XR-NALTREXONE
`AS AN ELEMENT OF THE COMPREHENSIVE MEDICAL
`RESPONSE TO THE OPIOID EPIDEMIC
`
`Adam Bisaga M.D.
`Columbia University and New York State Psychiatric Institute
`
`National Academies, Public Workshop on MAT, Washington DC, October 30, 2018
`
`Page 1 of 25
`
`ALKERMES EXHIBIT 2039
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`AS AN ELEMENT OF THE COMPREHENSIVE MEDICAL
`RESPONSE TO THE OPIOID EPIDEMIC
`
`Adam Bisaga M.D.
`Columbia University and New York State Psychiatric Institute
`
`National Academies, Public Workshop on MAT, Washington DC, October 30, 2018
`
`Page 1 of 25
`
`ALKERMES EXHIBIT 2039
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
`
`
`
`FDA-APPROVED MEDICATION FOR OUD (MOUD)
`
`Methadone
`
`Full
`Agonist
`
`μ OR
`
`Buprenorphine
`
`Partial
`Agonist
`
`μ OR
`
`XR-Naltrexone
`
`Antagonist
`
`μ OR
`
`Page 2 of 25
`
`
`
`FDA-APPROVED MEDICATIONS: ANTAGONIST
`
`• Naltrexone
`– Prevents activation of opioid receptors and “stabilizes” opioidergic
`system
`– Blocks effects of exogenous opioids and blocks re-development of
`physical dependence (prevents relapse)
`• relieves craving, stabilizes affect
`
`• Limitations
`– Can only be administered after resolution of physical dependence
`(opioid withdrawal)
`
`• Concerns
`– There are concerns about naltrexone, some are justified, others are not
`– Naltrexone is often “pitted against” agonists rather than seen as
`“complementing” the other medications
`
`Page 3 of 25
`
`
`
`NALTREXONE: CONCERNS
`
`• MYTHS
`
`– Ineffective (no effect on craving)
`
`– Dangerous (override/overdose)
`
`– Worsens the disorder (depression/suicidality)
`
`– Patients do not want it
`
`– Prevents patients from receiving beneficial treatment
`
`• REAL CONCERNS
`
`– Induction hurdle
`
`– Retention hurdle
`
`Page 4 of 25
`
`
`
`NALTREXONE: ORAL VS. XR PREPARATIONS
`
`• A lot of opinions about naltrexone relate to the oral form (daily pill),
`BUT: XR-naltrexone is superior to oral naltrexone
`
`Time to dropout: XR- vs. oral naltrexone
`
`(Sullivan et al., 2018)
`
`Page 5 of 25
`
`
`
`NALTREXONE: EVIDENCE
`
`• Effective
`– Effectiveness comparable with buprenorphine: similar effect on retention,
`craving and opioid use
`– But the initiation of treatment is more difficult in some patients
`
`• Risk of opioid use while on medications
`– Approximately 1/3rd of patients will try to use on XR-naltrexone (single episodes)
`– Cases of overriding blockade are very rare, but possible
`
`•
`
`Increased risk of overdose after treatment dropout
`– While on medication, risk is reduced (comparable to BUP and METH)
`– For all medications, patients need to stay on them to be effective
`– BUT: it is easier to discontinue NTX as there is no “withdrawal reminder”
`
`Page 6 of 25
`
`
`
`NALTREXONE: EVIDENCE (2)
`
`• Depression improves once the patient stops illicit opioids
`– Cases of depression and suicidality are rare, though more frequent than
`with agonists
`
`• Patients do not want it
`– Most patients, and many providers, do not know about XR-naltrexone
`medications
`
`• Prevents patients from receiving beneficial treatment
`– All patients should have access to all FDA-approved medications
`
`– In general, promoting one medication will increase the use/access to
`other medications (most treatments are still non-medical)
`
`– Introduction of buprenorphine destigmatized methadone
`
`Page 7 of 25
`
`
`
`INITIATING TREATMENT WITH NALTREXONE
`
`• Detoxified and abstinent (e.g., patients leaving controlled
`setting - residential treatment, prison)
`
`• Using opioids sporadically (high-risk)
`
`• Using daily, low-doses of opioids (oral Rx opioids)
