# Presentation: 158181

## MAKE ANALGESIC APPROVAL TRIALS MORE USEFUL TO CLINICIANS

- ARTHRITIS ADVISORY COMMITTEE
- FDA/CDER
-  29 July 2002
- Daniel Carr, MD
- Saltonstall Professor of Pain Research
- Tufts -New England Medical Center

## EBM:18,000 Citations Screened for 2001 AHRQ Cancer Pain Report  (WWW.AHRQ.GOV)

## IN AN IDEAL WORLD...

- Prospective identification, plans for patients at risk
- Prompt (?pre-emptive) individualized antinociceptive and behavioral interventions
- Effective treatments, rationally chosen and combined
- Ongoing titration/ optimization, plus strategies to minimize adverse effects and bridge analgesic gaps
- Monitoring of standardized outcomes to validate/ calibrate practice, accomplish CQI, meet JCAHO standards, identify best practices
- Followup to assess long-term costs, benefits
- Supportive climate: policies, payment, attitudes

## PAIN: RECENT INSIGHTS

- Blurring boundary between acute, chronic pain
- Widely distributed process, rapid onset [Wall]
- Chronic pain is itself a disease
- Reorganization of neural pathways [Woolf, Basbaum]
- “Combination analgesic chemotherapy” [Carr, Cousins]
- Potentially rapid onset [Crombie, Perkins/Kehlet]
- Long- and short-term benefits of aggressive Rx
- Pre-emptive analgesia [Devor/ Niv, Kehlet, Kissin]
- Evolving understanding of drug PK, PD; diversity
- opioid tolerance: “muffler” to active cancelling [Price, Mao]
- Disease-specific mechanisms, e.g., cancer
- Still, most pain treatment is empiric, generic

## IN AN IDEAL WORLD...

- Prospective identification, plans for patients at risk
- Prompt (?pre-emptive) individualized antinociceptive and behavioral interventions
- Effective treatments, rationally chosen and combined
- Ongoing titration/ optimization, plus strategies to minimize adverse effects and bridge analgesic gaps
- Monitoring of standardized outcomes to validate/ calibrate practice, accomplish CQI, meet JCAHO standards, identify best practices
- Followup to assess long-term costs, benefits
- Supportive climate: policies, payment, attitudes

## FOUR SIMPLE QUESTIONS...

- Who won the last presidential election?
- Did XXX corporation make money or lose money?
- What kind of pain does my patient have?
- What is the most effective treatment for my patient’s pain?

## Problems with “the Evidence”

- RCTs a tiny fraction of the literature
- 675 of 13,000 (acute pain, 1992)
- 180 of 20,000 (cancer pain, 2001)
- vast majority are observational or describe a technique
- Pooled efficacy estimates precluded by heterogeneity of diagnosis, patient, outcomes
- 125 instruments in 218 retrieved trials for 2002 SOTSC
- Generalizability limited by in-, exclusion criteria
- Little focus upon side effects
- Few patients per pain trial (e.g., dozens for cancer pain trials) vs hundreds or thousands in other areas -- a tiny fraction of those with the condition

## Is This Treatment Helping? 

- Translating efficacy into effectiveness
- To patients/families, low pain intensity is key
- Treatment goals:  QOL often trumps VAS
- Patients may self-titrate to VAS 5/10, yet do more
- Standardized consensus instruments needed
- JCAHO-AMA-NCQA
- generic vs condition-specific
- coarse instruments (e.g., SF-36) may overlook benefit
- Treatment Outcomes of Pain Survey (TOPS)
- patient, clinician, administrative burdens
- Side effects: a “different dimension”

## Outcomes Assessment (400 B.C.)

- 	If you and I were physicians, and were advising one another that we were competent to practice, should I not ask you, and would you not ask me, Well, what about Socrates himself, has he not good health?  And was anyone else ever been known to be cured by him, whether slave or freeman?

## Towards an Answer (1)

- To ask “when does acute pain become chronic?” is unfair and misleading
- Question equates time course, mechanism
- Prolonged (labor, arthritis, glaucoma, obstructed viscus, sunburn) or repetitive (headache, ulcer, muscle bruise/ soreness) nociception alone rarely induce chronic pain
- [Exception: psychosocial factors]
- BUT, acute-to-chronic pain progression is well documented clinically

## Towards an Answer (2)

- Evidence, logic mandate distinguishing intense nociception (“acute pain”) vs. rapid onset of PNS, CNS reorganization (“chronic”)
- Epidemiology of acute-to-chronic pain progression implies concordance of nerve injury (zoster, operation, ischemia...) and intense acute nociception, inflammation
- ? CP risk ~ PNS injury x CNS sensitization
- Genetics, cognition, disability influence factor weighting, exuberance, _+_ inhibition