drowsiness, euphoria, constipation, pupil constriction Clouding of mental function, depression of CNS and cardiac activity at high doses Overdoses result from respiratory depression University of Vermont 2

Actions of opioids Opioids can be self-administered via injection, inhalation, intranasally or orally Primary interaction is with the mu-opioid receptor (but also kappa, delta) The opioid binds to receptors in certain areas of the brain, including: areas within the reward pathway (including the VTA, nucleus accumbens and cortex) areas involved in the pain pathway (including the thalamus, brainstem and spinal cord), producing analgesia increase dopamine release University of Vermont 3

Tolerance With repeated use, tolerance may develop. Tolerance: Diminished sensitivity to drug (takes more to achieve same effect) High tolerance develops for respiratory depression, analgesia, sedation, euphoria Little tolerance develops for pupil constriction or constipation University of Vermont 4

Withdrawal Onsets at time of next habitual dose (typically 6-12 hrs after last use) Peaks in 24-48 hrs Tearing, runny nose, yawning, sweating, insomnia, dilated pupils, gooseflesh, irritability, tremor, chills, diarrhea, craving for opioids Not life threatening University of Vermont 5

Opioid abuse The U.S. saw a marked increase in prevalence of opioid abuse between 1990-2000. Opioid abuse and dependence continue to be a serious public health problem. Opioid abuse is associated with a host of adverse consequences: emergency department visits overdoses criminal activity risk for contracting and spreading HIV and hepatitis use of other drugs (e.g., alcohol, cocaine, benzodiazepines) numerous other psychiatric and psychosocial consequences Abuse of prescription opioids (PO) (e.g., Oxycontin, Vicodin, Percocet) has become a particularly serious problem. University of Vermont 6

Pharmacological treatments: University of Vermont 7

FDA-approved in 1984 A pure opioid antagonist, typically administered orally in tablet Maintenance on naltrexone Prevents receptor activation by other opioid compounds Effectively blocks the effects of other opioids High dropout rate, compliance problems need for behavioral and psychosocial services to enhance compliance with treatment sustained-release formulations University of Vermont 8

Methadone The most widely used intervention for opioid dependence (used since mid-1960s) Full opioid agonist Administered orally in liquid form, daily Functions as a mild reinforcer, while suppressing opioid withdrawal (for up to 24 hrs) Blocks effects of exogenously administered opioids Reduces illicit opioid and other drug use Reduces the frequency of HIV infection, frequency of drug injections and needle-sharing contacts Reduces other problems associated with illicit opioid abuse (e.g., crime, social/family, employment) University of Vermont 9

Buprenorphine (Suboxone, Subutex) FDA-approved in 2002 for treatment of opioid dependence Partial opioid agonist Administered via sublingual tablet Like methadone: - functions as a mild reinforcer (supporting adherence) - suppresses/prevents withdrawal (adherence) - a sufficient dose will block effects of other opioids (thereby reducing illicit opioid use, criminal activity & risk behavior) In contrast to methadone: - ceiling on agonist activity limits abuse liability, improves safety - can be administered less-than-daily (UVM studies) - limited withdrawal upon discontinuation (detox) - buprenorphine available from physicians who complete training & get certified to provide (Rx vs. clinic) University of Vermont 10

Prescription opioid abuse Abuse of prescription opioids (PO) (e.g., Oxycontin, Vicodin, Percocet) is increasing at an especially marked rate. New initiates: - annual number of new initiates increased > 400% between 1990 and 2000 (SAMHSA, 2003) - Increase was more marked for POs than for any other prescribed drug - increases evident across all age groups (adolescents, young adults, college students, adults) Annual number of new initiates of prescription drugs: 1965-2001 Source: 2002 National Survey on Drug Use and Health (SAMHSA, 2003) 2002 National Survey on Drug Use and Health (SAMHSA, 2003) University of Vermont 11

Initiation of PO abuse By 2007: Of those who initiated illicit drug use in the past year, more individuals began illicit drug use with POs than any other drug, including marijuana. Substance Abuse and Mental Health Services Administration, Office of Applied Studies (2008). Results from the National Survey on Drug Use and Health: National Findings. University of Vermont 12

