pain sucks:

Pain Sucks:

An evidence based guide to analgesia

Updated January 22nd, 2009Joe Vipond

Clinical Scenarios1) a 23 y.o. Male with multiple facial contusions and a broken nose. He is to follow up with ENT in 10 days.

Analgesia?

2) An 87 y.o. female with a knee strain. Xray reveals no acute fracture but +++OA.

Analgesia?

Objectives1) Knowledge of the evidence of efficacy of the commonly used analgesics

-Oxford League Table-what it means-its strengths and weakness

2) An understanding of benefits and harms of NSAID use

-Side effects

-Effect on Bone healing

3) An understanding of benefits and harms of combination analgesia

-Acetaminophen with codeine

-Acetaminophen with Ibuprofen

4) An understanding of the current knowledge on topical NSAIDs

The Oxford League Table

• From Bandolier: evidence-based reviews with an interest in pain

• www.jr2.ox.ac.uk/bandolier/booth/painpag

• Comparison versus placebo in randomised, double-blind, single dose studies in patients with moderate to severe pain

• Generally, studies are on post op patients (dental, tonsillectomy)

Oxford Table (Continued)

Analgesic Number of patients in comparison

Percent with at least 50% pain relief

NNT Lower confidence interval

Higher confidence interval

Ibuprofen 400 5456 55 2.5 2.4 2.7

NNT- Proportion of patients with at least 50% pain relief over 4-6 hours compared with placebo

NNT - What does it mean?

NNT (continued)

NNT (cont’d)

What about the validity of the results?Compare with….





Ibuprofen 600 203 79 2.4 2.0 4.2





Ibuprofen 400 5456 55 2.5 2.4 2.7

Placebo >10,000 18 N/A N/A N/A

And Explain this!!!





Oxycodone IR 5 + Paracetamol 500 150 60 2.2 1.7 3.2


Oxycodone IR 10+Paracetamol 1000 83 67 2.7 1.7 5.6



IM injections





Ketorolac 60 (intramuscular) 116 56 1.8 1.5 2.3

Pethidine 100 (intramuscular) 364 54 2.9 2.3 3.9

Morphine 1 0 (intramuscular) 946 50 2.9 2.6 3.6



NSAIDs and AcetaminophenValdecoxib 40 mg 473 73 1.6 1.4 1.8 Ibuprofen 800 76 100 1.6 1.3 2.2 Valdecoxib 20 mg 204 68 1.7 1.4 2.0 Ketorolac 20 69 57 1.8 1.4 2.5 Diclofenac 100 545 69 1.8 1.6 2.1 Celecoxib 400 298 52 2.1 1.8 2.5 Naproxen 440 257 50 2.3 2.0 2.9 Ibuprofen 600 203 79 2.4 2.0 4.2 Aspirin 1200 279 61 2.4 1.9 3.2 Ibuprofen 400 5456 55 2.5 2.4 2.7 Ketorolac 10 790 50 2.6 2.3 3.1 Diclofenac 25 502 53 2.6 2.2 3.2 Ibuprofen 200 3248 48 2.7 2.5 2.9 Diclofenac 50 1296 57 2.7 2.4 3.1 Naproxen 550 784 52 2.7 2.3 3.3 Naproxen 220/250 202 45 3.4 2.4 5.8 Paracetamol 500 561 61 3.5 2.2 13.3 Paracetamol 1500 138 65 3.7 2.3 9.5 Ibuprofen 100 495 36 3.7 2.9 4.9 Paracetamol 1000 2759 46 3.8 3.4 4.4 Aspirin 600/650 5061 38 4.4 4.0 4.9 Paracetamol 600/650 1886 38 4.6 3.9 5.5 Ibuprofen 50 316 31 4.7 3.3 7.9

Ibuprofen, put another way

GI risks of NSAIDsTable 2: NSAID -related deaths and admissions to hospital Event Canada Annual NSAID prescriptions 10 million NSAID -related admissions 3,900 NSAID -related deaths 365

Risk of gastric lesions: < 2 weeks 3.6% > 4 weeks 6.8%Risk of duodenal lesions: < 2 weeks 3.0%

> 4 weeks 4.0%

Koch M, Dezi A, Ferrario F, Capurso L. Prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal mucosal injury. Archives of Internal Medicine 1996 156: 2321-32.

