Do NSAIDs prevent bone healing?
To give [NSAIDs] or not to give [NSAIDs]; that is the question!
Pain related to orthopedic surgery, dental extractions, or any injury that involves connective tissue is caused in large part by inflammation which occurs because of prostaglandin release into the surrounding tissues. Non-steroidal Anti-inflammatory Drugs (NSAIDs) block these prostaglandins and therefore should be a mainstay of pain treatment alone or perhaps combined with other agents such as opioids as long as there are no medical contraindications. Or should they? Certainly some patients could benefit from the combined use of NSAIDs plus opioids – this should presumably have been true for a case such as the well-publicized basketball injury endured last year by Louisville athlete Keven Ware. But, there has been much unsubstantiated controversy over whether or not NSAIDs are beneficial or detrimental in cases involving bone healing.
Before delving into the facts regarding NSAID use post-orthopedic surgery, other very important issues lay the foundation on which the NSAID arguments are built.
According to a DEA Resource for Parents updated in 2012 Prescription for Disaster – How Teens Abuse Medicine, “Enough prescription painkillers were prescribed in 2010 to medicate every American adult around-the-clock for a month. Although most of these pills were prescribed for medical purposes, many ended up in the hands of people who misused or abused them.” (CDC Vital Signs, Nov. 2011) We know that 70% of youth get their prescription drugs from family and friends, yet fewer parents report safeguarding prescription medications. “Anyone can access prescription medicines in the medicine cabinet” went from 50% in 2010 to 64% in 2011, meaning medications are available to anyone in their homes.
Aside from these facts, this 2014 article in The New Republic: “Drug Dealers Aren’t to Blame for the Heroin Boom. Doctors Are”, Graeme Wood criticizes his dentist for prescribing hydrocodone to relieve pain after his wisdom tooth extraction.
Adding insult to injury, some believe that Medicare’s patient satisfaction surveys may significantly impact opioid abuse. I for one was mortified last year when asked to lecture to a large healthcare system in the Northeast. While teaching on general concepts of acute and chronic pain management, I learned that patients frequently were admitted through the emergency department for 2-3 days at a time pretty much to receive intravenous hydromorphone (aka Dilaudid) for unidentified pain. And yes, they got the drug even with a clear history of substance abuse. Why? Because the reimbursement model is based on their pain scores – and that may have been more important to the institution than doing the right thing medically. But what the heck, right – it was only a few days of hydromorphone; no harm, no foul, the hospital system looks good, and the reimbursement is elevated.
Here to present the facts regarding NSAID therapy is guest blogger Dr. Vaishali Shah, a PGY2 Pharmacy Resident practicing at the Stratton VA Medical Center in Albany NY. Here’s what she had to say…
There is a controversy on whether or not to treat with NSAIDS after orthopedic surgery, as various animal studies have found NSAIDs to delay bone healing. However this polemic stirs up significant angst and sometimes indifference among the surgeons who spend limited time addressing pain issues post-operatively unless there are pain-related surgical complications such as infection.
NSAIDs delay bone healing through their inhibition of prostaglandins. Cyclooxyygenase (COX) converts arachidonic acid into prostaglandin G2, and then prostaglandin H2. Prostaglandin H2 is the precursor to active prostaglandins and thromboxane. COX1 is expressed in most cells and is involved in physiological processes such as reducing acid secretion in the gastrointestinal tract and regulating blood flow in the kidneys. COX2 activation is results in pain, inflammation and fever. Selective blockade of COX2 therefore plays a critical role in reducing or preventing the inflammatory process following orthopedic surgery. But, many studies have also found that COX1, and especially COX2, also play an essential role in bone formation, bone union, and resorption following a fracture.
I was asked to address some seemingly very simple questions. I quickly found out that they weren’t so simple after all and the absence of evidence was astonishing and perhaps even unjustifiable.
Initial queries included:
- For what period of time after surgery do NSAIDs delay bone healing?
- After discontinuation of the NSAID, does time eventually make up for the delayed bone healing, and if so, are there adverse consequences?
- Are the diminished bone-fusion effects (if valid) reversible without adverse consequences once the NSAID is discontinued?
