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NSAID's and Repair

Summary References Re: The Effects of NSAID on Tissue Healing

In the light of an increasing number of papers and publications that relate to the potentially inhibitory effect of non steroidal anti inflammatory drugs on musculoskeletal tissues healing and repair, a number of the key references and abstracts are presented below for consideration. The most recent section (2003 - 2006) is available as a pdf download paper from the DOWNLOAD page for your convenience

Most Recent Papers - 2003 - 2006

Cohen, D. al. (2006)
Indomethacin and celecoxib impair rotator cuff tendon-to-bone healing
Am J Sports Med 34(3): 362-9.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are commonly prescribed after rotator cuff repair. These agents can impair bone formation, but no studies have evaluated their impact on tendon-to-bone healing. HYPOTHESIS: Traditional nonselective nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific nonsteroidal anti-inflammatory drugs interfere with tendon-to-bone healing. STUDY DESIGN: Controlled laboratory study. METHODS: One hundred eighty Sprague-Dawley rats underwent acute rotator cuff repairs. Postoperatively, 60 rats received 14 days of celecoxib, a cyclooxygenase-2-specific nonsteroidal anti-inflammatory drug; 60 received indomethacin, a traditional nonselective nonsteroidal anti-inflammatory drug; and 60 received standard rat chow. Animals were sacrificed at 2, 4, and 8 weeks and evaluated by gross inspection, biomechanical testing, histologic analysis, and polarized light microscopy to quantify collagen formation and maturation. RESULTS: Five tendons completely failed to heal (4 celecoxib, 1 indomethacin). There were significantly lower failure loads in the celecoxib and indomethacin groups compared with the control groups at 2, 4, and 8 weeks (P <.001), with no significant difference between nonsteroidal anti-inflammatory drug groups. There were significant differences in collagen organization and maturation between the controls and both nonsteroidal anti-inflammatory drug groups at 4 and 8 weeks (P <.001). Controls demonstrated progressively increasing collagen organization during the course of the study (P <.001), whereas the nonsteroidal anti-inflammatory drug groups did not. CONCLUSION: Traditional and cyclooxygenase-2-specific nonsteroidal anti-inflammatory drugs significantly inhibited tendon-to-bone healing. This inhibition appears linked to cyclooxygenase-2. CLINICAL RELEVANCE: 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.

Tsai, al. (2006)
Ibuprofen inhibition of tendon cell migration and down-regulation of paxillin expression.
J Orthop Res 24(3): 551-8.

Sports-related tendon injuries are commonly treated with nonsteroidal antiinflammatory drugs. Tendon healing requires migration of tendon cells to the repair site, followed by proliferation and synthesis of the extracellular matrix. This study was designed to determine the effect of ibuprofen on the migration of tendon cells intrinsic to rat Achilles tendon. Whether a correlation exits between this effect and the expression of paxillin, which is a positive regulator of cell spreading and migration, was also investigated. The migration of tendon cells was evaluated ex vivo by counting the number of initial outgrowths from the tendon explants and in vitro by transwell filter migration assay. The spreading of tendon cells in culture was also evaluated microscopically. The mRNA and protein expressions of paxillin were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis. Dose-dependent ibuprofen inhibition was demonstrated on the migration of tendon cells both ex vivo, and in vitro. Similar inhibition was also observed on the spreading of tendon cells. Suppression of mRNA expression and protein level of paxillin was revealed by RT-PCR and Western blot analyses. The expression of focal adhesion kinase (FAK) and tyrosine phosphorylation of FAK remained unchanged. In conclusion, ibuprofen inhibits tendon cell migration in a process that is probably mediated by the down-regulation of paxillin.

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Salcido, R. S. (2005)
Do anti-inflammatories have a role in wound healing?
Adv Skin Wound Care 18(2): 65-6.

Endo, K. et al. (2005)
Cyclooxygenase-2 inhibitor delays fracture healing in rats
Acta Orthop 76(4): 470-4.

BACKGROUND: Cyclooxigenase-2 (COX-2) inhibitors have been reported to delay fracture healing. To investigate the major inhibitory period of COX-2 inhibitors in fracture healing, we administrated etodolac, a COX-2-specific inhibitor, to a rat fracture model by altering the period of administration from early to late. METHOD: After closed fractures had been created at the middle of the femoral shafts in 12-week-old Wister rats, a standardized dose of etodolac was administrated in three ways: group I received it for 3 weeks, group II for just the first week after operation, and group III for just the third (final) week. Group IV was the vehicle control group. Bone maturation was estimated by radiographic scoring system, and mechanically by a three-point bending test. RESULTS AND INTERPRETATION: In both the radiographic and mechanical studies, groups I and II showed lower scores than group IV, indicating that even a short period of administration of a COX-2-specific inhibitor in the early phase of fracture healing creates a risk of delayed healing.

Clarke, S. and F. Lecky (2005)
Best evidence topic report. Do non-steroidal anti-inflammatory drugs cause a delay in fracture healing?
Emerg Med J 22(9): 652-3.

A short cut review was carried out to establish whether there is any evidence that non-steroidal anti-inflammatory drugs (NSAIDs) might delay fracture healing. A total of 514 papers were found using the reported search, of which three represent the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these best papers are tabulated. At present, although there are theoretical concerns about the adverse effects of NSAIDs on fracture healing, there is not enough clinical evidence to deny patients with simple fractures their analgesic benefits.