`
`• Using daily large amounts of short acting agents (heroin)
`
`• Using large amounts of long-acting agents (XR oxycodone,
`fentanyl, methadone)
`
`• Patients maintained on methadone or buprenorphine
`
`Page 8 of 25
`
`
`
`METHODS OF INITIATING TREATMENT WITH
`XR-NALTREXONE
`
`•
`
`Standard method of induction (detoxification followed by a 7-10 day opioid-free period) lasts 2
`weeks and has high attrition rate, which is a main barrier to start XR-naltrexone
`
`• We developed a shorter protocol (5-7 d) and adapted it to outpatient setting
`
`Oral NTX
`
`BUP
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`RETENTION
`
`Induction onto
`XR-NTX
`
`Received 2nd
`Injection
`
`(Sullivan et al., 2017)
`
`150 individuals with OUD were randomly
`assigned to BUP Taper or Oral NTX,
`outpatient induction onto XR-naltrexone
`
`Withdrawal
`
`NTX Induction
`
`BUP taper
`
`washout
`
`NTX
`
`Day 0
`
`5
`
`10
`
`15
`
`Withdrawal
`NTX Induction
`
`BUP clonidine/bdz
`
`NTX
`
`0
`
`5
`
`10
`
`15
`
`Rx Opioids
`
`Heroin
`
`100%
`
`90%
`
`80%
`
`70%
`
`60%
`
`50%
`
`40%
`
`30%
`
`20%
`
`10%
`
`0%
`
`Injection
`
`Percent Receiving First Naltrexone
`
`Page 9 of 25
`
`
`
`PATIENTS SHOULD HAVE A CHOICE OF MEDICATION
`
`• All patients should be educated about the chronic nature of the disorder
`and engaged in shared decision making about treatment choice
`
`– Discuss all available treatment options
`
`– Risks of treatment without medications
`
`– Explain difference between the three medication options
`
`• Assess patient’s motivation for treatment, goals, and preferences for any
`particular medication before a final recommendation
`
`– When available involve a family member or a significant other
`
`Methadone
`
`Full
`Agonist
`
`μ OR
`
`Buprenorphine
`
`Partial
`Agonist
`
`μ OR
`
`XR-Naltrexone
`
`Antagonist
`
`μ OR
`
`Page 10 of 25
`
`
`
`CANDIDATES FOR NALTREXONE (1)
`
`• Patients who are not interested or able to be on agonist
`maintenance
`– Highly motivated for abstinence from all opioids (e.g., active in 12S program)
`– In professions where treatment with agonist is restricted (e.g., healthcare
`professionals, pilots)
`
`• Patients who are detoxified and abstinent but at risk for relapse
`– Released from a controlled setting (prison, residential program)
`– Moving back to old neighborhood
`– With increased stress or worsening of psychiatric problems
`
`Page 11 of 25
`
`
`
`CANDIDATES FOR NALTREXONE (2)
`
`• Patients who failed prior treatment with agonist
`– Continued to have cravings and used of opioids, non-compliant with
`agonists, diverting/misusing agonists, dropped out of treatment
`
`• Patients with less severe form of a disorder
`– Short history of use, lower level of use
`
`• Young adults which are often unwilling to commit to a long-
`term agonist maintenance
`
`•
`
`Individuals who use opioids sporadically
`
`• Patients successful on agonist but who want to discontinue
`them without risking relapse
`
`Page 12 of 25
`
`
`
`CONTINUUM OF OUD CARE
`
`Residential Programs
`
`Inpatient Addiction Units
`
`Medical Setting (ER, med inps)
`
`Criminal Justice Setting
`
`PWUD in the community
`
`Recovery
`Management
`w/o medications
`
`XR-naltrexone
`
`Buprenorphine
`
`Methadone
`(comprehensive)
`
`Methadone
`(open access)
`
`SIFs/IV opioid
`maintenance
`
`Outreach
`Interventions
`
`Page 13 of 25
`
`
`
`IMPORTANT RESEARCH AREAS
`
`•
`
`Implementing available medications using best standards of
`care will significantly reduce opioid OD rates
`– Similarly to progress made in EU countries
`– Not clear which implementation strategies are the best
`• BUT: can we find a “cure” for opioid addiction?
