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Microsoft word - nsaid paper 2014.docx



Questioning the use of NSAIDs Given Inflammation is a Perfectly Healthy
Response Following Acute Musculoskeletal Injuries
Written by: Dr. Bahram Jam, PT

Advanced Physical Therapy Education Institute (APTEI), Thornhill, ON, Canada
July 14, 2014 Article published on "Clinical Library"
Nonsteroidal
anti-inflammatory The use of prescription NSAIDs is reported (NSAIDs) are often prescribed in the to be the 15th most common cause of death in treatment of musculoskeletal injuries and are the United States and it is conservatively calculated that in the last 3 decades 300,000 people in the United States have died from medications worldwide. It GI complications due to NSAIDs (Wolf et al is estimated that more than 30 million people take NSAIDs daily for a variety of conditions Before I begin my likely controversial ranging from headaches to low back pain discussion on the use of NSAIDs, it is (LBP) (McGettigan & Henry 2013). appropriate to clearly state that I am certainly not making a blanket statement that all Ibuprofen is the most commonly used NSAIDs are inappropriate for all medical NSAID in North America while diclofenac is conditions. In fact, there are studies the most popular throughout the world supporting their benefit with respect to pain (McGettigan & Henry 2013). Interestingly a and functional improvements in various 2013 review recommended that due to its conditions such as rheumatoid arthritis, high cardiovascular toxicity, diclofenac be osteoarthritis, ankylosing spondylitis, gout, and tension headaches. These and (McGettigan & Henry 2013). In fact it is well many other conditions where documented that all forms of NSAIDs are NSAIDs may be appropriate to use have one thing in common; gastrointestinal (GI), renal, hepatic, and cardiovascular effects (Hunt et al 2007). inflammatory response to an acute soft tissue injury following a specific trauma. In 1998 The American Journal of Medicine stated the following: Admittedly, there are several high quality studies supporting the use of various "Conservative calculations estimate that NSAIDs on patients post soft-tissue injuries approximately (although conflicting). There are systematic hospitalized annually for NSAID-related GI reviews supporting the use of NSAIDs for complications and at least 16,500 NSAID- back pain (Chung et al 2013, Griffin et al related deaths occur each year among 2002) and many other soft tissue injuries arthritis patients alone in the USA, 4,000 (Jones & Lamdin 2013). Then again the deaths in Great Britain and 1,650 deaths in Cochrane database concludes that there is Germany. The figures of all NSAID users insufficient and conflicting evidence to would be overwhelming, yet the scope of this support the use of NSAIDs in treating lateral problem is generally under-appreciated." elbow pain (Pattanittum et al 2013). (Singh et al 1998)





Despite the evidence, my goal is to have NSAIDs is in any way associated with the clinicians continue to question and scrutinize risk of recurrence. the use of NSAIDs on soft-tissue injuries. Sure you may think that "this Bahram Jam The million dollar question remains, could
guy is being hypocritical; in one breath he post-acute
promotes evidence-based practice and in musculoskeletal injuries actually increase
another breath he is questioning clear the risk of recurrence
medical evidence". inadequate
I will reply with, sure there are studies supporting the use of NSAIDs on soft-tissue injuries and that is precisely why health care remains unknown as the providers support their use, however the studies look at the short-term symptomatic involving rats and rabbits, recovery; what they fail to do is look at the
give conflicting results. However, in this long-term effects and recurrence rates
biased paper I shall summarize a number of with and without NSAIDs. At the expense of studies concluding that NSAIDs significantly faster recovery, what effects do NSAIDs reduce the quality and strength of bones and have on the actual quality of the bone, soft-tissues during healing. tendon, ligament or muscle repair? Based on 65 clinical trials, (Warden et al 2006) 60 rats received a controlled clearly supports the use of incision of their knee NSAIDs for patients with medial collateral ligament (MCL) simulating non-specific LBP (Roelfs et an acute grade II MCL sprain. After 2 weeks al 2008), hence nearly every patient with they demonstrated that compared to the acute LBP almost instantaneously consumes control group, the rats who received NSAIDs either over the counter or prescription (celecoxib) 5 days a week had significantly
NSAIDs in order to hasten their recovery. delayed healing where the MCL could
absorb 33% less energy before tearing.
Following an acute episode of LBP, the recurrence rate within 1-year is up to 72% In a second study (Ferry et al 2007) 200 rats (Klenerman et al 1995), and there has yet to received a controlled incision on their be study investigating if the use of NSAIDs patellar tendons at the inferior pole of the is in any way associated with the risk of randomized into 7 groups where they received one of the following analgesics for 2 weeks: ibuprofen, acetaminophen, naproxen, supported the use of piroxicam, celecoxib, valdecoxib, or control. post acute ankle sprain At 2 weeks, all the animals were sacrificed, (Slatyer et al 1997) yet ankle sprain recurrence within 1-year is up to 33% (Hupperets et al 2009). Again, there has demonstrated that the tendon strength in the
yet to be study investigating if the use of control group (no meds) was significantly



