Rescheduling of Hydrocodone combinations from Class III to Class II, clear-cut regulatory guideline for Abuse Deterrent drug formulation NDA & ANDA (solid oral) filing and CDC guideline for Prescribing Opioids for Chronic Pain (2016) are definite steps taken by FDA in last two years for creating “Abuse Deterrent Era” in a short span to stop opioid abuse and reversing opioid epidemic in USA. There were around 18,893deaths involving prescription of opioids in the United States in 2014 which was up 16% from 2013 as per NCHS (National Center for Health Statistics).
Around +6 plus extended release abuse deterrent formulations with Abuse deterrent (AD) labels are approved in last two years (Xtampza ER, MorphaBond ER, Hysingla ER, Embeda ER, Targiniq ER, Oxaydo) and are expected to provide improvements over existing formulations for abuse deterrent purpose. But they have some limitation for restricting abuse mainly through oral intake- swallowing a number of intact tablets or capsules. Despite, Extended release (ER) Abuse Deterrent Formulations partly control Opioids abuse (through nasal or injection routes), ER opioids has high potential of abuse, its AD formulation add significant value to create “Abuse Deterrent Era” in the coming time.
Around 20 plus Abuse Deterrent Formulations of opioids are in the pipeline and most of them are ER formulations which use different AD tech platform to make its ADF. Amongst these pipeline ADF drugs, 6 are of Hydrocodone, 8 are of Morphine and 6 are of Oxycodone based ADF formulations.
New NCEs targeting Opioids receptor are in pipeline which reduces Opioids abuse by its MoA (slow rate of entry in Brain) and may have potential to deal with reducing opioid abuse through restricting oral intake in coming years.
US Opioids market is of $8b in size and of which extended release formulations contribute 50%. ADF ER formulations and its generic versions & New NCEs targeting Opioid receptor will drive the growth of opioid market in US and Europe in coming years.
In this report, we have discussed a number of novel delivery technologies employed in the formulating abuse deterrent product, technologies employed in enhancing patient compliances, emerging novel mechanisms and late stage pipeline drugs in the management of pain.
Late stage NCE pipeline drugs (Cebranopadol, Mirogabalin, NKT-181, AVP-923,…) and Novel technologies targeting formulation change in old generic drugs (ORB-201, OX-51, ARX-04,CL-108, once daily Pregabalin..) for pain management has potential to reduce opioids use in future to treat pain. While TRKA receptor antagonist, NAV1.7 sodium channel modulator inhibitor and angiotension II antagonist are few new MoA which has promising drug in clinical development for moderate to severe pain management.

Executive Summary
a. ER formulation of Opioids- An initial target for pipeline Abuse deterrent drugs & a high priority by Regulators?
b. Late stage pipeline drugs and new MoA – which has potential to reduce Opioid use in moderate pain?
c. New FDA guidelines for Oral solid abuse deterrent generic formulations - A kick start of generic cycle for ADF formulations?
d. Key pipeline ER abuse deterrent drugs, its ROA, tech platform etc
e. Possible implications of rescheduling Hydrocodone from CIII to CII on Opioids market & ADF development.

2. Management of Pain
• Introduction
• Classification of Pain (Type and Intensity)
• Treatment of chronic pain – current approach
• Market Size of pain and current therapeutic options (acute, chronic pain and neuropathic pain)
• Unmet medical need and market opportunities in overall Pain management
• Overview of Marketed drugs for moderate to severe pain and neuropathic pain
• Limitations of non-opioids drugs and overview of marketed drugs
• Non-steroidal Anti-inflammatory Drugs (NSAID) – Mechanism of action
• Necessity for non-opiate treatment –Drug abuse deterrent and tolerance
• Opioid Abuse deterrent Epidemic- A Whistle Blower for FDA to take Stringent Action and start of abuse deterrent Era
• ER opioids vs. IR opioids- Abuse deterrent potential

3. FDA Schedule for controlled substances and advantage of Schedule III over II
• Hydrocodone rescheduling to Class II –
o Prescription trend post rescheduling
o Advantage to other Opiates & advantage to ER ADF opioids to grow due to rescheduling

4. FDA Perspective on Abuse deterrent formulations (Opioids)
• FDA perspective on Abuse deterrent Opioids- Observations from early experience with Abuse deterrent formulation development.
• FDA view of the Evolution of the Abuse deterrent Opioid market
• Tools FDA Intends to use to move the market toward its goal
• ADF Labeling – Importance and advantage for reimbursement, REMS need
• Our view on FDA guidelines for Abuse deterrent Formulation developments
• Our view on FDA guidelines for Generic Abuse deterrent Formulation developments

5. Approved Abuse deterrent Formulations by FDA - Development , label claim, Technology and current prescription trend
• Common Manufacturing approach for making ADF formulation
• Abuse deterrent drugs approval from FDA in 2014- its Technology platform and current prescription trend in US
• Abuse deterrent approval from FDA in 2015- its Technology platform and current prescription trend in US
• Recently approved ER Formulation of Patent expired molecules for pain management
• Nucynta ER
• Gralise
• Horizant

