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Tramadol: review of pharmacology

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... of pharmacology. Robert B. Raffa, Ph.D. Professor of Pharmacology & Chair, TUSP ... Applied pharmacology: Inject crushed CR? bypasses 1st-pass effect (less M1) ... – PowerPoint PPT presentation

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Title: Tramadol: review of pharmacology


1
Tramadol review of pharmacology
  • Robert B. Raffa, Ph.D.

Professor of Pharmacology Chair, TUSP and
Research Professor, TUSM Philadelphia, PA
2
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
3
The issues have been addressed
4
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
5
Tramadol enantiomers synergy
Source Raffa et al., J Pharmacol Exp Ther
267331-40, 1993
6
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

7
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)

8
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
9
Lack of naloxone block rats
  • tramadol is not a pro-drug

Source Raffa et al., J Pharmacol Exp Ther
260275-85, 1992
10
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
11
Applied pharmacologySnort?
  • bypasses 1st-pass effect (less M1)
  • Source http//www.tokeup.com/forums/showthread.ph
    p?t5430

12
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)

13
The end
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