“Breakthrough” in Chronic Non-Cancer Pain:

A Proposed Indication in Need of Further Study

Prepared for:

Joint Meeting of the Anesthetic and Life Support Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee

6 May 2008

John Markman MD

Breakthrough Pain in a Patient with Recurrent Osteosarcoma

The patient is a 36 year-old gentleman with osteosarcoma experiencing recurrent exacerbation of shooting left leg pain in the setting of relatively well-controlled baseline

pain taking around-the-clock opiods.

5

35

Cancer

Non Cancer

Portenoy RK et al. J of Pain 2006;7:583-91;Taylor DR et al. Pain Medicine 2007;8:281-88.

The Evidence Deficit

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Under-Dosing Long Acting Opioid

Opioid ToleranceOpioid-Induced Hyperalgesia

End-Of-Dose Effect

Incident Pain

The Complexity of Breakthrough Pain in Cancer

Progression ofUnderlying Cancer

Dosing / Pharmacokinetic

Pharmacodynamic

Pain-Related

The patient is a 54 year-old man with osteoarthritis with recurrent exacerbations of left leg pain in the setting of

relatively well-controlled baseline pain taking around-the-clock opioids.

Transient Flare of Pain in a Patient with Chronic Knee Pain

2.4 flares “breakthrough”/day

24 years

21,024 rapid-acting opioid doses

Pain intensity and temporal pattern are

not sufficient to make an acceptable

risk benefit determination.

Under-Dosing Long-Acting Opioid

Opioid ToleranceOpioid-Induced Hyperalgesia

End-Of-Dose Effect

Incident Pain

Diverse Factors Modulate Pain Intensity

Diurnal Variation in Pain

Intensity

Dosing / Pharmacokinetic

Pharmacodynamic

Pain-Related

For Which Transitory Flares of Pain Is Rapid-Acting Opioid Treatment Indicated?

Odrcich M et al. Pain 2006;120:307-212.

Central Claims

The unmet need, definition, and scope of breakthrough phenomena in chronic non-cancer pain

lack sufficient characterization.

This evidence gap will prevent clinicians from safely weighing the risks of prescribing the fentanyl buccal tablet

for the proposed indication in opioid tolerant patients.

Five Key Areas of Further Research for theProposed New Indication

1. Assessment of Rapid-Acting Opioid Treatment Efficacy with Chronic Pain Endpoints

2. Demonstration of Durability of Treatment Effect and Resultant Tolerance Relative to Established Alternatives

3. Identification of Population Sub-Groups Most Likely to Benefit from Potent, Rapid-Acting Opioids and Those at Greatest Risk for Prescription Opioid Abuse

4. Evaluation of Abuse Liability Compared with Less Rapidly-Acting Analgesics

5. Prospective Demonstration that Risk Management Program Reduces Harm to Household Collaterals