Radi, Z. A. and N. K. Khan (2005)
Effects of cyclooxygenase inhibition on bone, tendon, and ligament healing 
Inflamm Res 54(9): 358-66.

Cyclooxygenases (COX-1 and COX-2) catalyze the conversion of arachidonic acid to prostaglandins (PGs). PGs play a significant role in bone metabolism in health and disease. Conventional non-selective, non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXIBs) are widely used in patients with musculoskeletal conditions and as a post-surgical analgesics. Due to their effects on PG synthesis, these drugs have been hypothesized to affect the healing process of bone fractures and orthopedic surgical sites. A variety of experimental models of bone, ligament, and tendon repair have assessed the effects of these selective and non-selective COX inhibitors in animals, but with variable outcomes. At this time, large-scale, robust clinical study data do not exist, limiting the relevant assessment of experimental animal data to humans. Here, we provide a critical review of available data on the role of PGs and the effect of COX inhibitors on bone, tendon, and ligament repair. Collectively, this assessment suggests potential involvement of PGs in the healing process of these tissues via modulation by non-selective NSAIDs and selective COX-2 inhibitors.

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Beck, al. (2005)
Nonsteroidal anti-inflammatory drugs (NSAIDs) in the perioperative phase in traumatology and orthopedics effects on bone healing
Oper Orthop Traumatol 17(6): 569-78.

OBJECTIVE: To achieve analgesic, anti-inflammatory and antipyretic effects in traumatology and orthopedic surgery without side effects or with the least possible side effects, with special emphasis on bone healing. INDICATIONS: Acute and chronic inflammatory conditions, e. g., rheumatoid arthritis, ankylosing spondylitis. Degenerative joint disease. Posttraumatic and postoperative pain, edema, or fever. Prevention of heterotopic bone formation. CONTRAINDICATIONS: Hypersensitivity. Gastrointestinal ulceration or bleeding. Severe hepatic or renal impairment. RESULTS: Nonsteroidal anti-inflammatory drugs (NSAIDs) are invaluable in treating a variety of musculoskeletal conditions. As well as their excellent analgesic potency their anti-inflammatory effects are beneficial in treating posttraumatic and postoperative edema. In addition, NSAIDs inhibit heterotopic bone formation after hip arthroplasty. Animal studies, however, have demonstrated that they cause delayed fracture healing. Although clinical studies have not yet supplied unequivocal evidence of this effect in human subjects, the authors recommend that in the presence of other risk factors which may adversely affect fracture healing, such as smoking, diabetes mellitus or peripheral arterial occlusive disease, the indication of NSAID use for analgesia should be strictly limited. Therapeutic alternatives such as centrally acting agents (e. g., weak opioids) should be considered in these patients.

Bhattacharyya, al. (2005)
Nonsteroidal antiinflammatory drugs and nonunion of humeral shaft fractures
Arthritis Rheum 53(3): 364-7.

OBJECTIVE: To analyze the relationship between nonunion of humeral shaft fractures and nonsteroidal antiinflammatory drug (NSAID) exposure in older adults. METHODS: A cohort of 9,995 patients with humeral shaft fractures was identified using diagnosis and procedure codes from a Medicare database of >500,000 patients. Prescription NSAID as well as prescription opioid use was assessed from pharmacy claims data for 3 30-day periods immediately after the initial fracture. Nonunion was defined by the presence of procedure codes for repair of nonunion 90-365 days after the index fracture. We examined the association between NSAIDs and nonunion using multivariate Cox proportional hazards models. RESULTS: Of the 9,995 humeral shaft fractures, 105 patients developed nonunions (1.1%), and 1,032 (10.3%) were exposed to NSAIDs in the 90 days after fracture. NSAID exposure within the first 90 days was significantly associated with nonunion (relative risk [RR] 3.7, 95% confidence interval [95% CI] 2.4-5.6). When indicators for exposure to NSAIDs during each of the 3 30-day windows were placed into the same multivariate model, only the period 61-90 days post-fracture was significantly associated with nonunion (RR 3.9, 95% CI 2.0-6.2). We observed a similar association between opioids and nonunion, with exposure to opioids between 61 and 90 days associated with nonunion (RR 2.7, 95% CI 1.5-5.2), but exposure to opioids during neither of the 2 earlier 30-day periods significantly associated with nonunion. CONCLUSION: We found that exposure to nonselective NSAIDs or opioids in the period 61-90 days after a humeral shaft fracture was associated with nonunion. Although these associations may be causal, they are more likely to reflect the use of analgesics by patients with painful nonhealing fractures.

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Hanson, C. al. (2005)
The effect of analgesic agents on the healing rat medial collateral ligament
Am J Sports Med 33(5): 674-9.