`– We need to understand neurophysiological benefits of sustained opioid
`abstinence and the mechanisms of a sustained recovery?
`• Not clear to what degree the status of brain health can improve
`following opioid dependence
`– w/agonists vs. w/antagonist vs. w/o medications: effects on craving,
`brain-response to cues, executive function, working memory, mood
`regulation, sleep architecture, etc.
`
`Page 14 of 25
`
`
`
`EVOLUTION OF MEDICAL TREATMENT
`
`BUP ⇢ XR-NTX
`
`MET ⇢ BUP
`
`Buprenorphine Maintenance
`
`Buprenorphine Taper
`
`Detox ⇢ Oral Naltrexone
`
`Detox ⇢ XR- Naltrexone
`
`MET taper ⇢ Oral Naltrexone
`
`Methadone Maintenance
`
`Methadone Taper
`
`60s
`
`70s
`
`80s
`
`90s
`
`2000s
`
`10s
`
`20s
`
`Page 15 of 25
`
`
`
`ADDICTION TREATMENT SYSTEM
`
`• Current treatment system remains fragmented
`– stigma of addiction as moral weakness/character problem persists
`– traditional (drug-free treatment) vs. medical model (OTP, OBOT, PC)
`
`• Many programs offer a “single medication” (MET vs BUP vs
`NTX) based on the ideology
`
`• Among those who receive care, most do not receive evidence
`based medical treatment
`– in contrast to individuals who suffer from most other chronic
`disorders
`
`Page 16 of 25
`
`
`
`ADDICTION TREATMENT GAP
`
`• Few of the 2.5 million individuals with OUD gain access
`to and receive adequate medical treatment
`
`• Most patients with OUD do not have access to
`treatment in their community
`– Only 2-3% of physicians offer buprenorphine (90% urban)
`– Half of the counties do not have buprenorphine provider,
`only 1,500 OTPs (also mostly urban)
`– Very few programs offer all 3 FDA medications
`
`OUD Cascade of Care (2016)
`
`Treatment Gap
`(under 90% goal)
`
`(Williams et al., 2017 revised)
`
`Treatment Gap (% not receiving)
`
`Opioid.amfAR.org
`
`Untreated,
`1,050,000
`
`Treated
`1,450,000
`
`Buprenorphine
`1,000,000
`
`Methadone
`350,000
`
`XR-NTX 100,000
`
`Page 17 of 25
`
`
`
`INTERNATIONAL CONTEXT
`
`•
`
`Latest numbers show 72,000 drug OD deaths in the US, continually
`growing for >20 years, accelerating rather than slowing
`– Portugal (40/yr, down 75% since 2001), Switzerland down by 2/3rd from the
`peak in 1990’s
`– France (1/5th of the US population) 350 deaths/year –
`– Drug overdose rate is 20 times higher in US vs EU
`
`• Clearly, the approach we have taken to treat OUD is not the right one
`– Based on the myth that recovery from opioid addiction can happen using
`mutual-help fellowship alone, without medical care (this is known not to be
`true for 50 years)
`– Pervasive stigma against addiction and against the medical model of
`treatment
`
`Page 18 of 25
`
`
`
`INTERNATIONAL CONTEXT: SWISS APPROACH
`
`• Steps taken in Switzerland
`– Drug deaths down by 2/3rd in less than 10 years
`– Close to 80 percent of patients affected with opioid addiction are treated
`under a medical model
`
`• Destigmatizing addiction: medical rather than criminal/morel
`problem, medical education
`– Helped attract non-specialists to treat opioid addiction
`– Intensive outreach to people who use drugs, offering harm reduction
`interventions led to decrease in new users
`– Offering widespread (free) treatment, continuum of interventions: heroin,
`methadone, buprenorphine, HIV care
`– Public perception of opioid addiction has dramatically changed, it is now seen
`as a chronic medical condition (similar to HIV)
`
`Page 19 of 25
`
`
`
`OUD TREATMENT:
`TRANSITION TO A NEW MODEL
`OF CARE
`
`Page 20 of 25
`
`
`
`OUD TREATMENT IN TRANSITION
`
`• Chronic disorder model: different levels of care, medications, additional
`treatments needed over time
`
`• Detox no longer a primary treatment, phasing-out detox units to
`become medication-induction units
`
`•
`
`•
`
`•
`
`Shift away from residential treatment towards long-term outpatient
`treatment
`
`Focus on offering patient choice of medication: methadone vs.