After an extensive literature search, I was unable to find compelling evidence to unequivocally answer these dilemmas, but new questions surfaced.
Does the avoidance of NSAIDs have potential for elevating intolerable pain that could otherwise be kept at bay? And, could this uncontrolled pain following a bone fracture or orthopedic surgery lead to complications, such as the development of complex regional pain syndrome (CRPS), a chronic pain disorder that is extremely difficult to treat?
Complex regional pain syndrome is a chronic systemic disorder characterized by pain in combination with sensory, autonomic, trophic, and motor abnormalities. The exact pathophysiology of this disease state is not understood and therefore treatment of this syndrome is difficult. Patients with CRPS have chronic pain which in many cases can lead to disability. Many studies have found fractures and post-operative pain as risk factors for the development of CRPS. A population based study by Sandroni et al, found that previous fractures was the most common trigger for CRPS in 46% (34 out of 74 cases) of identified patients with CRPS. This study estimated an incidence rate of CRPS as 5.46/100 000/year. De Mos et al, found the overall incidence rate of CRPS was 26.2 per 100,000 person years and that a previous fracture was the most common precipitating event occurring in 44% of identified patients. Furthermore, a study published last year by Moseley, et al found a correlation between the level of pain post-fracture and the development of CRPS. They concluded that having a pain score of >5 on a scale of 1-10, as early as one week after wrist fracture puts the patient at a higher risk for development of CRPS. While the data is lacking on which fractures or surgeries most commonly increase the risk for developing CRPS, the most common ones seen through a literature search included fractures of the distal radius and post total knee arthroplasty, after fasciectomy for Dupuytren contracture, and after carpal tunnel surgery.
Through my extensive literature research I found that the effects of NSAIDS on bone healing were undoubtedly inconclusive. There have been no randomized controlled trials on the effects of NSAIDs on post-operative healing in humans. Every randomized controlled trial to date is an animal study which includes rats, mice, rabbits, goats, and even one trial on dogs. Animal data cannot necessarily be extrapolated to humans. The majority of trials reviewed studied fracture healing in the short-term. Many trials looked at fracture healing as early as 21 days post-surgery and at latest, 12 weeks post-surgery. Even though the healing time of a fracture in animals may differ compared to humans, normally it takes months for a fracture to completely heal. Therefore the short-term effect of NSAIDs on overall fracture healing in the long-term is unclear even in animal studies. While NSAIDs may or may not delay healing of fractures, if the fracture completely heals within a reasonable time period, does it matter how long it takes if there is a significantly lower risk of developing complications (i.e. CRPS, depression, anxiety, opioid-dependence) post-surgery? In my mind this is quite puzzling.
Orthopedists today generally hesitate to treat post-operative pain with the COX2 selective NSAID celecoxib (Celebrex). This is likely due to the retraction of several studies by Dr. Scott Reuben supporting the use of COX2 selective NSAIDs in the management of post-operative pain. Dr. Reuben, the former Chief of acute pain services at Baystate Medical Center in Springfield, MA, published various randomized controlled trials from 1996 to 2008 on the use of COX-2 specific drugs celecoxib, rofecoxib, and valdecoxib either pre-operatively, intra-operatively, or post-operatively. Due to his positive findings, many physicians began routinely prescribing COX2 selective NSAIDs for the management of post-operative pain. However in 2010, it was found that Dr. Reuben fabricated the data in at least 21 of his articles. In essence, according to Scientific American, over the course of 12 years, “anesthesiologist Scott Reuben revolutionized the way physicians provide[d] pain relief to patients undergoing orthopedic surgery for everything from torn ligaments to worn-out hips. Now, the profession is in shambles after an investigation revealed that at least 21 of Reuben’s papers were pure fiction, and that the pain drugs he touted in them may have slowed postoperative healing.” After this, orthopedists began to question the validity behind prescribing NSAIDs for post-operative pain.
