1. “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

2. 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. Portenoy RK et al. J of Pain 2006;7:583-91;Taylor DR et al. Pain Medicine 2007;8:281-88. The Evidence Deficit < >

3. Under-Dosing Long Acting Opioid Opioid Tolerance Opioid-Induced Hyperalgesia End-Of-Dose Effect Incident Pain The Complexity of Breakthrough Pain in Cancer Progression of Underlying Cancer Dosing / Pharmacokinetic Pharmacodynamic Pain-Related

4. 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.

5. Under-Dosing Long-Acting Opioid Opioid Tolerance Opioid-Induced Hyperalgesia End-Of-Dose Effect Incident Pain Diverse Factors Modulate Pain Intensity Diurnal Variation in Pain Intensity Dosing / Pharmacokinetic Pharmacodynamic Pain-Related

6. For Which Transitory Flares of Pain Is Rapid-Acting Opioid Treatment Indicated? Odrcich M et al. Pain 2006;120:307-212.

7. 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.

8. Five Key Areas of Further Research for the Proposed 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