Innovations in ost formulations and programme delivery

Innovations in OST:
Formulations and
Programme Delivery
DR ALOK AGRAWAL, MD
Assistant Professor
National Drug Dependence Treatment Centre
All India Institute of Medical Sciences, New Delhi
18-19 APRIL 2015 | VENUE: LT-1 | AIIMS, NEW DELHI
NATIONAL CME
Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Outline of the Presentation
• Are there issues with existing approaches?
• Why do we need innovations in OST?
• How can we approach the problem?
– Innovations in opioid formulations
– Innovations in service delivery mechanisms
– Innovations in programme design
– Other strategies
• Take-home message

What’s wrong with the existing approaches?
• Actually NOTHING!!
– They work and they work well
• But all strategies / treatment paradigms have
limitations
– Logistic issues -
• Need to visit daily
• Time and cost of travel
• Difficulty getting / maintaining employment
– Limited reach especially in rural areas
– Concerns regarding diversion
• Constant supply-demand gapPresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Why do we need innovations in OST?
• Strategies producing excellent outcomes (frequent
clinic visits, DOTS, intensive psychosocial services,
limited take-home)  decrease treatment
availability, practicality, acceptability, enrolment, and
retention
• Strategies most convenient for patients and
physicians (infrequent clinic visits, reduced oversight,
and longer-duration take-home)  increase risk of
diversion and undermine treatment outcomes.

Why do we need innovations in OST?
PARADOX
Effectiveness
Prevent adverse
outcomes Patient convenience
and satisfaction

How can we approach the problem?
• Designed for lesser abuse potential
• Formulation that can deter abuse / diversion
• Increase effectiveness of existing molecules
• Increase retention / compliance
• Decrease side-effects
• Increase cost-effectiveness
Innovations in opioid formulations
• Ensure accurate dosing
• Reduce risk of diversion / errors
Innovations in service delivery mechanisms
• To enhance accessibility of treatment
• Lower programme threshold
Innovations at programme level
Other strategies

Innovations in opioid
formulations

Innovations in opioid formulations
• Buprenorphine - Naloxone tablets
• Buprenorphine - Naloxone film
• Buprenorphine subdermal implant
• Buprenorphine transdermal patch
• Buprenorphine depot injection
• Other experimental approaches
Opioid Substitution Therapy
• Depot Naltrexone
• Naltrexone Implants
Antagonist maintenance

Buprenorphine Naloxone Film
• Orally dissolvable film
• Available in 2 strengths
– 2/0.5
– 8/2 mg
• Licensed in USA in 2010
• Reason:
– Difficulty supervising consumption of sub-lingual tablets —>
increased risk of diversion
– Increased risk of exposure in children (Boyer et al, 2010)
• Aims
– To address the above safety concerns
– Improve retention, bioavailability, absorption and dissolution timePresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

• Pharmacokinetics
– Similar to that of sublingual BPN-NLX tablet
– No clinically relevant increase in serum Buprenorphine
levels
– Dissolution times
• Compared with BPN-NLX tablet in 42 healthy volunteers
• For various dose combinations: 2/0.5, 4/1, 8/2, 12/3 mg
• Film took less time to dissolve than tablets (173s vs. 242s, p =
0.007)
(Lintzeris et al, 2013; FDA, 2014)

• Patient experiences and adverse events
– Largely similar to BPN-NLX including bitter taste
– Ease of use
• Tablets more likely to be accidentally swallowed (19%) compared
to film (5%).
• Patient preference higher for film (61%) than tablets (23%)
(Lintzeris et al, 2013)
– Adverse events
• Oral hypoesthesia (MC), glossodynia, oral mucosal erythema
• Less than 2% discontinuation rates (Soyka M, 2015)

• Clinical Experiences
– Study on heroin dependent subjects
• Compared plain BPN with BPN-NLX film for induction
• Patients can be switched from tablets to film and vice versa
• Safe and effective delivery methods for opioid induction
(Strain et al., 2011)
• Effectiveness
– Retrospective chart review, 12 month outcomes
• Film and tablet groups included 2796 and 1510 patients
• Time to treatment discontinuation was significantly longer in the
film group.
• Film group had more outpatient visits and lower probability to be
hospitalized (Clay et al, 2014)