Prevalence of PO abuse Substance Abuse and Mental Health Services Administration, Office of Applied Studies (2008). Results from the 2007 National Survey on Drug Use and Health: National Findings (NSDUH Series H-34, DHHS Publication No. SMA 08-4343). Rockville, MD. University of Vermont 13

Consequences of PO abuse PO abuse & dependence are associated with numerous adverse consequences: Emergency department (ED) visits: One example: Between 2004-5 alone, there was a 92% increase in ED visits attributable to hydromorphone or a hydromorphone combination. Of the ~600,000 ED visits in 2005 involved non-medical use of Rx or OTC drugs, the most frequently-reported drugs were POs (33% of visits). Substance Abuse and Mental Health Services Administration, Office of Applied Studies. DAWN, 2005: National Estimates of Drug-Related ED Visits. DAWN Series D-29, DHHS Publication No. (SMA) 07-4256, Rockville, MD, 2007. University of Vermont 14

PO-related deaths Marked increase in PO-related deaths in the U.S. between 2001-2005. Number of PO-related deaths exceed that of cocaine and heroin. Source: Centers for Disease Control and Prevention # University of Vermont 15

Vermont trends While the number of treatment admissions for POs in U.S. increased 3.5- fold between 1991-2002, the increase was 12.2-fold in Vermont. Number of Admissions/100,000 Population 60 50 40 30 20 10 0 Figure 3. Number of Primary Prescription Opioid Treatment Admissions in Vermont: 1991-2002 1990 1992 1994 1996 1998 2000 2002 Source: 2004 Treatment Episode Data Set (TEDS, 2004) University of Vermont 16

Characteristics of PO abusers Demographic & drug use characteristics remain largely unknown# Improved understanding important for developing effective treatments# Some early data suggested that PO (vs. heroin) abusers may possess several demographic & drug use characteristics predictive of favorable treatment outcome :# - less severe baseline opioid use# - Less severe route of administration (IN/oral > IV)# - Smaller amount of opioids per day# - Older age of opioid initiation# - Briefer duration regular opioid use at time of treatment intake! - greater social stability/ses# - More likely married, employed, more income, less severe family, social and legal problems# Several of these characteristics have been associated with favorable treatment outcome, including detoxification and naltrexone for opioid-dependent patients# University of Vermont 17

Characteristics of PO abusers Examined intake data from 75 patients in our UVM methadone clinic.# PO abusers reported:# - Less income from illegal sources# - Less IV use# - Smaller amount of opioids/day# - Less money spent on opioids/day# - Lower scores on ASI Opiate scale# - Lower scores on ASI Family/Social scale# Several of these characteristics have been associated with favorable treatment outcome, including detoxification and naltrexone for opioid-dependent patients# University of Vermont 18

Treating PO abusers Worth exploring whether a subset of PO abusers may be candidates for opioid detoxification (vs. long-term agonist maintenance)# - increasing number of PO-abusing adolescents & young adults warrants exploring potential alternatives to long-term maintenance# - many PO abusers may shun maintenance programs due to the stigma# - maintenance treatments are highly restricted by federal regulations such that patients with less severe or brief opioid histories may be ineligible# - limited access to opioid maintenance programs in many rural areas, which are also regions where PO abuse is particularly prevalent # While maintenance therapies may be deemed necessary for treating PO dependence, this should be determined empirically.# University of Vermont 19

Randomized clinical trial Aim:# - To characterize the demographics, drug use characteristics & treatment needs of PO-dependent adults# - To examine the efficacy of an intervention that includes:# - Pharmacotherapy! - Individual behavioral therapy# - Observed, on-site urine toxicology testing# University of Vermont 20

Randomized clinical trial NIDA-funded R01 project which aimed to:# - Characterize the demographics, drug use characteristics & treatment needs of POdependent adults# - Examine the efficacy of an intervention that includes:# - Pharmacotherapy! - Individual behavioral therapy# - Observed, on-site urine toxicology testing# University of Vermont 21