BACKGROUND: Studies have suggested that some nonselective nonsteroidal anti-inflammatory drugs, including piroxicam, may improve ligament healing, whereas other nonsteroidal anti-inflammatory drugs, including ibuprofen and the cyclooxygenase-2 inhibitor celecoxib, may have no effect on the mechanical properties or may even deter the healing process. These results might reflect variations in cyclooxygenase enzyme selectivity by different drugs or, alternatively, may be related to their analgesic properties because it is generally accepted that early activity improves ligament healing. HYPOTHESIS: Nonselective nonsteroidal anti-inflammatory drugs improve ligament healing, whereas other analgesics provide lesser degrees of improvement, and cyclooxygenase-2 inhibitors are detrimental. STUDY DESIGN: Controlled laboratory study. METHODS: One hundred fifty-five Sprague-Dawley rats were divided into 7 treatment groups (piroxicam, naproxen, rofecoxib, butorphanol, 2 doses of acetaminophen, and control). The right medial collateral ligament of each rat was transected, and the drugs were administered postoperatively on days 1 to 6. On day 14, the rats were sacrificed, and mechanical testing was performed on the medial collateral ligament. RESULTS: The piroxicam group demonstrated significantly greater load to failure (27%) compared with the control. No significant differences were observed between other groups. CONCLUSIONS: Piroxicam improves ligament healing, but this effect cannot be attributed to all nonselective nonsteroidal anti-inflammatory drugs. Opiate analgesics, acetaminophen, and cyclooxygenase-2 inhibitors do not appear to categorically affect ligament healing. CLINICAL RELEVANCE: In the treatment of ligament injury, piroxicam may be a drug of choice.

Wheeler, P. and M. E. Batt (2005)
Do non-steroidal anti-inflammatory drugs adversely affect stress fracture healing? A short review.
Br J Sports Med 39(2): 65-9.

A literature search was performed to determine whether non-steroidal anti-inflammatory drugs (NSAIDs) adversely affect the healing of stress fractures. Evidence exists from laboratory studies and animal subjects that NSAIDs can affect fracture healing. This link has not been proved or disproved in human subjects, particularly for stress fractures. In view of the high usage of NSAIDs in treating musculoskeletal disorders, research is required to investigate whether the healing of stress fractures is affected by these drugs.

Brown, K. al. (2004)
Effect of COX-2-specific inhibition on fracture-healing in the rat femur
J Bone Joint Surg Am 86-A(1): 116-23.

BACKGROUND: Nonsteroidal anti-inflammatory medications have been shown to delay fracture-healing. COX-2-specific inhibitors such as celecoxib have recently been approved for human use. Our goal was to determine, mechanically, histologically, morphologically, and radiographically, whether COX-2-specific inhibition affects bone-healing. METHODS: A nondisplaced unilateral fracture was created in the right femur of fifty-seven adult male rats. Rats were given no drug, indomethacin (1 mg/kg/day), or celecoxib (3 mg/kg/day) daily, starting on postoperative day 1. Fractures were analyzed at four, eight, and twelve weeks after creation of the fracture. Callus and bridging bone formation was assessed radiographically. The amounts of fibrous tissue, cartilage, woven bone, and mature bone formation were determined histologically. Morphological changes were assessed to determine fibrous healing, callus formation, and bone-remodeling. Callus strength and stiffness were assessed biomechanically with three-point bending tests. RESULTS: At four weeks, only the indomethacin group showed biomechanical and radiographic evidence of delayed healing. Although femora from rats treated with celecoxib appeared to have more fibrous tissue than those from untreated rats at four and eight weeks, radiographic signs of callus formation, mechanical strength, and stiffness did not differ significantly between the groups. By twelve weeks, there were no significant differences among the three groups. CONCLUSIONS: Postoperative administration of celecoxib, a COX-2-specific inhibitor, did not delay healing as seen at twelve weeks following fracture in adult rat femora. At four and eight weeks, fibrous healing predominated in the celecoxib group as compared with the findings in the untreated group; however, mechanical strength and radiographic signs of healing were not significantly inhibited. Clinical Relevance: Many orthopaedists rely on narcotic analgesia for postfracture and postoperative pain, despite deleterious side effects and morbidity. Traditional nonsteroidal anti-inflammatory medications have been shown to delay fracture union. This effect may be smaller with COX-2-specific inhibitors.

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Gerstenfeld, L. C. and T. A. Einhorn (2004)
COX inhibitors and their effects on bone healing.
Expert Opin Drug Saf 3(2): 131-6.

Prostaglandins (PGs) are released as part of the inflammatory response. They are synthesised from arachidonic acid by the cyclooxygenase enzymes, COX-1 and -2. NSAIDS inhibit COX activity and have become the primary means of alleviating chronic pain associated with rheumatoid and osteoarthritis. They are also widely used as analgesics in the treatment of acute postsurgical and traumatic pain. PGs are known to play important functions in bone repair and normal bone homeostasis. Animal studies suggest that, whilst both nonspecific and specific inhibitors of COXs impair fracture healing, some studies have suggested that this impairment is due to COX-2. Although these data raise concerns about the use of COX-2-specific inhibitors as anti-inflammatory or analgesic drugs in patients undergoing orthopaedic procedures, clinical reports have been largely inconclusive concerning the effects of NSAIDs on bone healing. Since animal data suggest that the effects of COX-2 inhibitors are both dose-dependent and reversible, in the absence of scientifically sound clinical evidence it is suggested that physicians consider short-term administration or use of other drugs in the management of these patients.

Aspenberg, P. (2004)
Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs
J Orthop Res 22(3): 684; author reply 685.


Seidenberg, A. B. and Y. H. An (2004)

Is there an inhibitory effect of COX-2 inhibitors on bone healing?
Pharmacol Res 50(2): 151-6.

The use of the new selective cyclooxygenase-2 (COX-2) inhibitors (such as celecoxib and rofecoxib) for the treatment of pain and inflammation caused by fractures, cementless total joint replacements, soft tissue healing to bone, and spinal fusion surgeries has been controversial due to the convincing data collected from nonspecific NSAIDs such as indomethacin and naproxen regarding their inhibitory effects on bone healing and the similar effects of COX-2 specific NSAIDs in animal models. Is there a significant inhibitory effect of COX-2 inhibitors on bone healing in humans? To answer this question, we reviewed existing scientific evidence (based mainly on a MedLine search) of the potential effects of COX-2 inhibitors on bone healing. The literature shows that COX-2 inhibitors do have inhibitory effects on bone healing in animal models, but the effects of COX-2 inhibitors on similar processes in humans remain largely unknown.

