MAKE ANALGESIC APPROVAL TRIALS MORE USEFUL TO CLINICIANS

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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

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EBM18,000 Citations Screened for 2001 AHRQ
Cancer Pain Report (WWW.AHRQ.GOV)
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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

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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

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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

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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
  patients pain?

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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

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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

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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?

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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

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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