Participants Inclusion Criteria: - Primary prescription opioid abusers - 18 years or older - DSM-IV opioid dependence - Interest in & willing to receive an opioid taper Exclusion criteria: - Pain that requires ongoing narcotic treatment - Benzodiazepine dependence - Pregnant or nursing University of Vermont 22

Pharmacotherapy Brief buprenorphine stabilization (approx 2 weeks)# Random assignment to receive a 1-, 2-, or 4-week buprenorphine taper# Subsequent transition to oral naltrexone therapy for subjects who successfully taper without resumption of opioid use # Throughout study:# - Double-blind, double-dummy administration of buprenorphine & naltrexone# - Opioid withdrawal assessed prior to dosing at each study visit# - Self-report ratings (VAS, CINA)# - Observer ratings by blinded research nurse (CINA)# - Pupil diameter as physiological measure (pupillometer)# - Non-opioid ancillary medications available throughout study to manage withdrawal symptoms (e.g., clonidine, hydroxyzine, loperamide, ibuprofen)# University of Vermont 23

Other treatment components Behavior Therapy:# - Individual behavioral therapy using the Community Reinforcement Approach (CRA) # - Twice-weekly sessions with Masters-level therapist, outreach as needed# - Customized treatment plan: # - social/recreational# - vocational/employment# - practical needs (e.g., housing, medical care, health insurance, childcare)# - skills training (e.g., money management, depression, assertiveness, anger management)# Urinalysis Monitoring:# - Observed by same-sex research staff; tested immediately on-site via EMIT# - Testing for opioids: 3x/week (MWF)# - Qualitative assays: opioids, methadone, propoxyphene, oxycodone# - Semi-quantitative assay: buprenorphine# - Testing for other illicit drugs: Randomly 1x/week (cocaine, amphet, benzo, THC)# University of Vermont 24

Study design Buprenorphine Stabilization (1-2 wks) 1-wk Bup Taper 2-wk Bup Taper 4-wk Bup Taper Naltrexone Naltrexone Naltrexone Daily visits ~ 6 wks 12 week duration MWF visits ~ 6 wks University of Vermont 25

Participants 70 PO abusers randomized to 1 of 3 treatment groups (1-, 2- or 4-week taper)# Demographic and drug use characteristics: # Buprenorphine stabilization:# #- Mean duration: 14.2 days (range 8-20)# Demographic Characteristics % Female 38 % Caucasian 96 Mean age (yrs) 27.3 ± 8.4 Mean years of education 12.4 ± 0.4 % FT employed 72 Drug Use Characteristics Primary opioid in past month % oxycodone product 72 % other (e.g., hydrocodone, buprenorphine) 28 % Primary IN Administration 65 % Primary Oral Administration 19 % Primary IV Administration 16 % Used IV 41 Mean opioids used per day (mgs) 79.3 ± 29.5 Mean days used opioids in past 30 days 24.6 ± 4.2 Mean duration of regular opioid use (yrs) 4.8 ± 3.7 #- Mean dose: 11.5 mg (range 2-20) # # # # ## University of Vermont 26

Opioid abstinence By end of stabilization, ~ 80% of subjects were opioid abstinent# Significant main effect of group at treatment midpoint (p=.02), with 64%, 29% and 29% of subjects in the 4-, 2- and 1-week groups, respectively, abstinent from opioids at Week 5.# Significant main effect at end of treatment (p=.03), with 50%, 17% and 21% of subjects in the 4-, 2- and 1-week groups, respectively, still opioid abstinent at Week 12.# At both timepoints, pairwise comparisons showed significantly better outcomes in the 4-week than either 1- or 2-week groups, with no differences between the latter 2 conditions. # University of Vermont 27

Retention Similar pattern seen with treatment retention: Significant main effect of taper duration at end of treatment (p=.04), with 50%, 21% and 21% of subjects in the 4-, 2- and 1-week groups, respectively, still retained at Study Week 12. University of Vermont 28

Naltrexone ingestion Trend toward an effect of taper duration on naltrexone ingestion at treatment midpoint (p=.08): - 55%, 25% and 29% of subjects in the 4-, 2- and 1-week groups, respectively, taking naltrexone at Week 5 Significant main effect of taper duration on naltrexone ingestion at end of treatment (p=.038): - 50%, 17% and 25% of subjects in the 4-, 2- and 1-week groups, respectively, still on naltrexone at Week 12 University of Vermont 29

