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IS THIS SEAT TAKEN?

IS THIS SEAT TAKEN?. A Review of TRAMADOL in Pain Management Jamie Falk, PharmD MCFP Annual Scientific Assembly April 22, 2010. Common Questions. How does tramadol work? Which patients might it benefit? Is it better tolerated than other analgesics? Does it have abuse potential?

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IS THIS SEAT TAKEN?

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  1. IS THIS SEAT TAKEN? A Review of TRAMADOL in Pain Management Jamie Falk, PharmD MCFP Annual Scientific Assembly April 22, 2010

  2. Common Questions • How does tramadol work? • Which patients might it benefit? • Is it better tolerated than other analgesics? • Does it have abuse potential? • Where does it fit in the analgesic continuum?

  3. How does it work? • Weak -opioid receptor effects • Structurally related to morphine and codeine • ~10-fold less affinity for  receptor than codeine and up to 6000-fold less than morphine • Metabolized to highly active M1 300-fold greater affinity than parent compound • Analgesia only partially blocked by naloxone (~33%) • Serotonin and norepinephrine reuptake inhibition • Effect reduced by > ½ by adrenergic receptor antagonist • Less than that with imipramine Grond S, et al. Clin Pharmacokin 2004;43:879-923. Raffa RB. J Clin Pharm Therap 2008;33:101-8.

  4. Kinetic/Dynamic Specs • Onset of action: ~ 30 minutes • Peak action: 2 – 3 hours • Duration of action: 4 – 6 hours • Extensive hepatic metabolism • Metabolized to M1 by CYP2D6 • Dose reduction required for cirrhosis • Urinary elimination • 30% as unchanged; 60% of M1 excreted • Dose reduction required for severe renal impairment Grond S, et al. Clin Pharmacokin 2004;43:879-923.

  5. Efficacy • Acute Pain • Chronic Pain • Osteoarthritis • Neuropathic Pain • Low back pain

  6. Acute Pain • Many small studies vs. opioids • Likley = morphine in equi-analgesic doses (T:M = ~10:1) up to 400 – 600mg/day maximum • NNT (50% reduction in pain vs. placebo) = 4.8 for tramadol 100mg = 3.6 for codeine 60mg + ASA • Many small studies vs. non-opioids • Similar analgesia compared to NSAIDs post-operatively in a variety of doses Grond S, et al. Clin Pharmacokin 2004;43:879-923.

  7. Osteoarthritis • Cochrane Review of Tramadol in OA • 11 RCTs (n=1939 with symptomatic OA of knee or hip) • Tramadol (+/- acetaminophen) vs. • placebo (6 studies), or • active control (5 studies – acetaminophen, diclofenac, dihydrocodeine, propoxyphene, pentazocine)  average n = 108 • Mean daily tramadol dose = 201.4mg +/- 50.15 • Average length of f/u = 35 days • Active control (non-placebo) = 17 days Cepeda MS, et al. CDSR 2009.

  8. Osteoarthritis Separate MA: Opioid NNH = 19 Separate MA: Opioid Δ = -0.7 Separate MA: Acetaminophen NNT = 6 Separate MAs: NSAID Δ = -10 Opioid Δ = -9 Acetaminophen Δ =-4 Most common AEs: Nausea, vomiting, dizziness, constipation, somnolence, tiredness, headache Separate MA: Opioid NNH = 12 Cepeda MS, et al. CDSR 2009.

  9. Chronic Low Back Pain • Insufficient evidence available to compare tramadol to traditional opioids • Two parallel studies comparing celecoxib to tramadol • Cochrane Review of Opioids in Chronic LBP • 3 RCTs (n=914) • Tramadol vs. placebo (3 studies) • Mean tramadol dose = 150 – 240mg/day • Duration of f/u = 4 wks – 3 months Chou R, et al. Ann Intern Med 2007;147:505-14. O’Donnell JD, et al. J Int Med Res 2009;37:1789-1802. Deshpande A, et al. CDSR 2008.

  10. Chronic Low Back Pain * all differences statistically significant Deshpande A, et al. CDSR 2008. O’Donnell JD, et al. J Int Med Res 2009;37:1789-1802.

  11. Neuropathic Pain • Canadian Pain Society Guidelines (2007) • Tramadol and opioid analgesics considered third-line • Scant evidence on which to draw any conclusions on comparative agents (opioids, TCAs, anti-convulsants) • Cochrane Review of Tramadol for Neuropathic Pain • 3 RCTs (n=303 ) of tramadol vs. placebo • Duration 4 – 6 wks • Tramadol dose = 100 – 400mg/day Moulin DE, et al. Pain Res Manage 2007;12:13-21. Duehmke RM, et al. CDSR 2009.

  12. Neuropathic Pain Duehmke RM, et al. CDSR 2009. Finnerup NB, et al. Pain 2005;118:289-305.

  13. Side Effect Profile Comparisons • Nausea, constipation: • tramadol < codeine and morphine • Respiratory depression: • Tramadol << morphine, oxycodone • GI bleeding, renal impairment, CV risk: • Non-existent with tramadol • Increased risk with NSAIDs, especially with risk factors Smith AB, et al. Am J Surg 2004;187:521-7. Grond S, et al. Clin Pharmacokin 2004;43:879-923.

  14. Other Serious Adverse Events • Serotonin Syndrome • Rare with monotherapy • Incidence increases with SSRIs, SNRIs, TCAs, etc. • Seizure risk • Incidence < 1% (possibly no greater than other analgesics) • May increase 2 - 6-fold with risk factors • EtOH abuse, past stroke or head injury, multiple seizure threshold-reducing drugs, multiple tramadol rx • Increased risk possible with higher doses and concomitant SSRIs, SNRIs, TCAs Gardner JS, et al. Pharmacotherapy 2000;20:1423-31. Grond S, et al. Clin Pharmacokin 2004;43:879-923.

  15. Abuse Potential • In rat models: • Peak brain M1 levels delayed until 20-60 min post-dose • As dose increases, brain tramadol:M1 increases • In humans: • Negative reports by drug abusers of delay in subjective CNS effects • Tramadol has 1/10 the potency of morphine for analgesia, but only 1/20 the potency for subjective CNS effects Raffa RB. J Clin Pharm Therap 2008;33:101-8.

  16. Abuse Potential • Adams, et al. • n=11,352 patients with chronic non-cancer pain • Positive scoring on Abuse Index within 12 months • NSAIDs = 2.5% • Tramadol = 2.7% • Hydrocodone = 4.9% (p<0.01) • Ortho-McNeil-funded surveillance program: • 454 cases of abuse over 3 yrs  1-3 cases per 100,000 pts • Monitoring program for impaired HCPs (n=1601) • 18 cases per 1000 person-yrs Adams EH, et al. J Pain Symptom Manage 2006;31:465-76. McDiarmid T, et al. J FamPract 2005;54:73.

  17. Dollars & Cents

  18. To sum up…

  19. Thank You jfalk@wrha.mb.ca

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