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 Δ Pain

intensity (0-100)

Δ Functional improvement (WOMAC 0-10)

Global improvement

(NNT for reporting moderate

improvement)Tramadol vs. placebo -8.5 -0.34 6

Cepeda MS, et al. CDSR 2009.

Intervention Minor adverse

event (NNH)

Major adverse

events (NNH)Tramadol vs. placebo 5 8

Most common AEs:Nausea, vomiting,dizziness, constipation,somnolence, tiredness,headache

Separate MAs:NSAID Δ = -10Opioid Δ = -9

Acetaminophen Δ =-4

Separate MA:Acetaminophen NNT =

6 Separate MA:

Opioid Δ = -0.7Separate MA:Opioid NNH = 12

Separate MA:Opioid NNH = 19

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 intensity (0-100)

Δ Functional Improvement

(RDQ 0-24 )Tramadol vs. placebo -10.8 -1.0

Adverse events

RD (%)

nausea 9%somnolence 9%dizziness 8%constipation 8%

dry mouth 7%headache 3%

Intervention 30% Pain Improvemen

t (%)

Withdrawal due to

tolerability (%)

Tramadol 50mg QID 52 13.4

celecoxib 200mg BID 63 10.6* all differences 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 PainIntervention 50% Pain

Improvement (NNT)

Withdrawal due to Side Effects

(NNH)Tramadol vs. placebo 3.8 7.7

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 & CentsMedication Approximate

equivalent dose

~$/30 days

Tramacet (tramadol 37.5mg + acetaminophen 325mg)

2 tabs q4-6h (8/day=300mg) 180

Tramadol long-acting (Ralivia, Tridural, Xytram XL) 300mg OD 100

Celecoxib 200mg BID 90

Naproxen 500mg BID 15

Tylenol #3 (codeine 30mg + acetaminophen 325mg)

2 tabs q4-6h (8/day=240mg) 20

Percocet (oxycodone 5mg + acetaminophen 325mg)

1 tab q6h (4/day=20mg) 15

Morphine SR 15mg q12h 25Amitriptyline 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 Youjfalk@wrha.mb.ca