Interestingly enough, I found many animal studies which compared the effects of COX2 selective NSAIDs with non-selective NSAIDs in delaying fracture healing. While some studies concluded COX2 selective NSAIDs delayed fracture healing more than their non-selective NSAID counterparts (such as ibuprofen or naproxen), many other studies found the opposite to be true. COX2 selective NSAIDs include celecoxib (Celebrex), rofecoxib (Vioxx, taken off market), and valdecoxib (Bextra, taken off market). Etodolac (Lodine) too is very COX2 selective however has never been marketed as such. Click here to see Cox-2 specificity by drug.
Conclusions of my literature review matched that of many other review articles and expert opinion articles published on the topic. These articles emphasized the contradictory nature of the topic and the need for large randomized clinical trials in humans. A summary of all the literature reviewed appears below for your reference. Perioperative NSAID use for orthopedic surgery is surely a ripe area for study!
Vaishali Shah is a PGY-1 Pharmacy resident at the Stratton VA Medical Center in Albany, NY. She completed her Doctor of Pharmacy degree at the University of Florida, College of Pharmacy. Over the past few years, she has taken a special interest in the area of ambulatory care and hopes to become a board-certified ambulatory care pharmacist. In her free time she enjoys cooking, spending time with family, and traveling.
Animal studies investigating the effects of prostaglandins on bone healing:
- Jee WS, Ueno K, Deng YP, et al. The effects of prostaglandin E2 in growing rats: increased metaphyseal hard tissue and cortico-endosteal bone formation. Calcif Tissue Int. 1985;37(2):148-57.
- Lin CH, Jee WS, Ma YF, et al. Early effects of prostaglandin E2 on bone formation and resorption in different bone sites of rats. Bone. 1995;17(4 Suppl):255S-259S.
- Machwate M, Harada S, Leu CT et al. Prostaglandin receptor EP(4) mediates the bone anabolic effects of PGE(2). Mol Pharmacol. 2001;60(1):36-41.
- Nefussi JR, Baron R. PGE2 stimulates both resorption and formation of bone in vitro: differential responses of the periosteum and the endosteum in fetal rat long bone cultures. Anat Rec. 1985;211(1):9-16.
- Pillbeam CC, Fall PM, Alander CB, et al. Differential effects of nonsteroidal anti-inflammatory drugs on constitutive and inducible prostaglandin G/H synthase in cultured bone cells. J Bone Miner Res. 1997;12(8):1198-203.
- Suponitzky I, Weinreb M. Differential effects of systemic prostaglandin E2 on bone mass in rat long bones and calvariae. J Endocrinol. 1998;156(1):51-7.
- Zhang X, Schwarz EM, Young DA, et al. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest. 2002;109(11):1405-15.
Animal studies concluding NSAIDs impair bone healing:
- Allen HL, Wase A, Bear WT. Indomethacin and aspirin: effect of nonsteroidal anti-inflammatory agents on the rate of fracture repair in the rat. Acta Orthop Scand. 1980;51(4):595-600.
- Altman RD, Latta LL, Keer R, et al. Effect of nonsteroidal antiinﬂammatory drugs on fracture healing: a laboratory study in rats. J Orthop Trauma 1995;9(5): 392-400.
- Beck A, Krischak G, Sorg T, et al. Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing. Arch Orthop Trauma Surg. 2003;123(7):327-32.
- Bergenstock M, Min W, Simon AM, et al. A comparison between the effects of acetaminophen and celecoxib on bone fracture healing in rats. J Orthop Trauma. 2005;19(10):717-23.
- Dimar JK, Ante WA, Zhang YP, et al. The effects of nonsteroidal anti-inflammatory drugs on posterior spinal fusions in the rat. Spine. 1996;21(16):1870-6.
- Endo K, Sairyo K, Komatsubara S, et al. Cyclooxygenase-2 inhibitor delays fracture healing in rats. Acta Orthop. 2005;76(4):470-4.
- Endo K, Sairyo K, Komatsubara S, et al. Cyclooxygenase-2 inhibitor inhibits the fracture healing. J Physiol Anthropol Appl Human Sci. 2002;21(5):235-8.
- Engesaeter LB, Sudmann B, Sudmann E, et al. Fracture healing in rats inhibited by locally administered Acta Orthop Scand. 1992;63(3):330-3.
- Gerstenfeld LC, Thiede M, Siebert K, et al. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res. 2003;21(4):670-5.