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Mason, L., R. A. Moore, et al. (2004)
Topical NSAIDs for acute pain: a meta-analysis.
BMC Fam Pract 5: 10.

BACKGROUND: A previous systematic review reported that topical NSAIDs were effective in relieving pain in acute conditions like sprains and strains, with differences between individual drugs for efficacy. More trials, a better understanding of trial quality and bias, and a reclassification of certain drugs necessitate a new review. METHODS: Studies were identified by searching electronic databases and writing to manufacturers. We selected randomised double blind trials comparing topical NSAID with either placebo or another active treatment in adults with acute pain, and extracted dichotomous information approximating to a 50% reduction in pain at one week, together with details of adverse events and withdrawals. Relative benefit and number-needed-to-treat (NNT), and relative risk and number-needed-to-harm (NNH) were calculated, with sensitivity analyses where appropriate to investigate differences between individual drugs and aspects of trial design. RESULTS: Twenty-six double blind placebo controlled trials had information from 2,853 patients for evaluation of efficacy. Topical NSAID was significantly better than placebo in 19 of the 26 trials, with a pooled relative benefit of 1.6 (95% confidence interval 1.4 to 1.7), and NNT of 3.8 (95% confidence interval 3.4 to 4.4) compared with placebo for the outcome of half pain relief at seven days. Results were not affected by outcome reported, or condition treated, but smaller trials yielded a larger estimate of efficacy. Indirect comparisons of individual topical NSAIDs showed that ketoprofen was significantly better than all other topical NSAIDs, while indomethacin was barely distinguished from placebo. Three trials, with 433 patients, compared topical with oral NSAID (two trials compared the same drug, one compared different drugs) and found no difference in efficacy. Local adverse events, systemic adverse events, or withdrawals due to an adverse event were rare, and no different between topical NSAID and placebo. CONCLUSIONS: Topical NSAIDs were effective and safe in treating acute painful conditions for one week.

Mason, L., R. A. Moore, et al. (2004)
Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis.
BMC Musculoskelet Disord 5: 28.

A previous systematic review reported that topical NSAIDs were effective in relieving pain in chronic conditions like osteoarthritis and tendinitis. More trials, a better understanding of trial quality and bias, and a reclassification of certain drugs necessitate a new review. METHODS: Studies were identified by searching electronic databases, and writing to manufacturers. We identified randomised, double blind trials comparing topical NSAID with either placebo or another active treatment, in adults with chronic pain. The primary outcome was a reduction in pain of approximately 50% at two weeks, and secondary outcomes were local and systemic adverse events and adverse event-related withdrawals. Relative benefit and number-needed-to-treat (NNT), and relative harm and number-needed-to-harm (NNH) were calculated, and the effects of trial quality, validity and size, outcome reported, and condition treated, were examined by sensitivity analyses. RESULTS: Twelve new trials were added to 13 trials from a previous review. Fourteen double blind placebo-controlled trials had information from almost 1,500 patients. Topical NSAID was significantly better than placebo with relative benefit 1.9 (95% confidence interval 1.7 to 2.2), NNT 4.6 (95% confidence interval 3.8 to 5.9). Results were not affected by trial quality, validity or size, outcome reported, or condition treated. Three trials with 764 patients comparing a topical with an oral NSAID found no difference in efficacy. Local adverse events (6%), systemic adverse events (3%), or the numbers withdrawing due to an adverse event were the same for topical NSAID and placebo. CONCLUSIONS: Topical NSAIDs were effective and safe in treating chronic musculoskeletal conditions for two weeks. Larger and longer trials are necessary to fully elucidate the place of topical NSAIDs in clinical practice.

Virchenko, al. (2004)
Parecoxib impairs early tendon repair but improves later remodeling
Am J Sports Med 32(7): 1743-7.

BACKGROUND: Cyclooxygenase-2 inhibitors inhibit bone repair. HYPOTHESIS: Cyclooxygenase inhibitors might also have a negative effect on early tendon repair, although a positive effect on late tendon repair previously has been shown. STUDY DESIGN: Controlled laboratory study. METHODS: Achilles tendon transection was performed on 80 rats. Sixty rats were given daily intramuscular injections of either parecoxib (6.4 mg/kg body weight) or saline for the first 5 days after surgery and sacrificed either at 8 or 14 days. The remaining 20 rats were given intramuscular parecoxib or saline injections from day 6 until sacrifice at 14 days. RESULTS: At 8 days, early parecoxib treatment caused a 27% decrease in force at failure (P =.007), a 25% decrease in maximum stress (P =.01), and a 31% decrease in energy uptake (P =.05). Stiffness and transverse area were not significantly affected. At 14 days, early parecoxib treatment caused a decrease in stiffness (P =.004). In contrast to early treatment, late parecoxib treatment caused a 16% decrease in cross-sectional area (P =.03) and a 29% increase in maximum stress (P =.04). CONCLUSIONS: During early tendon repair, a cyclooxygenase-2 inhibitor had a detrimental effect. During remodelling, however, inflammation appears to have a negative influence, and cyclooxygenase-2 inhibitors might be of value. CLINICAL RELEVANCE: The results suggest that cyclooxygenase-2 inhibitors should be used with care in the early period after tendon injury.

