Non steriodeal

antiinflammatory drugs and

fractures – any issues?

Professor Lars Engebretsen MD, PhD

Orthopeadic Clinic University of Oslo

Do not use it in fractures the first 3-5days

Introduction

Musculoskeletal & joint injuries common Time lost to competition & training

Account for days of inactivity & loss of performance

Challenge is to hasten return to sport without compromising tissue repair

NSAIDs - common intervention Control pain

Limits duration of inflammation

Analgesic, anti-inflammatory, antipyretic, and antithrombotic properties

Overuse in athletes

• Overuse and systematic prescribing of NSAIDs for sports injury is too frequent

• Relative unrestricted access – most available over the counter

• Not prohibited by WADA

• Many athletes use 2 or 3 NSAIDs concurrently– greater risk of side effects

• Often used prophylactically

What are NSAIDs?

Analgesic, anti-inflammatory, antipyretic, and antithrombotic properties

Inhibit cyclo-oxygenase (COX) leading to: Decrease synthesis of prostaglandins

Decrease inflammatory response

NSAIDs categorised by their selectivity for inhibiting COX-1 & COX-2

Prevalence of use of NSAIDs in

sport

Most used drug class in Olympic environment

Sydney 2000 - 1 in 4 athletes

Athens 2004 - 1 in 10 athletes

Football World Cup 2002-2010 – ½ all

athletes

PyeongChang 2018 FormularyPolyclinic Pharmacy

– Diclofenac 50mg tablets– Diclofenac 75mg tablets– Diclofenac gel– Ibuprofen 200mg tablets– Ibuprofen 400mg tablets– Ketoprofen 100mg IM injection– Ketoprofen 30mg patch– Ketorolac injection 30mg– Naproxen 200mg capsule– Aspirin 500mg tablet– Tramadol10mg injection– Oxycodone 5mg tablet– Morphine 5mg injection– Paracetamol 500mg oral

25% of all prescriptions

Rio 2016 Team Physician Survey

107 Olympic Team Physicians surveyed

• Significant variations in practice and attitudes

• Most reported appropriate use

• 24% of physicians reported frequent/routine NSAID use in most athletes they treat

Rio 2016 Team Physician Survey

Importance of factors influencing treatment plan

• Pain management 81%

• Enabling rehabilitation exercises 71%

• Impact on recovery 68%

• Pain reduction during comp or training 61%

• Ensuring performance continuation 45%

• Impact on performance 41%

[% of physicians indicating important]

FORMULATIONS

Oral

• Most common route

• Given as single doses or in short-term intermittent therapy

• Generally only small differences in anti-inflammatory activity between the various NSAIDs

• Responses of individual patients vary widely -if a patient fails to respond to one NSAID, another drug may be successful

Topical application

• Absorbed through skin tissue penetration

• Lower adverse effects due to lower amount circulating in the bloodstream

• Patches less effective for fast return to sport

Intramuscular injection

• Used frequently in professional sport e.g. ketorolac

• Faster acting, but similar reduction of pain compared with oral

• Increased side effects compared to oral– Risk of haemorrhage

– Renal complications

Adverse effects

• Greater when given in high doses or prolonged time

• Non-selective NSAIDS:– Dyspepsia

– Haemorrhage

– Intestinal bleeding

– Peptic ulceration

– Renal dysfunction

Adverse effects

• Selective COX-2 inhibitors

– Inhibit the formation of inflammatory prostaglandins without the COX-1 inhibition

– Thus less GI side effects

• Associated with serious cardiovascular events

– Rofecoxib withdrawn globally 2004

– Others now have strong warnings

Rio 2016 Team Physician Survey

Dose• 12% of physicians prescribe doses double the

manufacturer recommendations immediately before competition

Duration• 31% prescribe 1 – 3 days duration• 42% prescribe 3 – 5 days duration• 21% prescribe > 7 days

Significant risk of adverse effects with high doses for long periods

INJURY TYPES

Bone injuries

• Prostaglandins play important role in bone formation after an injury

• As NSAIDs inhibit prostaglandins, regular use may impair bone healing and delay bone consolidation following fracture

• NSAIDs should be avoided in the first week after a fracture

SUMMARY:

These animal data, together with the view of limited scientifically robust clinical evidence in humans, indicate that physicians consider only short-term administration of COX-2 inhibitors or other drugs in the pain management of patients who are in the phase of fracture or other bone defect healing. COX-2-inhibitors should be considered a potential risk factor for fracture healing, and therefore to be avoided in patients at risk for delayed fracture healing.

RECENT FINDINGS:

Prostaglandins play an important role as

mediators of inflammation and COX are

required for their production.

Inflammation is an essential step in the

fracture healing process in which

prostaglandin production by COX-2 is

involved. Data from animal studies

suggest that NSAIDs, which inhibit COX-

2, can impair fracture healing due to

the inhibition of the endochondral

ossification pathway. Animal data

suggest that the effects of COX-2

inhibitors are dependent on the timing,

duration, and dose, and that these

effects are reversible.

