innovations in ost formulations and programme delivery

Innovations in OST: Formulations and Programme Delivery

DR ALOK AGRAWAL, MDAssistant ProfessorNational Drug Dependence Treatment CentreAll 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

EffectivenessPrevent 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 strategiesPresented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

Innovations in opioidformulations


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)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi


• 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)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi


• 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)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi

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)Presented at the national CME "OST: Policy and Practice" on 18th-19th April 2015 at AIIMS, New Delhi


• 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




• 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 havecontradictory requirements

• Efforts are underway to decrease the threshold for Opioidsubstitution therapy without compromising on theeffectiveness or increase the risk of diversion – no magic bulletas yet

• Need to look beyond formulations, multiple approaches toaddress 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

[email protected]


innovations in ost formulations and programme delivery

Health & Medicine

national cme ost

new delhi national cme

costeffectiveness innovations

buprenorphine naloxone

treatment outcomes

strategies treatment

retention strategies

strategies takehome