# Presentation: 110156

## 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 opioid’s 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

- 2mg
- pill

- IV dose: 0.2mg

- Oral BA = 10%

- Extended-Release

- 10mg
- pill

- Crushed IV dose: 10mg

- 10 X

- 5 X

- 50 X

## Optimal Scenario:Methadone Resists Abuse

- 5mg
- pill

- IV dose: 5mg

- Oral BA = 90%

- Extended-Release
- not necessary

- Crushed IV dose: 5mg

- 1 X

- 1 X

- 1 X

- 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 

**Abuse-Resistance In Practice**

- Remoxy
- Intact

**Crushed**

- Oxycontin®
- Intact

**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, mu-receptor 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, anti-analgesia
- Often leads to overdosing and death due to perceived patient discomfort by nurse/MD

## Post-Operative Pain

**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

**Phase I Data in 12 Subjects**

## 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