`buprenorphine vs XR-naltrexone
`
`Staged treatment: methadone buprenorphine XR-naltrexone
`
`Page 21 of 25
`
`
`
`OUD TREATMENT IN TRANSITION (2)
`
`•
`
`•
`
`Extended-release preparations to overcome nonadherence, the major
`challenge in medication treatment
`
`Expanding of care models (from low-threshold to comprehensive)
`
`• Acceptance of other measures of treatment success than complete
`abstinence: harm-reduction framework
`
`•
`
`Incorporating recovery framework and peer advocates
`
`Page 22 of 25
`
`
`
`CHOOSING AGONIST VS. ANTAGONIST
`BASED TREATMENT
`
`Before starting
`
`treatment
`
`Delay
`
`Physical
`
`dependence
`
`METHADONE or BUPRENORPHINE
`
`XR-NALTREXONE
`
`Detoxification is not needed
`
`Detoxification and a washout period are
`
`required in active users
`
`Minimal delay
`
`0-2 weeks before starting treatment
`
`Patients remain physically dependent,
`
`withdrawal symptoms if a dose is delayed or
`
`After detoxification, patients are no longer
`
`physically dependent - no opioid withdrawal
`
`missed
`
`if dose is missed
`
`Adherence with
`
`Improved, because patients may experience
`
`There is no discomfort if the dose is
`
`the medication
`
`physical discomfort if the dose is
`
`delayed, and patients may be more
`
`delayed
`
`likely to stop medication prematurely
`
`Effect on
`
`craving/use
`
`Effect on
`
`preventing
`
`overdose
`
`Decreased craving and opioid use
`
`Patients who are adherent with treatment are protected against overdose
`
`Increased risk of overdose after treatment dropout and stopping medication
`
`Page 23 of 25
`
`
`
`CHOOSING AGONIST VS. ANTAGONIST
`BASED TREATMENT (2)
`
`METHADONE or BUPRENORPHINE
`
`XR-NALTREXONE
`
`Potential for
`
`misuse
`
`Overdose risk
`
`Side effects
`
`Treatment of
`
`pain
`
`Can be abused and diverted
`
`Methadone during induction
`
`Both when combined with sedatives
`
`None
`
`None
`
`
`
`(Early) Sedation, dizziness Insomnia, diarrhea, low energy, anxiety
`
`(Late) Constipation, excessive sweating
`
`headache, depression, inj site reactions
`
`Opioid painkillers can be used
`
`Usual doses of opioids not effective,
`
`specialist pain treatment
`
`Opposition to
`
`Stigma against methadone, limited acceptance
`
`Less stigma against in traditional
`
`treatment
`
`Availability
`
`in traditional treatment settings
`
`treatment settings
`
`Barriers to availability of agonists in criminal
`
`justice system
`
`Few programs offer
`
`Page 24 of 25
`
`
`
`
`
`Fame|Providers SUPPORTING PROVIDERS
`SUPPORTING PROVIDERS
`
`Clinical Support
`
`
`|
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`e2) STR-TA
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`Consortium
`State Targeted Response Technical Assistance
`
`ABOUT US>
`
`TECHNICAL ASSISTANCE >
`
`Technical Assistance Site
`
` ance (TA) Consortium was created
`The State Targeted Response (STR) Technical
`Ass
`to support yourefforts in addressing opioid use disorder prevention, treatment and
`
`
`
`°
`
`f Intranasal Form of Long-Acting
`
`Page 25 of 25
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`Page 25 of 25
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`
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