- Giordano V, Giordano M, Knackfuss I, et al. Effect of tenoxicam on fracture healing in rat tibiae. Injury. 2003;34(2):85-94.
- Goodman S, Ma T, Trindade M, et al. COX-2 selective NSAID decreases bone ingrowth in vivo. J Orthop Res. 2002;20(6):1164-9.
- Ho ML, Chang JK, Wang GJ. Effects of ketorolac on bone repair: a radiographic study in modeled demineralized bone matrix grafted rabbits. Pharmacology. 1998;57(3):148-59.
- Hogevold HE, Grogaard B, Reikeras O, et al. Effects of short-term treatment with corticosteroids and indomethacin on bone healing. A mechanical study of osteotomies in rats. Acta Orthop Scand. 1992;63(6):607-11.
- Kaygusuz, Turan CC, Aydin NE, et al. The effects of G-CSF and naproxen sodium on the serum TGF-β1 level and fracture healing in rat tibias. Life Sciences. 2006;80(1):67-73.
- Keller J, Bayer-Kristensen I, Bak B, et al. Indomethacin and bone remodeling. Effect on cortical bone after osteotomy in rabbits. Acta Orthop Scand. 1989 Feb;60(1):119-21.
- Keller J, Bunger C, Andreassen TT, et al. Bone repair inhibited by indomethacin. Effects on bone metabolism and strength of rabbit osteotomies. Acta Orthop Scand. 1987;58(4):379-83.
- Krischak G, Augat P, Sorg T, et al. Effects of diclofenac on periosteal callus maturation in osteotomy healing in an animal model. Arch Orthop Trauma Surg. 2007;127(1):3-9.
- Leonelli SM, Goldberg BA, Safanda J, et al. Effects of a cyclooxygenase-2 inhibitor (rofecoxib) on bone healing. Am J Orthop (Belle Mead NJ). 2006;35(2):79-84.
- Li KH, Cheng L, Zhu Y, et al. Effects of a selective cyclooxygenase-2 inhibitor (celecoxib) on fracture healing in rats. Indian J Orthop. 2013 Jul;47(4):395-401
- Martin, GJ, Boden SD, Titus L. Recombinant human bone morphogenetic protein-2 overcomes the inhibitory effect of ketorolac, a nonsteroidal anti-inflammatory drug (NSAID), on posterolateral lumbar intertransverse process spine fusion. Spine. 1999;24(21):2188-2193.
- Martins MV, da Silva MA, Medici Filho E, et al. Evaluation of digital optical density of bone repair in rats medicated with ketoprofen. Braz Dent J. 2005;16(3):207-12.
- Murnaghan M, Li G, Marsh DR. Nonsteroidal anti-inflammatory drug-induced fracture nonunion: an inhibition of angiogenesis? J Bone Joint Surg Am. 2006;88 Suppl 3:140-7.
- Obeid G, Zhang X, Wang X, et al. Effect of ibuprofen on the healing and remodeling of bone and articular cartilage in the rabbit temporomandibular joint. J Oral Maxillofac Surg. 1992;50(8):843-9; discussion 849-50.
- O’Connor JP, Capo JT, Tan V, et al. A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing. Acta Orthop. 2009;80(5):597-605
- Reikerass O, Engebretsen L. Effects of ketorolac tromethamine and indomethacin on primary and secondary bone healing. An experimental study in rats. Arch Orthop Trauma Surg. 1998;118(1-2):50-2.
- Ribeiro FV, Cesar-Neto JB, Nociti FH Jr, et al. Selective cyclooxygenase-2 inhibitor may impair bone healing around titanium implants in rats. J Periodontol. 2006;77(10):1731-5.
- Riew KD, Long J, Rhee J, et al. Time-dependent inhibitory effects of indomethacin on spinal fusion. J Bone Joint Surg Am. 2003;85-A(4):632-4.
- Sato S, Kim T, Arai T, et al. Comparison between the effects of dexamethasone and indomethacin on bone wound healing. Jpn J Pharmacol. 1986;42(1):71-8.