Conclusions This randomized, double-blind trial sought to compare the efficacy of 1-, 2- and 4- week buprenorphine tapers for treatment of PO-dependent outpatients.# The 4-week buprenorphine taper produced striking improvements over the briefer tapers that were largely sustained after transition to naltrexone. # These outcomes are substantially (i.e., 2-3 fold) better than those seen in prior studies of outpatient buprenorphine detoxification. # University of Vermont 30

Conclusions Taken together, our results suggest that a meaningful proportion of PO abusers may respond to a 4-week outpatient buprenorphine taper. # Important to know if a meaningful subset of PO users may not require long-term maintenance (especially younger, less severe PO abusers).# Continued research efforts also needed to better understand the demographic or drug use characteristics that may prospectively predict whether a PO abuser is a good candidate for a taper or will require longer-term treatment for a good outcome.# University of Vermont 31

Opioid use and abstinence as behavior With repeated administration opioid use produce physiological dependence, which helps to maintain use (tolerance, withdrawal). The most common and effective interventions tend to be pharmacological. However, opioid use and abstinence are still behaviors that are governed by operant principles. Behavioral treatments have been demonstrated effective in promoting important clinical behaviors across short and long-term opioid treatments: Opioid maintenance: increasing opioid abstinence in patients who continue to use, decreasing cocaine/other drug use, improving counseling attendance Opioid detoxification: increasing opioid abstinence/preventing relapse, improving adherence with naltrexone therapy University of Vermont 32

Reinforcing opioid abstinence during maintenance University of Vermont 33

Reinforcing opioid + cocaine abstinence during maintenance University of Vermont 34

Reinforcing opioid abstinence during detox University of Vermont 35

Reinforcing opioid abstinence during detoxification University of Vermont 36

Reinforcing naltrexone adherence University of Vermont 37

Reinforcing naltrexone adherence University of Vermont 38

Reinforcing attendance among methadone patients University of Vermont 39

Reinforcing attendance among methadone patients University of Vermont 40

Conclusions Opioid dependence is a chronic, relapsing disease and represents a serious public health problem. Of particular concern in recent years is the striking increase in nonmedical use of prescription opioid medications. The most effective treatments for opioid dependence involve a pharmacological component (e.g., buprenorphine, methadone, naltrexone). Data also show that longer-duration approaches (e.g., prolonged agonist maintenance, more gradual opioid tapers) will likely produce more favorable outcomes than brief treatments. University of Vermont 41

Conclusion There will be a subset of opioid-dependent patients who may be candidates for briefer or less intensive approaches. Efforts to identify the demographic and drug use characteristics of this group are important. The majority of opioid-dependent patients are likely to require more intensive or lengthy treatment. Combining pharmacotherapies with other treatment components will further improve treatment outcomes. Behavioral treatments have been empirically demonstrated to promote important clinical behaviors in opioid-dependent patients (e.g., abstinence, medication adherence, treatment engagement). These could be used to improve outcomes generally or to tailor treatment intensity for more treatment-resistant patients. Taken together, a comprehensive approach and a longer view will provide the most efficacious treatments for opioid dependence. University of Vermont 42

Acknowledgements National Institute on Drug Abuse (NIDA)# 1R01 DA019989# T32 DA007242 # Co-Investigators# Stephen Higgins, Ph.D. # Sarah Heil, Ph.D.# Pre- and Post-doctoral Fellows# Kelly Dunn, Ph.D.# Mollie Patrick, B.S.# Kathryn Saulsgiver, Ph.D.# Biostatistician# Gary Badger, M.S. # Therapist# Bruce Brown, M.S.W.# Research Nurses# Betsy Bahrenburg, R.N.# Nancey Kinlin, R.N.# Susan Schmidt, R.N.# Maria Spadanuda, R.N.# Research Assistants# Abby Cooper# Allison Newth# Edward Reimann# Matthew Scanlin# University of Vermont 43