New Opioid New Opioid Formulations:Formulations:

Hope on the HorizonHope on the HorizonPamela P. Palmer, MD PhDPamela P. Palmer, MD PhD

Professor and Director, Professor and Director, UCSF PainCAREUCSF PainCARE

Chief Medical Officer, Chief Medical Officer, AcelRx Pharmaceuticals, Inc.AcelRx Pharmaceuticals, Inc.

Outpatient: Critical Outpatient: Critical IssuesIssues

Utilize Optimal OpioidsUtilize Optimal Opioids Optimize Route of DeliveryOptimize Route of Delivery Abuse-Resistant FormulationsAbuse-Resistant Formulations Safe Dosing/PrescribingSafe Dosing/Prescribing Opioid Tolerance/Dose Opioid Tolerance/Dose

EscalationEscalation

Utilizing Optimal OpioidsUtilizing Optimal Opioids Avoid opioids with active metabolites Avoid opioids with active metabolites Avoid untoward effects (e.g., Avoid untoward effects (e.g.,

histamine release)histamine release) Match opioid half-life to indication to Match opioid half-life to indication to

avoid lack of titration for acute pain avoid lack of titration for acute pain and extended-release formulations for and extended-release formulations for chronic painchronic pain

Decreased respiratory depressionDecreased respiratory depression Decreased physical dependenceDecreased physical dependence Decreased opioid toleranceDecreased opioid tolerance

Optimize Route of Optimize Route of DeliveryDelivery

Choose route that avoids poor Choose route that avoids poor bioavailability, thereby avoiding bioavailability, thereby avoiding excess opioid loadingexcess opioid loading

Choose route that matches the Choose route that matches the opioid’s intrinsic characteristicsopioid’s intrinsic characteristics

Pick route of delivery to match Pick route of delivery to match indication indication

(acute vs. chronic pain)(acute vs. chronic pain)

Need to Improve Need to Improve BioavailabilityBioavailability

Oral Route Bioavailability:Oral Route Bioavailability: Oral morphine (MSContin, Avinza) – 30%Oral morphine (MSContin, Avinza) – 30% Oral oxymorphone (Opana IR, ER) – 10% Oral oxymorphone (Opana IR, ER) – 10% Oral hydromorphone (Dilaudid) – 30-35% Oral hydromorphone (Dilaudid) – 30-35% Oral oxycodone (OxyIR, OxyContin) – 60-80% Oral oxycodone (OxyIR, OxyContin) – 60-80%

Other Routes:Other Routes: Fentanyl patch (IonSys, Duragesic) – 30-70% Fentanyl patch (IonSys, Duragesic) – 30-70% Fentanyl TM (Actiq, Fentora) – 50-65% Fentanyl TM (Actiq, Fentora) – 50-65%

Double TroubleDouble Trouble::Extended-Release Low Extended-Release Low

Bioavailable Drug Bioavailable Drug FormulationsFormulations

2mgpill

IV dose: 0.2mg

Oral BA = 10%

Extended-Release

10mgpill

Crushed IV dose: 10mg

10 X

5 X

50 X

Optimal ScenarioOptimal Scenario::Methadone Resists AbuseMethadone Resists Abuse

5mgpill

IV dose: 5mg

Oral BA = 90%

Extended-Releasenot necessary

Crushed IV dose: 5mg

1 X

1 X

1 X

5mgpill

Abuse-Resistant Abuse-Resistant FormulationsFormulations

Need to avoid the ability to crush or Need to avoid the ability to crush or rapidly extract drug with ethanol rapidly extract drug with ethanol (OxyContin, Palladone)(OxyContin, Palladone)

Remoxy – SABER technology Remoxy – SABER technology (Durect/Pain Therapeutics/King (Durect/Pain Therapeutics/King Pharmaceuticals)Pharmaceuticals)

Naloxone/Naltrexone additive Naloxone/Naltrexone additive

- Suboxone (buprenorphine/naloxone)- Suboxone (buprenorphine/naloxone)

- Oxytrex (oxycodone/naltrexone)- Oxytrex (oxycodone/naltrexone)

Abuse-Resistance In Practice

RemoxyIntact Crushed

Oxycontin®

Intact Crushed

No Rapid Release of Oxycodone = No Euphoria

Transdermal OpioidsTransdermal Opioids

Due to delay in onset of plasma levels, Due to delay in onset of plasma levels, this route appears best for chronic pain this route appears best for chronic pain conditionsconditions

Opioids delivered transdermally:Opioids delivered transdermally:

Fentanyl (Duragesic, IonSys)Fentanyl (Duragesic, IonSys)

Sufentanil (Endo, in development)Sufentanil (Endo, in development)

Buprenorphine (Europe, Australia)Buprenorphine (Europe, Australia)

Hydromorphone (Altea, in Hydromorphone (Altea, in development)development)

Outpatient Cancer Outpatient Cancer Breakthrough PainBreakthrough Pain

Actiq, Fentora (buccal TM delivery of Actiq, Fentora (buccal TM delivery of fentanyl)fentanyl)