- Simon AM, O’Connor JP. Dose and time-dependent effects of cyclooxygenase-2 inhibition on fracture-healing. J Bone Joint Surg Am. 2007;89(3):500-11.
- Torkvist H, Lindholm TS, Netz P, et al. Effect of ibuprofen and indomethacin on bone metabolism reflected in bone strength. Clin Orthop Relat Res. 1984;(187):255-9.
Animal studies concluding NSAIDs have no effect on bone healing or in short term have no effect on bone healing:
- Boiskin I, Epstein S, Ismail F, et al. Long term administration of prostaglandin inhibitors in vivo fail to influence cartilage and bone mineral metabolism in the rat. Bone Miner. 1988;4(1):27-36.
- Brown KM, Saunders MM, Kirsch T, et al. Effect of COX-2-specific inhibition on fracture healing in the rat femur. J Bone Joint Surg Am. 2004;86-A(1):116-23.
- Elves MW, Bayley I, Roylance PJ. The effect of Indomethacin upon experimental fractures in the rat. Acta Orthop Scand. 1982;53(1):35-41.
- Fracon RN, Teofilo JM, Moris LC, et al. Treatment with paracetamol, ketorolac or etoricoxib did not hinder alveolar bone healing: a histometric study in rats. J Appl Oral Sci. 2010;18(6):630-4.
- Gerstenfeld LC, Al-Ghawas, Alkhiary YM, et al. Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing: reversibility of effects after short-term treatment. J Bone Joint Surg Am. 2007;89(1):114-25.
- Goodman SB, Ma T, Mitsunaga L, et al. Temporal effects of a COX-2-selective NSAID on bone ingrowth. J Biomed Mater Res A. 2005;72(3):279-87.
- Hak DJ, Schulz KS, Khoie B, et al. The effect of Cox-2 specific inhibition on direct fracture healing in the rabbit tibia. J Orthop Sci. 2011;16(1):93-8
- Huo MH, Troiano NW, Pelker RR, et al. The influence of Ibuprofen on fracture repair: biomechanical, biochemical, histologic, and histomorphometric parameters in rats. J Orthop Res. 1990;9(3):383-90.
- Karachalios T, Boursinos L, Poultsides L, et al. The effects of the short-term administration of low therapeutic doses of anti-COX-2 agents on the healing of fractures: an experimental study in rabbits. J Bone Joint Surg Br. 2007;89(9):1253-60.
- Keller J, Kjaersgaard-Andersen P, Bayer-Kristensen I, et al. Indomethacin and bone trauma. Effects on remodelling of rabbit bone. Acta Orthop Scand. 1990;61(1):66-9.
- Long J, Lewis S, Kuklo T, et al. The effect of cyclooxygenase-2 inhibitors on spinal fusion. J Bone Joint Surg Am. 2002;84-A(10):1763-8.
- Mbugua SW, Skoglund LA, Lokken P, et al. Effects of phenylbutazone and indomethacin on the post-operative course following experimental orthopaedic surgery in dogs. Acta Vet Scand. 1989;30(1):27-35.
- Mullis BH, Copland ST, Weinhold PS, et al. Effect of COX-2 inhibitors and non-steroidal anti inflammatory drugs on a mouse fracture model. 2006;37(9):827-37.
- Reikerass O, Engebretsen L. Effects of ketorolac tromethamine and indomethacin on primary and secondary bone healing. An experimental study in rats. Arch Orthop Trauma Surg. 1998;118(1-2):50-2.
- Sudmann E, Tveita T, Hald J Jr. Lack of effect of indomethacin on ordered growth of the femur in rats. Acta Orthop Scand. 1982;53(1):43-9.
- Tiseo BC, Namur GN, de Paula EJ, et al. Experimental study of the action of COX-2 selective nonsteroidal anti-inflammatory drugs and traditional anti-inflammatory drugs in bone regeneration. Clinics (Sao Paulo). 2006;61(3):223-30.
- Tornkvist, Lindholm TS. Effect of ibuprofen on mass and composition of fracture callus and bone. An experimental study on adult rat. Scand J Rheumatol. 1980;9(3):167-71.