• Risk of exposure among children
– Review of 2380 cases of unintentional exposures to buprenorphine-
containing products among children < 6 years
– Exposures to film significantly less than to BPN tablets (ratio 3.5) and
BPN-NLX tablets (ratio 8.8) (Lavonas et al, 2013)
• Risk of diversion
– Unit-dose packaging, easier to track a dose of the medication
– Comparison of diversion rates
• Those not in treatment - Levels of injection for film comparable
with methadone and buprenorphine tablet
• Those in treatment - More frequent injection less in film (3%) than
BPN tablet clients (11%), but similar to methadone and BPN-NLX
tablets. (Larance et al, 2014)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Buprenorphine Sub-mucosal Patch
• BioDelivery Sciences International developing submucosal patch of
Buprenorphine-NLX
• Potential treatment of opioid dependence
• Utilizes the company's BioErodible MucoAdhesive (BEMA) technology to
deliver buprenorphine and naloxone.
• Would be a direct competitor to Reckitt's Suboxone sublingual film.

Subdermal Buprenorphine Implant
• Trade name - Probuphine
• Manufactured by Titan Pharma
• Small, solid “rod” (26 mm × 2.5 mm)
• Made from a mixture of ethylene
vinyl acetate
• Contains about 80 mg Buprenorphine
• Buprenorphine released over 6 months
• Benefits
– Decreased risk of diversion and accidental pediatric exposure
– Improved adherence, convenience

• Implant procedure
– Patients are first inducted onto sublingual Buprenorphine
for 3–7 days
– Out-patient procedure, takes about 15 minutes
– Rod is placed subdermally (2-3 mm below the skin) in the
upper arm
– Removed in a similar manner at the end of the treatment
period
– No sutures are required for implantation (sutures were
used at removal
– Standard implant dose is 4 rods (up to 6 if additional
medication is needed)

• Effectiveness
• Phase 3 randomized placebo controlled trial
– 6-month double blind trial in 163 opioid-dependent subjects
– Both groups allowed to receive additional buprenorphine tablets for
craving, withdrawal
– Implant group had
• Significantly more urine samples negative (40.4% vs. 28.3%)
• More treatment completers (65.7% vs. 30.9%)
• Less withdrawal symptoms and craving
– Both groups had similar rates of concomitant BPN prescriptions
• Phase III trial comparing Probuphine with placebo and
Suboxone
– 24-week follow-up
– Similar efficacy to sublingual BPN 12–16 mg/day (Ling et al, 2010)

• Adverse events
– Minor implant site reactions most common
– Major reactions (e.g. cellulitis) rare
– No unscheduled implant removal or attempted removal
• Current status
– FDA has not approved for use
• Too low dose of BPN
• Patients in the earlier studies were new to medication treatment
– Another Phase III trial in progress
• Double-blind and double-dummy
• Patients on lower BPN doses & stabilized for 3 months
(Titan Pharma press release, September 2014)

Buprenorphine Transdermal Patch
• Indication
– Detoxification of opioid dependent subjects
• Formulation
– Available in 3 and 7 day patches
– Average delivery of 1.9 mg/day of buprenorphine
– BPN levels peak by 48hours and then gradually decline
• Clinical experience
– Safe, well- tolerated, and clinically effective for detoxification
– Both subjective and objective withdrawals significantly reduced within
24 h of patch application
– Continued to decline thereafter, did not reappear after removal
– A single 7-day patch may be enough (Lanier et al, 2007; 2008)

