Tramadol: review of pharmacology

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Tramadol review of pharmacology

• Robert B. Raffa, Ph.D.

Professor of Pharmacology Chair, TUSP and
Research Professor, TUSM Philadelphia, PA
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Disclosures

• Scientific Advisory Board
• Pain Therapeutics
• Consulting History
• Adolor
• Alteon
• Asta Medica
• Discovery Research Consultants
• Grünenthal (buprenorphine)
• Johnson Johnson (tramadol, Tramacet)
• LAPID
• Novartis
• Onconova

current research grant stock speaker
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The issues have been addressed
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Binding profile (affinity, nM)

• µ-OR NE 5-HT
• Morphine 0.3 IA IA
• Buprenorphine 4 IA IA
• Oxycodone 9 IA IA
• Hydrocodone 10 IA IA
• d-Propoxyphene 30 IA IA
• Codeine 200 IA IA
• Dextromethorphan 1,300 20 200
• Tramadol 2,100 800 1,000
• () enantiomer 1,300 2,500 500
• () enantiomer 24,800 430
  2,400
• Imipramine 3,700 20 7

Source Raffa et al., J Pharmacol Exp Ther
260275-85, 1992 Raffa et al., J Pharmacol Exp
Ther 267331-40, 1993
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Tramadol enantiomers synergy
Source Raffa et al., J Pharmacol Exp Ther
267331-40, 1993
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Summary of mechanisms
M1

• tramadol is a racemate with only weak opioid
  binding
• the enantiomers have synergistic pharmacologies
• M1 metabolite is opioid (?)
• No other metabolites are active

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Opioid component

• The expression of the opioid component of
  tramadol requires its metabolic conversion (via
  CYP450-2D6) to M1
• But conversion of tramadol to M1 is not required
  for analgesic effect (Collart et al., Brit J Clin
  Pharmacol 3573P)
• The less the metabolic conversion to M1, the less
  an opioid effect (e.g., by bypassing the 1st-pass
  effect as in i.v. injection)

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Tramadol vs M1 in brain

• more tramadol than M1 enters the brain
• the ratio increases with dose

mice rats
Source Tao et al., J Clin Pharm Ther
2799-106, 2002
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Lack of naloxone block rats

• tramadol is not a pro-drug

Source Raffa et al., J Pharmacol Exp Ther
260275-85, 1992
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Lack of naloxone block humans

• Randomized, placebo-controlled, crossover study
• Transcutaneous electrical stimulation of the
  sural nerve
• Analgesia assessment
• Objective test (R-III Reflex)
• Subjective test (Pain Visual Analog PVA scale)
• Tramadol (100 mg, po) ? naloxone (0.8 mg, iv)
• Mean maximal inhibition of tramadol analgesia by
  naloxone was 26 (R-III) and 31 (PVA)
• Reduced gt50 by yohimbine

Source Desmeules et al., Brit J Clin Pharmacol
417-12, 1996
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Applied pharmacologySnort?

• bypasses 1st-pass effect (less M1)

• Source http//www.tokeup.com/forums/showthread.ph
  p?t5430

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Applied pharmacologyInject crushed CR?

• bypasses 1st-pass effect (less M1)
• amount of M1 in brain does not increase as much
  as tramadol increases seizure risk (well known
  in the abuse community)

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The end