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Rahusen, F. al. (2004)
Nonsteroidal anti-inflammatory drugs and acetaminophen in the treatment of an acute muscle injury
Am J Sports Med 32(8): 1856-9.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are frequently used to treat muscle injuries in athletes. It is not known whether the anti-inflammatory effects of these drugs are important or whether their effectiveness is a result of their central analgesic effect. HYPOTHESIS: The effects of nonsteroidal anti-inflammatory drugs are no different than the effects of an analgesic (acetaminophen) without anti-inflammatory action in an experimental, acute muscle contusion model. STUDY DESIGN: Controlled animal study. METHODS: A standardized, unilateral, nonpenetrating injury was created to the tibialis anterior muscle of 96 adult male mice. Four treatment groups were used: group 1, placebo treatment; group 2, treatment with rofecoxib, a nonsteroidal anti-inflammatory drug with cyclooxygenase-2 selectivity, and treatment after the injury; group 3, rofecoxib treatment starting 24 hours before the injury; and group 4, acetaminophen treatment after the injury. The muscle and the contralateral normal muscle were evaluated at 2, 5, and 7 days after injury by grading of gait, wet weight as a measure of edema, and histologic evaluation. RESULTS: Group 1 had significantly more gait disturbances at day 2 than all other groups (P <.05). No differences were found at days 5 and 7. Wet weights showed an increase at day 2 in group 1 (P <.01). Again, no differences were found at days 5 and 7. Histology revealed similar inflammatory changes at day 2 in all groups, with regeneration of muscle fibers at days 5 and 7. CONCLUSIONS: The results indicate that rofecoxib as a nonsteroidal anti-inflammatory drug and acetaminophen as a non-nonsteroidal anti-inflammatory drug analgesic have similar effects. The lack of differences in wet weights and histology suggests that the anti-inflammatory effects of rofecoxib are not an important feature of its action. CLINICAL RELEVANCE: The routine use of nonsteroidal anti-inflammatory drugs in muscle injuries may need to be critically evaluated because low-cost and low-risk analgesics may be just as effective.

Tsai, W. al. (2004)
Ibuprofen inhibition of tendon cell proliferation and upregulation of the cyclin kinase inhibitor p21CIP1
J Orthop Res 22(3): 586-91.

Sports-related tendon injuries are commonly treated with nonsteroidal antiinflammatory drugs. This study was designed to determine the in vitro effect of ibuprofen on the proliferation of tendon cells intrinsic to rat Achilles tendon. Furthermore, the existence of a correlation between this effect and the expression of the cyclin kinase inhibitor p21(CIP1) and retinoblastoma (Rb) protein was also examined. Using cultured tendon cells, cell viability was evaluated by MTT assay. To determine whether apoptosis was related to the effect of ibuprofen, terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay was used. The mitotic index (MI) was calculated from the number of cells in the mitotic phase as stained and identified by propidium iodide. The mRNA expression of p21(CIP1) was determined by reverse transcription-polymerase chain reaction (RT-PCR). Protein expressions of p21(CIP1) and Rb protein were determined by Western blot analysis. A dose-dependent decrease in the cellularity of tendon cells by ibuprofen was demonstrated by MTT assay (p<0.001). However, TUNEL assay revealed no evidence of apoptosis. Ibuprofen dose-dependently reduced the MI (p<0.001). Upregulation of p21(CIP1) both at the levels of mRNA expression and protein was revealed from RT-PCR and Western blot analyses. The inhibition of Rb protein phosphorylation was also noted in ibuprofen-treated cells. In conclusion, ibuprofen inhibits tendon cell proliferation in a process that is probably mediated by the upregulation of p21(CIP1) and reduced phosphorylation of Rb protein.

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Evans, C. E. and C. Butcher (2004)
The influence on human osteoblasts in vitro of non-steroidal anti-inflammatory drugs which act on different cyclooxygenase enzymes
J Bone Joint Surg Br 86(3): 444-9.

There is increasing evidence that non-steroidal anti-inflammatory drugs (NSAIDs) can adversely affect bone repair. We have, therefore, studied the in vitro effects of NSAIDs, which differentially inhibit cyclooxygenases (COX), the prostaglandin/thromboxane synthesising enzymes, on human osteoblasts. Indomethacin and the new nitric oxide (NO)-donating NSAIDs block the activity of both COX-1 and COX-2. Indomethacin and 5,5-dimethyl-3-(3 fluorophenyl)-4-(4 methylsulphonal) phenyl-2 (5H)-furanone (DFU) reduced osteoblast numbers in a dose-dependant manner and increased collagen synthesis and alkaline phosphatase activity. The reduction in osteoblast numbers was not caused by loss of adhesion and was reversible. Neither NSAID influenced DNA synthesis. There was no difference between the effects of indomethacin and DFU. NO-NSAIDs did not affect cell numbers. These results suggest that care should be taken when administering NSAIDs to patients with existing skeletal problems and that NO-NSAIDs may be safer.

Hochberg, M. al. (2003)
Cox-2 inhibitors and fracture healing: an argument against such an effect
J Bone Miner Res 18(3): 583; author reply 584-7.


Riew, K. al. (2003)

Time-dependent inhibitory effects of indomethacin on spinal fusion
J Bone Joint Surg Am 85-A(4): 632-4.