Rapinyl (sublingual fentanyl tablet)Rapinyl (sublingual fentanyl tablet) Many other fentanyl formulations in Many other fentanyl formulations in

pipelinepipeline Saliva response results in at least half of Saliva response results in at least half of

the drug being swallowed, lowering the drug being swallowed, lowering bioavailabilitybioavailability

AcelRx sublingual sufentanil NanoTabAcelRx sublingual sufentanil NanoTabTMTM formulation – above 90% bioavailabilityformulation – above 90% bioavailability

Safer Dosing/PrescribingSafer Dosing/Prescribing Scheduled drugs less trackable than UPSScheduled drugs less trackable than UPS Patient reported usage, pill counting and Patient reported usage, pill counting and

urine testing only methods to determine urine testing only methods to determine opioid usageopioid usage

Need better tracking around opioid dosing Need better tracking around opioid dosing historyhistory

RFID chip on OxyContin bottles only helps RFID chip on OxyContin bottles only helps track from manufacturer to pharmacytrack from manufacturer to pharmacy

AcelRx electronic NanoTabAcelRx electronic NanoTabTMTM dispensers dispensers will allow download of dosing historywill allow download of dosing history

Opioid ToleranceOpioid Tolerance

Opioid dose escalation at all time highOpioid dose escalation at all time high Pain now the “5Pain now the “5thth Vital Sign”, fears Vital Sign”, fears

slightly abating around high-dose slightly abating around high-dose prescribingprescribing

Dose escalation driven by tolerance and Dose escalation driven by tolerance and disease progressiondisease progression

Research into novel mechanisms to Research into novel mechanisms to treat or avoid opioid tolerance are vitaltreat or avoid opioid tolerance are vital

Until then, opioid rotation is only optionUntil then, opioid rotation is only option

Opioid ToleranceOpioid Tolerance

Complex clinical phenomenon, not Complex clinical phenomenon, not easy to studyeasy to study

Studies not run long enough, nor Studies not run long enough, nor detailed enoughdetailed enough

Recent studies suggest age plays Recent studies suggest age plays important roleimportant role

Targets: NMDA antagonists, mu-Targets: NMDA antagonists, mu-receptor antagonists, bivalent mu/delta receptor antagonists, bivalent mu/delta ligands, RGS protein modulatorsligands, RGS protein modulators

Inpatient: Critical IssuesInpatient: Critical Issues

#1 hospital medication error: Analgesics#1 hospital medication error: Analgesics Most common mistake: Wrong DoseMost common mistake: Wrong Dose Patient-Controlled Analgesia (PCA) Patient-Controlled Analgesia (PCA)

IV PCA – misprogramming, basal rates, IV PCA – misprogramming, basal rates, etcetc

IonSys – trandermal fentanyl on-demandIonSys – trandermal fentanyl on-demand

AcelRx – sublingual sufentanil AcelRx – sublingual sufentanil NanoTabsNanoTabsTMTM

with hand-held PCA dispenserwith hand-held PCA dispenser

Is Morphine the Gold Is Morphine the Gold Standard?Standard?

Morphine suffers from a number of pitfallsMorphine suffers from a number of pitfalls Relatively high-level of side-effects Relatively high-level of side-effects

compared to other opioidscompared to other opioids Active metabolites, M3G and M6G, that Active metabolites, M3G and M6G, that

build up particularly rapidly in the elderlybuild up particularly rapidly in the elderly M3G produces dysphoria, anxiety, anti-M3G produces dysphoria, anxiety, anti-

analgesiaanalgesia Often leads to overdosing and death due Often leads to overdosing and death due

to perceived patient discomfort by to perceived patient discomfort by nurse/MDnurse/MD

Post-Operative PainPost-Operative Pain

Is IV Route the Gold Is IV Route the Gold Standard?Standard?

For acute pain, IV route of For acute pain, IV route of administration often held up as the administration often held up as the gold standardgold standard

However, IV opioids often achieve However, IV opioids often achieve rapid, high plasma drug levels that rapid, high plasma drug levels that can lead to respiratory depressioncan lead to respiratory depression

Sublingual sufentanil NanoTabsSublingual sufentanil NanoTabsTMTM offer rapid onset with safer drug offer rapid onset with safer drug plasma profileplasma profile

Human Clinical Study

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0 20 40 60 80 100 120 140 160 180 200

Time (min)

Su

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10 mcg Sufentanil NanoTab

5 mcg Sufentanil NanoTab

2.5 mcg Sufentanil NanoTab

5 mcg IV infusion

Phase I Data in 12 SubjectsPhase I Data in 12 Subjects

SummarySummary Need to pursue optimal opioids with Need to pursue optimal opioids with

optimal routes of delivery based on optimal routes of delivery based on patient needspatient needs

More aggressive tracking of patient More aggressive tracking of patient dosing history in outpatient settingdosing history in outpatient setting

Pursue novel therapies to avoid or treat Pursue novel therapies to avoid or treat opioid tolerance to minimize dose opioid tolerance to minimize dose escalation in chronic pain conditionsescalation in chronic pain conditions

Simplified patient-controlled opioid Simplified patient-controlled opioid dosing dosing

Never avoid pursuing optimal pain Never avoid pursuing optimal pain therapies out of fear of abuse/diversiontherapies out of fear of abuse/diversion