Hope on the Horizon - National Institute on Drug Abuse

New Opioid Formulations: Hope on the Horizon Pamela P. Palmer, MD PhD Professor and Director, UCSF PainCARE Chief Medical Officer, AcelRx Pharmaceuticals, Inc. Outpatient: Critical Issues Utilize Optimal Opioids Optimize Route of Delivery Abuse-Resistant Formulations Safe Dosing/Prescribing Opioid Tolerance/Dose Escalation

Utilizing Optimal Opioids Avoid opioids with active metabolites Avoid untoward effects (e.g., histamine release) Match opioid half-life to indication to avoid lack of titration for acute pain and extended-release formulations for chronic pain Decreased respiratory depression

Decreased physical dependence Decreased opioid tolerance Optimize Route of Delivery Choose route that avoids poor bioavailability, thereby avoiding excess opioid loading Choose route that matches the opioids intrinsic characteristics Pick route of delivery to match indication (acute vs. chronic pain)

Need to Improve Bioavailability Oral Route Bioavailability: Oral morphine (MSContin, Avinza) 30% Oral oxymorphone (Opana IR, ER) 10% Oral hydromorphone (Dilaudid) 30-35% Oral oxycodone (OxyIR, OxyContin) 60-80% Other Routes: Fentanyl patch (IonSys, Duragesic) 30-70% Fentanyl TM (Actiq, Fentora) 50-65% Double Trouble: Extended-Release Low Bioavailable Drug Formulations IV dose: 0.2mg

Crushed IV dose: 10mg 50 X 10 X Oral BA = 10% 2mg pill ExtendedRelease 5X 10mg pill Optimal Scenario:

Methadone Resists Abuse IV dose: 5mg Crushed IV dose: 5mg 1X 1X ExtendedRelease not necessary Oral BA = 90% 5mg pill 1X

5mg pill Abuse-Resistant Formulations Need to avoid the ability to crush or rapidly extract drug with ethanol (OxyContin, Palladone) Remoxy SABER technology (Durect/Pain Therapeutics/King Pharmaceuticals) Naloxone/Naltrexone additive

- Suboxone (buprenorphine/naloxone) - Oxytrex (oxycodone/naltrexone) Abuse-Resistance In Practice Remoxy Intact Oxycontin Intact Crushed Crushed No Rapid Release of Oxycodone = No Euphoria Transdermal Opioids

Due to delay in onset of plasma levels, this route appears best for chronic pain conditions Opioids delivered transdermally: Fentanyl (Duragesic, IonSys) Sufentanil (Endo, in development) Buprenorphine (Europe, Australia) Hydromorphone (Altea, in development) Outpatient Cancer Breakthrough Pain

Actiq, Fentora (buccal TM delivery of fentanyl) Rapinyl (sublingual fentanyl tablet) Many other fentanyl formulations in pipeline Saliva response results in at least half of the drug being swallowed, lowering bioavailability AcelRx sublingual sufentanil NanoTabTM formulation above 90% bioavailability Safer Dosing/Prescribing

Scheduled drugs less trackable than UPS Patient reported usage, pill counting and urine testing only methods to determine opioid usage Need better tracking around opioid dosing history RFID chip on OxyContin bottles only helps track from manufacturer to pharmacy AcelRx electronic NanoTabTM dispensers will allow download of dosing history Opioid Tolerance

Opioid dose escalation at all time high Pain now the 5th Vital Sign, fears slightly abating around high-dose prescribing Dose escalation driven by tolerance and disease progression Research into novel mechanisms to treat or avoid opioid tolerance are vital Until then, opioid rotation is only option Opioid Tolerance

Complex clinical phenomenon, not easy to study Studies not run long enough, nor detailed enough Recent studies suggest age plays important role Targets: NMDA antagonists, mureceptor antagonists, bivalent mu/delta ligands, RGS protein modulators Inpatient: Critical Issues

#1 hospital medication error: Analgesics Most common mistake: Wrong Dose Patient-Controlled Analgesia (PCA) IV PCA misprogramming, basal rates, etc IonSys trandermal fentanyl on-demand AcelRx sublingual sufentanil NanoTabsTM with hand-held PCA dispenser Is Morphine the Gold Standard?

Morphine suffers from a number of pitfalls Relatively high-level of side-effects compared to other opioids Active metabolites, M3G and M6G, that build up particularly rapidly in the elderly M3G produces dysphoria, anxiety, antianalgesia Often leads to overdosing and death due to perceived patient discomfort by nurse/MD Post-Operative Pain Is IV Route the Gold Standard?

For acute pain, IV route of administration often held up as the gold standard However, IV opioids often achieve rapid, high plasma drug levels that can lead to respiratory depression Sublingual sufentanil NanoTabsTM offer rapid onset with safer drug plasma profile Phase I Data in 12 Subjects Human Clinical Study Sufentanil Plasma Concentration (pg/ml) 90 80 10 mcg Sufentanil NanoTab

70 5 mcg Sufentanil NanoTab 2.5 mcg Sufentanil NanoTab 60 5 mcg IV infusion 50 40 30 20 10 0 0

20 40 60 80 100 Time (min) 120 140 160 180

200 Summary Need to pursue optimal opioids with optimal routes of delivery based on patient needs More aggressive tracking of patient dosing history in outpatient setting Pursue novel therapies to avoid or treat

opioid tolerance to minimize dose escalation in chronic pain conditions Simplified patient-controlled opioid dosing Never avoid pursuing optimal pain therapies out of fear of abuse/diversion