BACKGROUND: The use of nonsteroidal anti-inflammatory drugs following spine arthrodesis is discouraged because of the negative effects on bone-healing. We are not aware of any data regarding when nonsteroidal anti-inflammatory drugs may be safely resumed postoperatively. We hypothesized that these drugs have a time-dependent deleterious effect on fusion, with the greatest inhibition during the early phases of fusion. METHODS: Seventy New Zealand White rabbits underwent posterior intertransverse process arthrodesis at L5-L6 with use of iliac autograft. Rabbits randomly received indomethacin (10 mg/kg orally) starting at two weeks after surgery (twenty-four animals), indomethacin starting at four weeks postoperatively (twenty-three), or saline starting at two weeks postoperatively (twenty-three) (the control group). The animals were killed at six weeks, and the spines were denuded of soft tissues and palpated for L5-L6 motion. Fusion was defined as the complete absence of motion. RESULTS: Sixty-five percent (fifteen) of the twenty-three spines in the control group and 48% (eleven) of the twenty-three in the four-week group fused. However, only 21% (five) of the twenty-four spines in the two-week group fused. The difference between the two-week and control groups was significant (p < 0.002), as was the difference between the two and four-week groups (p = 0.05). The difference between the four-week and control groups was not significant (p = 0.2). CONCLUSIONS: The earlier that indomethacin was resumed postoperatively, the greater was its negative effect on fusion. Indomethacin appears to play a significant inhibitory role in the early phase of healing. Initiating indomethacin treatment in the latter phase of healing does not appear to significantly affect fusion rates, although there was a nonsignificant trend toward inhibition. To our knowledge, this is the first investigation of the time-dependent nature of indomethacin's effect on bone-healing.

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Kjaersgaard-Andersen, P. and K. Jensen (2003)
Cox inhibitors and bone healing
Acta Orthop Scand 74(2): 230-1; author reply 231.


Beck, al. (2003)
Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture healing
Arch Orthop Trauma Surg 123(7): 327-32.

INTRODUCTION: Nonsteroidal antirheumatics (NSAR; NSAID) are often used in patients with fractured bones for analgetic reasons. This animal experiment was performed to determine the influence of NSAR on the process of fracture healing. As an alternative, tramadol, the centrally acting analgetic without peripheral effects, was included in this experiment. MATERIALS AND METHODS: Wistar rats were operated on by a transverse osteotomy of the proximal tibia of the left leg. The fracture was stabilized by intramedullary nailing (healing period 21 days). All drugs were applied orally twice a day. The animals were divided into four groups with 10 rats each: Group 1 was treated with placebo (P), group 2 with tramadol (T; 20 mg/kg body weight/day), group 3 with diclofenac sodium (DS; 5 mg/kg bw/day) for 7 days followed by 14 days of placebo, group 4 with diclofenac sodium (DL; 5 mg/kgbw/day) over 21 days. On day 21 the rats were killed, and each leg was examined by X-ray, then the tibia was examined by CT scan, three-point bending, and histology. RESULTS: The results of CT and three-point bending showed that rats treated by diclofenac presented with delayed fracture healing compared with those treated by placebo or tramadol. Bone density in CT was highest in group 1 (mean 611.4+/-50.1 mg/ml), followed by group 2 (mean 542.5+/-29.5 mg/ml). Groups 3 (mean 411+/-34.0 mg/ml; p=0.006) and 4 (mean 395.2+/-15.4 mg/ml; p=0.009) were significantly lower. The stability of the bones, as measured by the breaking force (F(max)), was highest in group 1 (mean 45.8+/-19.0 N), followed by group 2 (mean 39.0+/-7.9 N; NS); group 3 (mean 20.6+/-7.8 N; p=0.01) was significantly lower than the placebo animals, followed by group 4 (mean 26.5+/-8.3 N; p=0.03). Similar results were shown for bending stiffness: group 1 (mean 1404.6+/-611.4 Nmm/mm), group 2 (mean 1033.2+/-232.1 Nmm/mm; NS), group 3 (mean 564.2+/-457 Nmm/mm; p=0.045), and group 4 (mean 494.8+/-340.2 Nmm/mm; p=0.028). There were no significant differences between groups 1 and 2 and between groups 3 and 4, respectively. Diclofenac serum levels on day 21 in rats with long-term diclofenac application (mean 301.4+/-83.3 ng/ml) were comparable to those in humans. CONCLUSION: Oral application of diclofenac significantly delayed fracture healing in rats. This effect might be comparable to other NSAR and fracture healing in humans.

Marsolais, al. (2003)
Nonsteroidal anti-inflammatory drug reduces neutrophil and macrophage accumulation but does not improve tendon regeneration
Lab Invest 83(7): 991-9.