NSAIDs and fracture healing.

Geusens P1, Emans PJ, de Jong JJ, van

den Bergh J. JOR 2014

SUMMARY:

These animal data, together with the

view of limited scientifically robust

clinical evidence in humans, indicate

that physicians consider only short-term

administration of COX-2 inhibitors or

other drugs in the pain management of

patients who are in the phase of

fracture or other bone defect healing.

COX-2-inhibitors should be considered a

potential risk factor for fracture

healing, and therefore to be avoided in

patients at risk for delayed fracture

healing.

J Trauma Acute Care Surg. 2014 Mar;76(3):779-83. doi:

10.1097/TA.0b013e3182aafe0d.

Nonsteroidal anti-inflammatory drugs' impact on nonunion

and infection rates in long-bone fractures.

Jeffcoach DR1, Sams VG, Lawson CM, Enderson BL, Smith ST,

Kline H, Barlow PB, Wylie DR, Krumenacker LA, McMillen JC,

Pyda J, Daley BJ; University of Tennessee Medical Center,

Department of Surgery.

LBF patients who received NSAIDs in the

postoperative period were twice as likely

and smokers more than three times likely

to suffer complications such as

nonunion/malunion or infection. We

recommend avoiding NSAID in traumatic

LBF.

Clinical studies

• What about clinical studies?

Clinical studies

• Two studies on Colles’ fractures did not show any negative effects of NSAIDs.

• Adolphson, P. et al. “No effects of piroxicam on osteopenia and recovery after Colles’ fracture. A randomized, double-blind, placebo-controlled, prospective trial.” Acta Orthop Trauma Surg, 1993

• Davis, T.R. and Ackroyd C.E. “Non-steroidal anti-inflammatory agents in the managemant of Colles’ fractures.” Br J Clin Pract, 1988

Clinical studies

• No prospective, randomized clinical trials have been performed on the effects of NSAIDs and selective COX-2 inhibitors on long bone fractures.

Clinical studies

• One study on femoral shaft fractures.

• Retrospective study.

• There was a marked association between nonunion and the use of NSAIDs after injury.

• Delayed healing was also noted in patients who took NSAIDs and whose fractures had united.

• Giannoudis, P. V. et al. “Nonunion of the femoral diaphysis. The influence of reaming and NSAIDs.” J Bone Joint Surg Br 2000

Clinical studies

• The best clinical study in my opinion is the study published by Burd in 2003.

• Burd T.A. et al. “Heterotopic ossification profylaxis with indomethacin increases the risk of long-bone nonunion.” J Bone Joint Surg Br, 2003

• Of 282 patients operated for acetabular fracture, 166 were randomized to indomethacin or localized irradiation for prevention of heterotopic ossification.

• Burd, T.A. et al. “Indomethacin Compared with Localized Irradiation for the Prevention of Heterotopic Ossification Following Surgical Treatment of Acetabular Fractures.” J Bone Joint Surg Br, 2001

Clinical studies

112 of these patients also had a long bone fracture.– 36 without indometacin or radiation

– 38 received radiation

– 38 received indometacin 25 mg x 3 in 6 weeks

Clinical studies

112 of these patients also had a long bone fracture.– 36 without indometacin or radiation 6% nonunion

– 38 received radiation 8% nonunion

– 38 received indometacin 25 mg x 3 in 6 weeks 29% nonunion

Clinical studies

112 of these patients also had a long bone fracture.– 36 without indometacin or radiation 6% nonunion

– 38 received radiation 8% nonunion

– 38 received indometacin 25 mg x 3 in 6 weeks 29% nonunion

– No nonunions in the acetabular fractures!

Summary

• Strong evidence that cox inhibitors impaires bone healing in animals

• Weaker, but compelling evidence in humans

Summary

• Prostaglandins are necessary for fracture healing.

• COX-2 is critically involved in fracture healing the first 3 weeks after fracture.

• NSAIDs and COX-2 inhibitors impair fracture healing.

• Findings also indicate that NSAIDs and COX-2 inhibitors impair tendon-to-bone healing.

SUMMARY - NSAIDs

• Effective analgesics, anti-inflammatory

• Benefits are mainly in the early phase of injury when inflammation is more severe; long term use may delay the repair process

• The ability to assist return to play should be balanced against the potential detriment to tissue healing

• Always use lowest effective dose with the shortest duration of administration

IOC Consensus Statement on Pain Management in Elite Athletes

bjsm.bmj.comJuly 2017

Register your interest

www.sportsoracle.com

IOC Certificate in

Drugs in Sport

The Oslo Sports Trauma Research Center

has been established at

the Norwegian School of Sport Sciences

through generous grants from the Royal Norwegian Ministry of

Culture, the South-Eastern Norway Regional Health Authority,

the International Olympic Committee, the Norwegian Olympic

Committee & Confederation of Sport, and Norsk Tipping AS