6. Abuse Deterrent Technology Platforms employed in marketed drugs and pipeline
g. IntelliPaste
k. Implantable pump for intrathecal delivery
m. Small molecule delivery
n. Bio-MD-prodrugs platform
o. Ligand activated Therapy (LAT)
s. Inspirion delivery Technologies
t. Intellitab Technology
u. Trigger lock platform –Micropump
v. Proprietary / OraGuard Technology
w. Pain Therapeutics
x. Fenrock
y. Smart Patch PNS system
z. ALO-02/Troxyca ER
aa. BeadTek and INTELLITAB technology
bb. Acuform Technology
cc. OROS Technology
dd. Resistec Technology
ee. SENTRYBOND Technology

7. Pipeline analysis of Novel Technologies and new mechanisms in Pain management
Novel Technologies-
a. Multi-day formulation of Tramadol
b. Bio-MD Platform
c. Orexo- Sublingual technology
d. Fentanyl based therapy formulation modification (micro and nano tab)
e. Acorda Therapeutics
f. Bilayered oral formulation- Charleston lab
g. ZilrettaTM
h. Steroidal intraarticular injection
i. Intrathecal drug delivery system
j. Oromucosal delivery

New mechanisms in Pain management
a. Angiotension II antagonist
b. Anti-NGF
c. Ligand Activate Therapy
d. Nav1. 7 inhibitor
e. GPCR –Dimer Screen Technology
f. CB agonist
g. Kappa Receptor agonists
h. TrkA receptor antagonist
i. MAP kinase inhibitor
j. Opioid alternatives (dexmedetomidine)
k. Peptide Therapeutics (conopeptide)
l. TRPV1 antagonist
m. Gene therapy
n. Others

8. Late stage pipeline developments in neuropathic pain
a. Cebranopadol (oral, once daily, Grunenthal/ Depomed, PhIII, chronic pain)-A potential threat to abuse deterrent formulations
b. Mirogabalin- Key MOA diff vs. Lyrica, Pros & Cons analysis based on reported PhII data
c. CL-108
d. Hydromorphone
e. Convergence/ biogen Idec- CNV-2197944
f. Convergence/ biogen Idec- CNV-1014802
g. Sativex
h. Once daily pregabalin
i. Topical clonidine gel
j. Topical ketamine and amitraline
k. Amorsa therapeutics
l. Pregabalin CR
m. Eladur
n. GRC-17536
o. DWP05195
p. AVP-123
q. Algiax Pharmaceuticals

Appendix – I FDA Guidelines for the development of abuse Deterrent Formulations
• Types of Abuse deterrent formulation as per current guidance
• Pre market studies
• Post market studies
• Labeling Recommendations

Appendix- II General Principles for Evaluating the Abuse deterrent Generic Solid Oral Opioid Drug Products
 Need for regulatory filing and other key requirements
 Route of Abuse deterrent
 Comparative in Vitro Studies
 Other Consideration
 Data Analysis
 Additional

ompanies mentioned:
• AbbVie
• AcelRx pharma
• Acorda Therapeutics
• Actavis
• Acura Pharma
• Acorda Therapeutics
• Altus formulations
• Alkermes
• Algiax Pharmaceuticals
• Amorsa Therapeutics
• AnGes
• AstraZeneca
• Balerna
• Biogen
• BioDelivery Sciences International Inc
• Biopharma
• Cara Therapeutics
• Catalent
• Charleston
• Celltech
• Collegium Pharma
• Convergence
• Columbia Labs
• Convatech
• Daiichi Sankyo
• Daewoong
• Depomed
• Durect
• Egalet
• Eli Lilly
• Elite Pharma
• Endo
• Ensyce Bioscience
• EpiCept
• Flamel Technologies
• Flexion Therapeutics
• Forest
• Glenmark
• Grunenthal
• GlaxoSmithKline
• GW Pharma
• Immune Pharmaceuticals
• Impax Pharmaceuticals
• Inspirion
• Intelli Pharmaceutics
• IRX Therapeutics
• Johnson and Johnson
• KemPharm
• Kineta
• Kunwha Pharmaceutical
• Medallion Therapeutics
• Mallinckrodt
• Nektar
• Novartis
• Noven
• Orbis Biosciences
• Orexo
• Otsuka
• Pain Therapeutics
• Pfizer
• ProPharma
• Purdue
• Recro pharma
• Relmada Therapeutics
• Reckitt Benckiser pharmaceutical
• Signature Therapeutics
• Spinifex pharma
• SPR Therapeutics
• Strativa
• Teikoku
• Teva
• Tesa Labtec GmpH
• Trevena Inc
• Tris Pharma
• Valeant
• ViroMed
• Wooddiff Lake
• Xenon Pharma
• XenoPort