stronger and had greater maximum load
biomechanical strength of their repaired
compared with the celecoxib, valdecoxib, rotator cuff tendon when compared to the
and piroxicam groups. placebo group (Chechik et al 2014). Here is a summary quote from the paper, Enough rat studies, let's take a look at this study (Cohen et al 2006) where 180 rabbits "Anti-inflammatory
with
the
received rotator cuff exception of ibuprofen, had a detrimental
effect on healing strength at the bone-
tendon junction" and "Acetaminophen had
no effect on healing strength." (Ferry et al
placebo or one of two NSAIDs (celecoxib or indomethacin) for 2 To continue, here is the third rat study weeks post-op. The animals were then (Dimmens et al 2009) where the Achilles sacrificed after 2, 4 and 8 weeks and their tendons of 60 rats were not only cut, but a 3 rotator cuff tendons were biomechanically mm segment of the tendon was fully cut out and histologically analyzed. There were and left unrepaired. Post-injury, the rats were significantly lower rotator cuff failure
given one of two NSAIDs (parecoxib or loads in the rabbits who received the
indomethacin) or placebo for one week. After NSAIDs and in fact 5 of the tendons in the
2 weeks when the rats were sacrificed, they NSAID group completely failed to heal found that those who received NSAIDs had
whereas all the tendons in the control group impaired tendon healing and had
Collagen
significantly lower Achilles tendon tensile
maturation was significantly poorer in the
strength when compared to the control
NSAID group at 4 and at 8 weeks post-op.
group. Relative to the control group, the Here is a quote from the paper published in diameter of the tendons were reduced in
the American Journal of Sports Medicine, both NSAID groups.