Risk factors for NSAID bleeds• 8843 men and women w/ RA taking NSAIDS

– mean age 68 years

• Placebo 1.4% GI Events over six months– 4 major risk factors: age>75, hx of PUD, hx GI Bleed, hx CHF

• Risk of GI Bleed related to number of risk factors– none: 0.8%– one: 2%– three :8-10%– four : 18%

• FE Silverstein, DY Graham, JR Senior et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid

arthritis receiving nonsteroidal anti-inflammatory drugs. Annals of Internal Medicine 1995 123:241-9.

Use of GI protectants?• Misoprostol group 0.8% incidence

– NNT of 83– NNH of 20 (diarrhea, abdominal pain, and flatulence)– note that NNT decreases as risk of bleed increases: if initial risk is

18%, NNT is 12.8.

• H2 receptor blockers do not seem to be very effective• Omeprazole may be even better than misoprostol

– two studies looking at existing ulcers in people needing to take NSAIDs– NNT of 3.0 vs. 5.8 for misoprostol

• 14 CJ Hawkey, JA Karrasch, L Szczepanki et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. New England Journal of Medicine 1998 338: 727-34. 15 ND Yeomans, Z Tulassay, L Juhasz et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs.

New England Journal of Medicine 1998 338: 791-26.

Which NSAID sucks the most?

Table 5: Relative risk of gastrointestinal complications with NSAIDs, relative to ibuprofen or non -use (shaded)

Drug Case-control studies [12] Cohort study [7] Italian case -control [13] Nonuse 1.0 Ibuprofen 1.0 1.0 2.1 (0.6 to 7.1) Aspirin 1.6 ( 1.3 to 2.0) Diclofenac 1.8 (1.4 to 2.3) 1.4 (0.7 to 2.6) 2.7 (1.5 to 4.8) Naproxen 2.2 (1.7 to 2.9) 1.4 (0.9 to 2.5) 4.3 (1.6 to 11.2) Indomethacin 2.4 (1.9 to 3.1) 1.3 (0.7 to 2.3) 5.4 (1.6 to 18.9) Ketorolac 24.7( 9.6 to 63.5) 7 TM MacDonald, SV Morant, GC Robinson et al. Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study. British Medical Journal 1997 315: 1333-7. 12 D Henry, L Lim, L Garcia Rodriguez et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. British Medical Journal 1996 312: 1563-6. 13 LA Garcia Rodriguez et al. Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs. Archives of Internal Medicine 1998 158: 33-39.

More evidence

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.Dose–response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient dataBr J Clin Pharmacol. 2002

September; 54(3): 320–326.

NSAID effect on bone healing?• NSAIDs affect healing in rabbits• No effect on Colles fractures•

P Adolphson et al. No effects of piroxicam on osteopenia and recovery after Colles' fracture. Arch Orthop Trauma Surg 1993 112: 127-130. • IM Ketorolac decreases fusion rates in spinal fusion

surgery (esp. with smoking)•

SD Glassman et al. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine 1998 23: 834-838. • Case control study suggesting increased non-union with

femur fractures• PV Giannoudis et al. Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br 2000 82: 655-658.

• ? Increased non-union with indomethacin use to prevent heterotopic bone formation

•PV Giannoudis et al. Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br 2000 82: 655-658.

What about Tylenol #3?

Paracetamol 1000 + Codeine 60 197 57 2.2 1.7 2.9

Paracetamol 1000 2759 46 3.8 3.4 4.4 Paracetamol 600/650 + Codeine 60 1123 42 4.2 3.4 5.3

Paracetamol 600/650 1886 38 4.6 3.9 5.5 Paracetamol 300 + Codeine 30 379 26 5.7 4.0 9.8

Codeine 60 1305 15 16.7 11.0 48.0 Placebo >10,000 18 N/A N/A N/A

Side effects of T#3s?• Table 2--Frequency of side effects in studies of paracetamol-codeine combinations

versus paracetamol alone

• Single dose studies (n = 15) RELATIVE RATE• No of patients reporting >/=1 event 484 488 1.1 (0.8 to

1.5)• No with adverse reaction 116 100• No of events:• Dizziness 14 11• Drowsiness 39 35• Nausea 18 17• Vomiting 6 7• Other 43 41• Multidose studies (n = 3)• No of patients reporting >/=1 event 307 164 2.5 (1.5 to

4.2)• No with adverse reaction 122 37• No of events:• Dizziness 42 2• Drowsiness 12 2• Nausea 69 9• Vomiting 19 3• Constipation 17 7• Other 90 38

• de Craen AJM, Di Giulio G, Lampe-Schoenmaeckers AJE, Kessels AGH, Kleijnen J. Analgesic efficacy and safety of paracetamol-codeine combinations versus paracetamol alone: A systematic review. British Medical Journal 1996; 313:321-325.