- Urrutia, J. Mardones R, Quezada F, et al. The effect of ketoprophen on lumbar spinal fusion healing in a rabbit model. Laboratory investigation. J Neurosurg Spine. 2007;7(6):631-6.
- Utvag SE, Fuskev OM, Shegarfi H, et al. Short-term treatment with COX-2 inhibitors does not impair fracture healing. J Invest Surg. 2010;23(5):257-61.
- vanderHeide JK, Hannik G, Buma P, et al. No effect of ketoprofen and meloxicam on bone graft ingrowth: a bone chamber study in goats. Acta Orthop. 2008;79(4):548-54.
Review Articles/Expert Opinion on the effects of NSAIDs on bone healing:
- Gerstenfeld LC, Einhorn TA. COX inhibitors and their effects on bone healing. Expert Opin. Drug Saf. 2004;3(2):131-136.
- Pountos I, Georgouli T, Calori GM, et al. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. ScientificWorldJournal. 2012;2012:606404.
- Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process.Basic Clin Pharmacol Toxicol. 2008;102(1):10-4.
CRPS and Fractures:
- de Mos M, de Bruijn AG, Huygen FJ,et al. The incidence of complex regional pain syndrome: A population-based study. Pain 2007;129:12–20.
- Moseley GL, Herbert RD, Parsons T, et al. Intense pain soon after wrist fracture strongly predicts who will develop complex regional pain syndrome: prospective cohort study. J Pain. 2014;15(1):16-23
- Sandroni P, Benrud-Larson LM, McClelland RL, et al. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003;103:199–207.
The List of Studies by Scott S. Reuben, MD, That Have Been or Likely Will Be Recalled relating to use of NSAIDs post-surgery
- Reuben SS, Connelly NR. Postarthroscopic meniscus repair analgesia with intraarticular ketorolac or morphine. Anesth Analg 1996;82:1036-1039.
- Reuben SS, Connelly NR, Maciolek H. Postoperative analgesia with controlled-release oxycodone for outpatient anterior cruciate ligament surgery. Anesth Analg 1999;88:1286-1291.
- Reuben SS, Connelly NR. Postoperative analgesic effects of celecoxib or rofecoxib after spinal fusion surgery. Anesth Analg 2000;91:1221-1225.
- Reuben S. The effect of intraoperative valdecoxib administration on PGE2 levels in the CSF. J Pain 6(suppl 1):S21. Abstract 649.
- Reuben SS, Ekman EF. The effect of cyclooxygenase-2 inhibition on analgesia and spinal fusion. J Bone Joint Surg Am 2005;87:536-542
- Reuben SS, Pristas R, Dixon D, Faruqi S, Madabhushi L, Wenner S. The incidence of complex regional pain syndrome after fasciectomy for Dupuytren’s contracture: a prospective observational study of four anesthetic techniques. Anesth Analg 2006;102:499-503.
- Reuben SS, Buvanendran A, Kroin JS, Raghunathan K. The analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesth Analg 2006;103:1271-1277.
- Reuben SS, Buvanendran A, Kroin JS, Raghunathan K. Analgesic efficacy of celecoxib, pregabalin, and their combination for spinal fusion surgery. Anesthesiology 2006;105:A1194.
- Reuben SS, Buvanendran A, Kroin JS, Steinberg RB. Postoperative modulation of central nervous system prostaglandin E2 by cyclooxygenase inhibitors after vascular surgery. Anesthesiology 2006;104:411-416.
- Reuben SS, Ekman EF, Raghunathan K, Steinberg RB, Blinder JL, Adesioye J. The effect of cyclooxygenase-2 inhibition on acute and chronic donor-site pain after spinal-fusion surgery. Reg Anesth Pain Med 2006;31:6-13.
- Reuben SS, Ekman EF, Charron D. Evaluating the analgesic efficacy of administering celecoxib as a component of multimodal analgesia for outpatient anterior cruciate ligament reconstruction surgery. Anesth Analg 2007;105:222-227.
- Reuben SS, Buvanendran A, Katz B, Kroin JS. A prospective randomized trial on the role of perioperative celecoxib administration for total knee arthroplasty: improving clinical outcomes. Anesth Analg 2008;106:1258-1264.