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					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?

 Where does it fit in the analgesic continuum?
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.
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.
Efficacy
            Acute Pain

            Chronic Pain
              Osteoarthritis
              Neuropathic Pain
              Low back pain
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.
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.
     Osteoarthritis

Intervention                                              Global
                                   Δ Functional        improvement
               Δ Pain intensity
                   (0-100)
                                  improvement         (NNT for reporting
                                  (WOMAC 0-10)            moderate
                                                        improvement)
Tramadol vs.
                    -8.5              -0.34                    6
placebo


Intervention       Minor                Major        Most common AEs:
               adverse event      adverse events     Nausea, vomiting,
                  (NNH)               (NNH)          dizziness, constipation,
                                                     somnolence, tiredness,
Tramadol vs.                                         headache
                      5                 8
placebo
                                                   Cepeda MS, et al. CDSR 2009.
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.
     Chronic Low Back Pain

Intervention      Δ Pain            Δ Functional              Adverse             RD
                 intensity         Improvement                events              (%)
                    (0-100)         (RDQ 0-24 )               nausea              9%
Tramadol vs.                                                  somnolence          9%
                      -10.8             -1.0
placebo
                                                              dizziness           8%
                                                              constipation        8%
Intervention                30% Pain     Withdrawal
                         Improvement        due to            dry mouth           7%
                              (%)       tolerability (%)      headache            3%
Tramadol 50mg QID             52               13.4
                                                             * all differences
celecoxib 200mg BID           63               10.6            statistically significant

                                   Deshpande A, et al. CDSR 2008.
                                   O’Donnell JD, et al. J Int Med Res 2009;37:1789-1802.
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.
      Neuropathic Pain
Intervention     50% Pain
                             Withdrawal due to
               Improvement
                             Side Effects (NNH)
                   (NNT)
Tramadol vs.
                   3.8              7.7
placebo




                                          Duehmke RM, et al. CDSR 2009.
                                          Finnerup NB, et al. Pain 2005;118:289-305.
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.
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.
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.
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 Fam Pract 2005;54:73.
Dollars & Cents
Medication                       Approximate
                                                    ~$/30 days
                                 equivalent dose
Tramacet (tramadol 37.5mg +          2 tabs q4-6h
                                   (8/day=300mg)
                                                       180
acetaminophen 325mg)
Tramadol long-acting (Ralivia,       300mg OD          100
Tridural, Xytram XL)
Celecoxib                            200mg BID          90

Naproxen                             500mg BID          15

Tylenol #3 (codeine 30mg +           2 tabs q4-6h
                                   (8/day=240mg)
                                                        20
acetaminophen 325mg)
Percocet (oxycodone 5mg +             1 tab q6h
                                   (4/day=20mg)
                                                        15
acetaminophen 325mg)
Morphine SR                         15mg q12h           25

Amitriptyline                        25-100mg           10
       To sum up…
Acute pain management

Osteoarthritis

Chronic low back pain

Neuropathic pain

Minor side effects (e.g. nausea, constipation, sedation)

Serious side effects (e.g. sz, serot synd, resp depression)

Abuse potential

Cost
Thank You
jfalk@wrha.mb.ca

				
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