Whether nonsteroidal anti-inflammatory drugs have a beneficial effect on tendon regeneration is still a matter of debate. Given that inflammatory cells are thought to induce nonspecific damage following an injury, we tested the hypothesis that a 3-day treatment with diclofenac would protect tendons from inflammatory cell injury and would promote healing. Neutrophil and ED1(+) macrophage concentrations were determined in the paratenon and the core of the rat Achilles tendon following collagenase-induced injury. Hydroxyproline content, edema, and mechanical properties were also evaluated at 1, 3, 7, 14, and 28 days post-trauma. Collagenase injections induced a 70% decrease in the ultimate rupture point at Day 3. Diclofenac treatments (1 mg/kg bid) selectively decreased the accumulation of neutrophils and ED1(+) macrophages by 59% and 35%, respectively, in the paratenon, where blood vessels are numerous, but did not reduce the accumulation of neutrophils and ED1(+) macrophages in the core of the tendon. Edema was significantly reduced on Day 3 but persisted during the remodeling phase in the diclofenac-treated group only. The inhibition of leukocyte accumulation by diclofenac did not translate into a reduction of tissue damage or a promotion of tissue healing, because the mechanical properties of injured Achilles tendons were identical in placebo and diclofenac-treated groups. These results indicate that diclofenac reduced both edema and the accumulation of inflammatory cells within the paratenon but provided no biochemical or functional benefits for the Achilles tendon.

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Harder, A. T. and Y. H. An (2003)
The mechanisms of the inhibitory effects of nonsteroidal anti-inflammatory drugs on bone healing: a concise review
J Clin Pharmacol 43(8): 807-15.

Nonsteroidal anti-inflammatory drug (NSAID) use continues to expand at a remarkable rate due both to the broad spectrum of clinical applications for these medications and to the relatively recent introduction of the popular COX-2-selective inhibitors. The use of NSAIDs is particularly prevalent in patients with a variety of musculoskeletal conditions and injuries. Reports of impaired bone healing associated with NSAID use, therefore, are a particular cause for concern. Animal and in vitro studies have demonstrated impaired bone healing in the presence of traditional NSAIDs, as measured by a variety of different parameters. More recently, initial studies investigating the effects of COX-2-selective inhibitors on bone healing have yielded similar results. With mounting evidence that NSAIDs do in fact interfere with proper bone healing in various animal models, questions have arisen regarding the potential mechanism through which NSAIDs produce this outcome and whether these results can be translated to clinical settings. A likely pathway for these observed effects results from an understanding of the steps involved in bone healing itself. These steps include an inflammatory response, bone resorption, and new bone formation. Investigations over the past several decades have elucidated a role for prostaglandins (PGs) in each of these areas. Specifically, PGs have been shown to elicit and participate in inflammatory responses, increase osteoclast activity and subsequent bone resorption, and increase osteoblast activity and new bone formation. This apparent integral role for PGs in the process of bone healing, coupled with the knowledge that NSAIDs act by inhibiting the production of PGs, results in an understanding of the likely mechanism through which NSAIDs impart their deleterious effects on bone healing. By inhibiting the COX enzymes and the subsequent production of PGs, NSAIDs not only achieve their desired anti-inflammatory effects but also inhibit the increased production of PGs that is necessary for bone healing to occur. Despite this understanding of the potential mechanism through which NSAIDs inhibit bone healing in a laboratory setting, few studies exist that show whether these inhibitory effects are also evident clinically. Thus, further studies will need to decipher whether similar inhibitory effects occur in a clinical setting.

Gajraj, N. M. (2003)
The effect of cyclooxygenase-2 inhibitors on bone healing
Reg Anesth Pain Med 28(5): 456-65.


Allami, M. K. and P. V. Giannoudis (2003)
Cox inhibitors and bone healing
Acta Orthop Scand 74(6): 771-2.


Martel-Pelletier, al. (2003)
Cyclooxygenase-2 and prostaglandins in articular tissues
Seminars in Arthritis and Rheumatism 33(3): 155-167.


Ankarath, al. (2003)
Non steroidal anti-inflammatory drugs in orthopaedic practice: an update
Current Orthopaedics 17: 144-149.


References - before 2003

It is appreciated that this is not a comprehensive bibliography, but may assist those who wish to further evaluate the evidence in this critical area.

Allen, H. L., A. Wase, et al. (1980). "Indomethacin and aspirin: effect of nonsteroidal anti-inflammatory agents on the rate of fracture repair in the rat." Acta Orthop Scand 51(4): 595-600.

A total of 210 male Charles River CD rats, 45 days old, were subjected to a fracturing of the right radius and ulna by digital pressure while under ether anesthesia. These animals were then assigned randomly to dose groups (1, 2 or 4 mg/kg/day of indomethacin and 100, 200, or 300 mg/kg/day of aspirin) and were dosed for 21 days. Dose levels were chosen to provide approximately equipotent levels of the test compounds with the highest dose approaching toxicity. Radiographs were taken of control-rat fractures on days 8, 14, and 21. Three rats at 4 mg/kg/day of indomethacin died of interstinal perforation prior to scheduled sacrifice. On day 22, all remaining rats were sacrificed by exsanguination under anesthesia. Histologic secretions of the radius and ulna were examined in random sequence without knowledge of the treatment regimen. A histologic grade based on the morphologic stage of fracture healing was given. There was a drug- and dose-related retardation of fracture healing, which was statistically significant at all dose levels of indomethacin and the highest level of aspirin, as compared to controls. Decreased mean grades in the groups given 100 and 200 mg/kg/day of aspirin, though not statistically significant, suggest a retarding effect on fracture healing at these levels also. No statistically significant changes in numbers of pseudoarthroses were found.

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Almekinders, L. C. (1999). "Anti-inflammatory treatment of muscular injuries in sport. An update of recent studies." Sports Med 28(6): 383-8.