Depot Buprenorphine
• Subcutaneous depot, contains 58 mg of Buprenorphine
• Microcapsules consisting of BPN base and a biodegradable
polymer
• Plasma level increases gradually, peaks at 2-3 days and then
decreases gradually, becomes undetectable by 6 weeks
• Effectiveness
– Provides effective relief from opioid withdrawal
– Substantial opioid blockade effect persisting for 6 weeks
• Adverse effects
– At injection site - Transient pain and tenderness
– Non-depot sites - Rash, itching, bumps and peeling of skin
(Sobel et al, 2004; Sigmon et al, 2006, 2008)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Other innovations in formulations
• Thicker Methadone syrup
– less likely to be injected
• Sugar less methadone
– safe in diabetics
• Methadone/Naloxone combination
– (50:1) preparation
– developed in Australia
– to eliminate diversion and injection of prescribed methadone
(Bell et al, 2009)
• Methadone implant
– evaluated in-vitro and in-vivo in animals
– methadone release at a steady rate for 1 week and 1 month duration
(Negrín et al, 2004)

Innovations in service
delivery mechanisms

• Automatic dispensers
– Dispensing of methadone syrup / tablets through an
automatic vending machine
– Advantages
• Accurate dispensing
• No need for specialist staff
– Disadvantages
• Cost
• Safety of dispensers

• Bio-metric dispensing system
– Dispensing linked to a biometric reader –
with or without an automatic dispenser
– Advantages
• Easy client identification
• No need for dispensing staff
• Prevents double registration of clients
– Disadvantages
• Cost of bio-metric system
• Needs constant electricity
• Interconnected system

Innovations in
programme design

• Methadone by Bus, Amsterdam
– Began in 1979
– Distributes methadone to about 200
people throughout the city
– Runs 365 days a year, four 1-hour
stops/day
– Staffed only by nurses and a driver
– Aim
• To reach most at-risk clients through
low-threshold programs
– Strategy
• Package of services – from low to high
threshold
• Drug users can freely move between
the different programs - Incentives to
move to higher-threshold programs
Innovations in programme design

• Methadone on Demand: The Hong Kong Model
– MMT is available on demand
– Clinics operate seven days a week and are open early and late
– Staffed by Auxiliary Medical Service volunteers (shoe salesman to
housewife to bank clerk)
• Treatment by Prescription: French Model
– Mainstreaming drug dependence treatment by delivery in primary
care
• All general practitioners can prescribe buprenorphine
• Daily supervised initially followed by take-home
• Can be purchased at pharmacies and reimbursed

• Pharmacy-based dispensing: Australia
– Community pharmacies
– For daily dispensing of methadone
– Take away doses when prescribed by physician
• Flexible Take-home Doses: Croatia
– MMT
• Methadone provided at general practitioner’s office
• Take-home doses common and available for up to one week
– BMT
• Buprenorphine exclusively as take-home for one week at a time
• Available in pharmacy like any other medicine

• Sheway – Women-centric services, Vancouver
– Woman-centered, harm reduction based health and social
support services
– Exclusive services for pregnant and newly parenting
women drug users
– Features
• Outreach, drop-in services, daily free lunch
• prenatal care and support to pregnant women and post-delivery
for 18 month
• Satellite centres
• Integrated care clinics
• Medication-assisted Treatment in Prisons – coming soon…

Other strategies
• Heroin-assisted treatment
• Trials in several countries - Switzerland, United Kingdom, Netherlands,
Spain, Germany , Canada, Denmark and Luxembourg
– Britain – injecting, twice a day
– Netherlands – injecting and inhalation
– Switzerland - oral pill
– Cochrane review, 2011
• Eight studies involving 2007 patients
• Heroin helps patients to remain in treatment
• Decrease in the illicit drug use, criminal activity and incarceration,
possible reduction in mortality
• Recommendation
– Added value of heroin maintenance alongside MMT for long-
term, treatment refractory, opioid users
– Should be provided in clinical settings with proper follow-up
(Ferri et al, 2011)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Other strategies
Opium registry!!!

Take Home Message
• The clinical practice and policy of OST often may have
contradictory requirements
• Efforts are underway to decrease the threshold for Opioid
substitution therapy without compromising on the
effectiveness or increase the risk of diversion – no magic bullet
as yet
• Need to look beyond formulations, multiple approaches to
address the limitations
• In the meantime … JUST DO IT, BUT DO IT WELL!Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

THANK YOU
dralok.nddtc.aiims@gmail.com

Innovations in ost formulations and programme delivery

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