And Tramadol?Tramadol 100 882 30 4.8 3.8 6.1

Tramadol 50 770 19 8.3 6.0 13.0

Codeine 60 1305 15 16.7 11.0 48.0

NNH for Vomiting for 100mg: approx 12

NSAIDs and Acetaminophen• Frequently used• ?evidence• Two reviews in 2002• Rømsing J, Møiniche S, Dahl JB. Rectal and parenteral paracetamol, and paracetamol in combination with NSAIDs, for

postoperative analgesia. Br J Anaesth 2002; 88: 215–26

• Hyllested M, Jones S, Pedersen JL, Kehlet H. Comparative effect of paracetamol, NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 2002; 88: 199–214

• Evidence suggests combining NSAID with Acetaminophen better than acetaminophen alone, but perhaps not the opposite

• neither were formal quantitative reviews• both suggested quality of the studies were

inadequate to give adequate data

Ibuprofen and Oxycodone• Combination oxycodone 5mg/ibuprofen 400 mg for

the treatment of pain after abdominal or pelvic surgery in women: a randomized, double-blind, placebo and active controlled parallel-group study Clin Ther 2005 Jan ;27(1):45-57

• Combination significantly better, than ibuprofen (12 vs ibuprofen 10 vs oxycodone 8 vs placebo 6)

• Also less adverse events (55% placebo vs. 44% oxycodone vs 42% ibuprofen 40% combination)

Ibuprofen and Oxycodone cont’d

• Analgesic efficacy and tolerability of oxycodone 5 mg/ibuprofen 400mg compared with those of oxycodone 5 mg/acetaminophen 325 mg and hydrocodone 7.5 mg/acetaminophen 500mg in patients with moderate to severe post-op pain: a randomized, double-blind, placebo-controlled single-dose, parallel group study in a dental pain model Clin Ther 2005 Apr;27(4):418-29

• Totpar 15 vs. perc 9.5, dilaudid 8.3 placebo 5.5• Also fewer adverse events (50%, and similar to placebo)

– Suggestion of some anti-emetic effect of ibuprofen

Ibuprofen/oxycodone in children

• Single study: Effectiveness of oxycodone, ibuprofen or the combination in the initial mangement or orthopedic injury-related pain in children Paed Emerg Care 2007 sep 23(9): 627-33

• No sign. Difference in effectiveness • Increased adverse effects in combination

group

Topical NSAIDs• Controversial: geographical variance in use is HUGE• variability in skin penetrance

– diclofenac is reasonable at 11%• Tissue concentrations much higher than serum

concentrations

Clinical Effectiveness-systemic review of topical NSAIDs in Acute Pain L Mason et al. Topical NSAIDs for acute pain: a metaanalysis.BMC Family Practice 2004 5:10

Effectiveness (cont’d)

AA Bookman et al. Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritisof the knee: a randomized controlled study. Canadian Medical Association Journal 2004 171: 333-338.

SH Roth, JZ Shainhouse. Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment ofprimary osteoarthritis of the knee. Archives of Internal Medicine 2004 164: 2017-2023.

PS Tugwell et al. Equivalence study of a topical diclofenac solution (PENNSAID) compared with oraldiclofenac in the symptomatic treatment of osteoarthritis of the knee: a randomized controlled study.Journal of Rheumatology 2004 31: 2002-2012.

Safety of Topical NSAIDs

Clinical Scenarios1) a 23 y.o. Male with multiple facial contusions and a broken nose. He is to follow up with ENT in 10 days.

Analgesia?

2) An 87 y.o. female with a knee strain. Xray reveals no acute fracture but +++OA.

Analgesia?

Summary• The Oxford table is an imperfect but helpful

guide to analgesic efficacy.• NSAIDs, overall, are more effective than

Acetaminophen. Ibuprofen Tops!• Omeprazole may help decrease GI bleeding

with NSAIDs.• The overall efficacy of APAP/Codeine is

suspect.• Topical NSAIDs may be a reasonable NSAID

alternative.

Summary (cont’d)

• Acetaminophen/NSAID combination therapy: evidence not there yet….

pain sucks:

Documents

comparison percent

pain sucks

nnt continuednnt contdwhat

post op patients dental

understanding of benefits

evidence of efficacy

evidencebased reviews

current knowledge