".nonsteroidal anti-inflammatory drugs
significantly

healing. If the results of this study are
verified in a larger animal model, the
common practice of administering non-
steroidal anti-inflammatory drugs after
rotator cuff repair should be reconsidered."
(Cohen et al 2006)
Despite all the above-mentioned animal
studies, the most recent literature review on
this topic concludes that there is insufficient
evidence to support that NSAIDs may have a In the most recent and fourth study, once detrimental effect on soft-tissue healing; again rats received surgical rotator cuff however there is clear evidence that some repairs. They showed that those given NSAIDs have an inhibitory effect on bone NSAIDs (meloxicam) between 11-20 days healing (Chen & Dragoo 2013). after post-op had significantly reduced
Here a sample study (O'Connor et al 2009) As typically observed in human studies, where 67 rabbits received fibula osteotomies within one week post injury, those who and were then allocated to receive either received NSAIDs had more functional placebo medications or NSAIDs (iboprofin recovery however after 4 weeks the NSAID or rofecoxib). After 6 weeks the rabbits were group had a greater deficit in their muscular sacrificed and they clearly demonstrated that force generation when compared to the compared to the placebo untreated controls. received
This study demonstrated that although NSAIDs had significantly
NSAIDs provided short-term improvements higher percentage of non-
in the initial week following the injury, after 4 weeks the rabbits treated with NSAIDs had torsional
mechanical
significantly decreased torque and tension strength.
production of their effected muscles. Once again, this study concluded that a brief
And to quote the paper published in The course of NSAIDs did provide short-term
Journal of the American Academy of benefit but it was a decrement in long-
Orthopaedic Surgeon, term muscle function.
"When fracture healing or spine fusion is
Here is a direct quote from the above- desired, nonsteroidal anti-inflammatory
mentioned paper published in The Journal of drugs should be avoided." (Dahners et al
Bone and Joint Surgery, "By suppressing the initial inflammatory
Here is the only experimental study I could reaction, the NSAID permits improved
find on the effects of NSAIDs on muscle performance in early time-periods but
healing (Mishra et al 1995). This time rabbit appears to suppress the stimulus that may
be needed for cellular remodeling in longer
experimentally induced eccentric contraction muscle injuries, simulating an eccentric overload injury of the hamstrings or A review paper (Ziltener et al 2010) gastrocnemius muscle that frequently occurs published in the Annals of Physical and in athletes (e.g. sprinters). Rehabilitation Medicine written by sports medicine physicians states, Following the induced muscle injury, half the rabbits received NSAIDs (iboprofin) two "We do not recommend their use (NSAIDs)
times a day for six days and the other half for muscle injuries".
served as the control (natural healing). The rabbits' muscles were histologically and Considering all the aforementioned studies structurally analyzed at one week and 4 and review papers one may question why weeks post injury. there is still controversy over the use of NSAIDs on soft-tissue injuries. Simple: animal studies hold limited value in medicine and human trials have not yet demonstrated the same adverse effects on tissue healing as the speculation has not yet been researched. As one can appreciate, due to obvious ethical reasons experimentally induced injuries followed by in vivo histological examination of the injured muscle, tendon, or ligament is not possible. However, the one human study that is worth mentioning here involved 364 Australian army sustained ankle sprains Anterior Drawer Test (Ankle): With the tibia
(Slatyer et al 1997). and fibula stabilized, the talus is drawn forward and the degree of laxity is noted and compared to the contra-lateral side. injury the recruits were randomized to receive on day 1, 3, 7 and 14. Initially following the either NSAIDs (piroxicam) or placebo. Not ankle sprains the patients in both groups surprisingly they clearly demonstrated that (NSAID and placebo) had similar ankle those who took the NSAIDs experienced laxity using the anterior drawer test. significantly less pain, more rapid functional However at day 3, 7 and 14 the patients
endurance. The mean number of military treated with NSAIDs had significantly
training days lost was 2.7 from the NSAID greater ankle instability than the placebo
group and 8.5 from the placebo groups, group. After 3 days, 74% of the patients which proved NSAIDs to be a cost-effective given placebo had a reversal of their ankle instability test where their anterior drawer test became negative, compared to 28% of If you simply finish reading the paper based those taking NSAIDs demonstrated the same on these facts then case closed, a physician is reversal. After 14 days, the reversal of the perfectly justified in prescribing NSAIDs for anterior drawer test was seen in 97% of the a patient with an ankle sprain and the injured patients given placebo compared to 78% of athlete would be crazy not to take NSAIDs those taking NSAIDs. considering it clearly reduces pain and improves function. The study then boldly Compared to the placebo group, the patients concludes that, NSAIDs should form an given NSAIDs had significantly less ROM
integral part in the management of acute ankle sprains. (Note: Study funded by Pfizer Pty Lt)
inversion at 7 and 14 days. Ironically those
treated with NSAIDs subjectively reported
Let's hold on here though. Could the short- greater swelling at 7 days, 14 days, 3
term decreases in pain and improvements in months and 6 months post injury. function with NSAIDs be at the expense of the injured soft-tissue in the long-term? Interestingly there were no differences between the placebo and NSAID group emphasize the ankle instability and range of with respect to recovery motion (ROM) findings that were measured from ankle bruising. Although the study reports that the recurrence rate was 25% within the 6 months of the study, regrettably they did not analyze the difference in recurrence between the two groups. It is hypothesized that since the patients in the NSAID group had reduced pain, they may have resumed activity prematurely thereby explaining the increased swelling, loss of mobility and greater ligamentous laxity. movement(s) in the right direction(s) performed at the optimum intensity and Here is a quote from another paper pushed in frequency may be potentially more effective The Open Rehabilitation Journal; in both short and long-term in individuals post acute soft-tissue injuries. "…NSAIDs are no longer recommended for
