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Three Part Question

In [adults with acute ligament injury]do [oral NSAIDs] delay or impair [the natural healing process]

Clinical Scenario

A 27 year male presents several hours after a grade 1 injury to his medial collateral ligament (MCL). You propose to prescribe analgesics and oral NSAIDs. A colleague queries whether NSAIDs are appropriate at such an early stage due to a possible inhibition of the healing process. You decide to investigate

Search Strategy

MEDLINE 1950-12/08, CINAHL 1982 –12/08, AMED 1985-12/08, EMBASE 1980-12/08 via the OVID interface and also the Cochrane database.

Medline, CINAHL, EMBASE, AMED,: [{(exp soft tissue injury OR exp soft tissue injuries OR exp knee injury OR exp knee injuries OR exp ankle injury OR exp ankle injuries OR exp wounds and injuries OR exp ligament and tendon injury OR exp musculoskeletal injury OR exp ligament injury OR exp injury OR exp ligaments) AND (exp antiinflammatory agents, non-steroidal OR exp nonsteroidal anti inflammatory agent OR NSAID.mp OR exp Ibuprofen OR exp Diclofenac OR exp Naproxen OR exp cox-2 inhibitors OR exp cyclooxygenase 2 inhibitor OR cox 2.mp)}] LIMIT to English language.

The Cochrane database: NSAIDs.

Search Outcome

There were 4 papers retrieved all of which were placebo controlled studies on either rat or rabbit ligaments. There were no systematic reviews or Cochrane reviews.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Dahners et al. 1998 USA	2 groups Piroxicam v Placebo	Animal study MCL rats	1. Normalised ruptured forces@ 6days @14 days @ 21 days	1. Piroxicam better than placebo (P<0.01)@ 6 days. Piroxicam better than placebo (p<0.05) @ 14 days. NSS@21days
			2. Healing stiffness	2. NSS
			3. Collagen synthesis	3. NSS
Moorman et al 1999 USA	2 groups Ibuprofen v placebo	Animal study on MCL rabbits	1. Failure Load@ 2 weeks @4 weeks	1. Ibuprofen (17%) better than Placebo @ 2 weeks(NSS); 16% diff @4 weeks (NSS)	Possible type 2 error due to small sample size
			2. Failure deformation@ 2weeks @ 4weeks	2. Ibuprofen (9%) worse than Placebo @ 2 weeks; 0% diff @4weeks
			3. Stiffness @ 2 weeks @ 4 weeks	3. Ibuprofen (76%)better than Placebo(NSS); Ibuprofen 54% worse than Placebo (NSS)
			4. Work-to-failure @ 2 weeks @ 4 weeks	4. Ibuprofen 2% worse than Placebo (NSS); Ibuprofen 17% better than Placebo NSS)
Elder et al 2001 USA	2 groups Celecoxib v Placebo for 6 days, Dosage normalised to rat BW	Animal study MCL rats	1. Failure Load @ 2 weeks	1. 32% worse in Celecoxib group (p = 0.004)	Limited data some means (SD) missing. No long term effects or FU.
			2. Energy to failure @ 2 weeks	2. 41% worse in Celecoxib group (p = 0.014)
			3. Stiffness @ 2 weeks	3. 21% worse in Celecoxib group (NSS)
Warden et al 2006 USA	4 groups i)Celecoxib ii)placebo Celecoxib iii)ultrasound iv)placebo ultrasound dosage normalised to rat BW	Animal study MCL rats	1. Ultimate force @ 2weeks	1. NSS	No long term FU
			2. energy to failure @ 2weeks	2. 33% worse in Celecoxib group ( p < .05)
			3. stiffness @ 2 weeks	3. NSS
			4.Ultimate force @4 & 12 weeks	4. NSS
			5. energy to failure @ 4 & 12 weeks	5. NSS
			6. stiffness @ 4 & 12 weeks	6. NSS

Comment(s)

There is no RCT evidence of the tissue level effect of NSAIDs or COX2 inhibitors in humans. There is some contradictory evidence, all animal studies, of the effect on ligament healing. The longest follow up (12 weeks) indicates that although ligament healing may be delayed, ultimately it is not inhibited. Therefore NSAIDs or COX2s taken for anti-inflammatory effect and analgesia may be justified if ligament injury occurs.

Clinical Bottom Line

Oral anti-inflammatory medication can be used after injury to the medial collateral ligament of the knee.

References

1. Dahners, LE, Gilbert, JA, Lester, GE, Taft, TM, Payne, LZ. The effect of a nonsteroidal anti-inflammatory drug on the healing of ligaments. American Journal of Sports Medicine, 1998; 16 (6): 641-646.
2. Moorman, CT, Kukreti, U, Fenton, DC, Belkoff, SM. The early effect of ibuprofen on the mechanical properties of healing medial collateral ligament, American Journal of Sports Medicine, 1999; 27 (6) : 738-741.
3. Elder, CL, Dahners, LE, Weinhold, PS. The cyclooxygenase-2 inhibitor impairs ligament healing in the rat. American Journal of Sports Medicine 2001 ; 29 (6) : 801-805.
4. Warden, SJ, Avin, KG, Beck, EM, DeWolf, ATC, Hagemeier, MA, Martin, KM. Low intensity pulsed ultrasound accelerates and a nonsteroidal antiinflammatory drug delays knee ligament healing American Journal of Sports Medicine 2006 ; 34 (7) : 1094-1102.