chronic soft-tissue (ligament) injuries, and
The follow-up to this paper will review the their use is cautioned in athletes who have
evidences supporting physical therapists / ligament injuries." (Hauser et al 2013)
physiotherapists as the ideal health care providers with the ability to effectively "In the case of acute ligament injuries,
evaluate and efficiently prescribe the NSAIDs should be used for the shortest
optimum daily exercise / movement program time possible, if used at all" (Hauser et al
musculoskeletal injuries. I will make a confession that this has been a very biased paper where I have selectively References:
presented the studies that show the potential 1. Chechik O1, Dolkart O, Mozes G, Rak O, Alhajajra F, negative side of NSAID usage. However, Maman E. Timing matters: NSAIDs interfere with the late proliferation stage of a repaired rotator cuff tendon from an unbiased view, thus far there is still healing in rats. Arch Orthop Trauma Surg. 2014 Apr;134(4):515-20. completely dismiss the use of NSAIDs to 2. Chen MR1, Dragoo JL. The effect of nonsteroidal anti- treat acute soft-tissue injuries. inflammatory drugs on tissue healing. Knee Surg Sports Traumatol Arthrosc. 2013 Mar;21(3):540-9. In conclusion, considering the undeniable 3. Chung JW1, Zeng Y, Wong TK. Drug therapy for the cardiovascular and GI risks in the use of treatment of chronic nonspecific low back pain: systematic review and meta-analysis. Pain Physician. NSAIDs, and taking into account the 2013 Nov-Dec;16(6):E685-704. potential hindrance to tissue recovery, we 4. Cohen DB1, Kawamura S, Ehteshami JR, Rodeo SA. must continue to question the ever growing Indomethacin and celecoxib impair rotator cuff tendon- use of NSAIDs in those post acute soft-tissue to-bone healing. Am J Sports Med. 2006 Mar;34(3):362-9. 5. Dahners LE1, Mullis BH. Effects of nonsteroidal anti- inflammatory drugs on bone formation and soft-tissue On a more positive note, there is mounting healing. J Am Acad Orthop Surg. 2004 May- evidence that EXERCISE and PHYSICAL Jun;12(3):139-43. ACTIVITY have anti-inflammatory benefits. 6. Dimmen S1, Engebretsen L, Nordsletten L, Madsen JE. Therefore instead of immediately reaching Negative effects of parecoxib and indomethacin on for the NSAID bottle, perhaps the correct tendon healing: an experimental study in rats. Knee Surg Sports Traumatol Arthrosc. 2009 Jul;17(7):835-9. 7. Ferry ST, Dahners LE, Afshari HM, Weinhold PS. The low back pain. Cochrane Database Syst Rev. 2008 Jan effects of common anti-inflammatory drugs on the healing rat patellar tendon. Am J Sports Med. 2007 20. Singh Gurkirpal, MD, "Recent Considerations in Aug;35(8):1326-33. Nonsteroidal Anti-Inflammatory Drug Gastropathy", 8. Griffin G1, Tudiver F, Grant WD. Do NSAIDs help in The American Journal of Medicine, July 27, 1998, p. acute or chronic low back pain? Am Fam Physician. 2002 Apr 1;65(7):1319-21. 21. Slatyer MA1, Hensley MJ, Lopert R. A randomized 9. Hauser RA, E.E. Dolan, H.J. Phillips, A.C. Newlin, R.E. controlled trial of piroxicam in the management of acute Moore and B.A. Bentham Ligament Injury and Healing: ankle sprain in Australian Regular Army recruits. The A Review of Current Clinical Diagnostics and Kapooka Ankle Sprain Study. Am J Sports Med. 1997 Therapeutics The Open Rehabilitation Journal, 2013, 6, Jul-Aug;25(4):544-53. 22. Warden SJ1, Avin KG, Beck EM, DeWolf ME, 10. Hunt RH1, Choquette D, Craig BN, De Angelis C, Hagemeier MA, Martin KM. Low-intensity pulsed Habal F, Fulthorpe G, Stewart JI, Turpie AG, Davis P. ultrasound accelerates and a nonsteroidal anti- inflammatory drug delays knee ligament healing. Am J cyclooxygenase-2 Sports Med. 2006 Jul;34(7):1094-102. traditional NSAIDs? Can Fam Physician. 2007 23. Wolfe M. MD, Lichtenstein D. MD, and Singh Jul;53(7):1177-84. "Gastrointestinal 11. Hupperets MD1, Verhagen EA, van Mechelen W. Effect Nonsteroidal Anti-inflammatory Drugs", The New of unsupervised home based proprioceptive training on England Journal of Medicine, June 17, 1999, Vol. 340, recurrences of ankle sprain: randomised controlled trial. No. 24, pp. 1888-1889. BMJ. 2009 Jul 9;339:b2684. 24. Ziltener JL1, Leal S, Fournier PE.Non-steroidal anti- 12. Jones P1, Lamdin R. Oral cyclo-oxygenase 2 inhibitors inflammatory drugs for athletes: an update. Ann Phys versus other oral analgesics for acute soft tissue injury: Rehabil Med. 2010 May;53(4):278-82, 282-8. systematic review and meta-analysis. Clin Drug Investig. 2010;30(7):419-37. 13. Klenerman L, et al The prediction of chronicity in patients with an acute attack of low back pain in a general practice setting. Spine. 1995 Feb 15;20(4):478-84. 14. McGettigan P1, Henry D. Use of non-steroidal anti- inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 2013;10(2):e1001388. 15. Mishra DK1, Fridén J, Schmitz MC, Lieber RL. Anti- inflammatory medication after muscle injury. A treatment resulting in short-term improvement but subsequent loss of muscle function. J Bone Joint Surg Am. 1995 Oct;77(10):1510-9. 16. O'Connor JP1, Capo JT, Tan V, Cottrell JA, Manigrasso MB, Bontempo N, Parsons JR. A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing. Acta Orthop. 2009 Oct;80(5):597-605. 17. Pattanittum P1, Turner T, Green S, Buchbinder R. Non- steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults. Cochrane Database Syst Rev. 2013 May 31;5: 18. Pattanittum P1, Turner T, Green S, Buchbinder R. Non- steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults. Cochrane Database Syst Rev. 2013 May 31;5:CD003686. 19. Roelofs PD1, Deyo RA, Koes BW, Scholten RJ, van Study summaries are available on www.aptei.com "Clinical Library" accessible by APTEI Report subscribers Tulder MW. Non-steroidal anti-inflammatory drugs for To request a copy of this article simply email jam@aptei.com

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