Stretch-induced muscle injuries or strains, muscle contusions and delayed-onset muscle soreness (DOMS) are common muscle problems in athletes. Anti-inflammatory treatment is often used for the pain and disability associated with these injuries. The most recent studies on nonsteroidal anti-inflammatory drugs (NSAIDs) in strains and contusions suggest that the use of NSAIDs can result in a modest inhibition of the initial inflammatory response and its symptoms. However, this may be associated with some small negative effects later in the healing phase. Corticosteroids have generally been shown to adversely affect the healing of these acute injuries. Animal studies have suggested that anabolic steroids may actually aid in the healing process, but clinical studies are not yet available and the exact role of these drugs has yet to be determined. Studies on anti-inflammatory treatment of DOMS have yielded conflicting results. However, the effect of NSAIDs on DOMS appears small at best. Future research may have to focus on different aspects of these injuries as the emphasis on anti-inflammatory treatment has yielded somewhat disappointing results.

Almekinders, L. C. and J. A. Gilbert (1986). "Healing of experimental muscle strains and the effects of nonsteroidal antiinflammatory medication." Am J Sports Med 14(4): 303-8.

The healing process of muscle strains and the effect of nonsteroidal antiinflammatory medication were studied using an experimental animal model. A standardized strain of the tibialis anterior muscle in adult male rats was produced by a controlled stretch of the muscle. Groups I and II underwent a unilateral strain of the tibialis anterior muscle and were immobilized in the postinjury period. The rats in Group II were fed piroxicam in the postinjury period. Group III underwent a sham procedure and were also immobilized. At 0, 2, 4, and 11 days postinjury both injured and contralateral control muscles were evaluated by determining tensile strength characteristics and histologic appearance. Group I showed a significant drop in maximum failure load to 25.7% of the control leg at Day 2 with a gradual return to the level of Group III at Days 4 and 11 (40.9% and 50.1%). Group II showed a similar drop but was still stronger than Group I at 2 days with 40.8% of the control leg and continued to drop until 4 days postinjury (33.7%). Histology showed a delay in inflammatory reaction and muscle regeneration in Group II. At 11 days both Groups I and II showed regenerated muscle fibers bridging the entire defect and an increase in endomyseal fibrosis. It is concluded that muscle strains continue to weaken in the early postinjury period. Non-steroidal antiinflammatory medication, such as piroxicam, might delay muscle regeneration.

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Arceiz, E., A. Lanas, et al. (1997). "Platelet-derived growth factor reverses the effects induced by NSAIDs on ulcer healing." Eur J Gastroenterol Hepatol 9(12): 1179-84.

BACKGROUND: It is known that non-steroidal anti-inflammatory drug (NSAID) use delays the healing of peptic ulcers and that growth factors play an important role in the ulcer healing process. AIM: To evaluate the effect of platelet-derived growth factor (PDGF) in healing chronic gastric ulcers in rats treated with NSAIDs. METHODS: Chronic gastric ulcers were induced with acetic acid in male Wistar rats and then treated with either aspirin (100 mg/kg/day), indomethacin (2 mg/kg/day), PDGF-BB (0.1 nM/kg/day) or combinations. Gastric secretion and ulcer size, wound contraction, mucosal regeneration and cell proliferation were assessed in histological specimens. RESULTS: Both aspirin and indomethacin delayed the healing rate of gastric ulcers and reduced ulcer contraction, mucosal regeneration and cell proliferation. All these effects were completely reversed by oral treatment with PDGF- BB without affecting gastric acid secretion. CONCLUSION: Oral administration of PDGF accelerates ulcer healing and reverses the effects induced by NSAIDs on ulcer healing without affecting gastric secretion.

Bertsch, S. and F. Marks (1982). "A comparative study on wound-healing in neonatal and adult mouse epidermis in vivo." Cell Tissue Kinet 15(1): 81-7.

A cut made into the back skin of either newborn or adult mice evokes, at both ages, a hyperproliferative response in the epidermis. Differences in the reaction of neonatal as compared with adult epidermis are found in the spatial distribution of proliferative activity as well as in its time course. The response in adult mouse epidermis is inhibited by local application of indomethacin, whereas the response of the newborn epidermis is not.

Bo, J., E. Sudmann, et al. (1976). "Effect of indomethacin on fracture healing in rats." Acta Orthop Scand 47(6): 588-99.

The healing of closed, non-immobilized femoral fractures in rats was seriously impaired by indomethacin given orally at a dose of 2 mg/kg daily. The fracture haematomas were larger and disappeared later in the animals receiving indomethacin. Mechanical strength testing of fracture healing showed that maximal tensile strength, elastic stiffness and maximal bending moment between fragments were significantly diminished in the indomethacin-treated animals. Radiological examination showed a smaller amount of mineralized callus and a more pronounced angulation between the fragments in these animals than in the placebo-treated ones. Hsitological examination showed bridging between the fragments by callus tissue 24 days after fracture in placebo-treated animals, whereas indomethacin treatment was followed by histological findings resembling those seen in early pseudarthrosis development.

Bourne, M. S. (1980). "The effect on healing of analgesic and anti-inflammatory therapy." Br J Sports Med 14(1): 26.


Carlstedt, C. A. (1987). "Mechanical and chemical factors in tendon healing. Effects of indomethacin and surgery in the rabbit." Acta Orthop Scand Suppl 224: 1-75.


Carlstedt, C. A., K. Madsen, et al. (1986). "The influence of indomethacin on collagen synthesis during tendon healing in the rabbit." Prostaglandins 32(3): 353-8.

The influence of indomethacin on collagen synthesis in intact and healing plantaris longus tendons in the rabbit was investigated. Forty- four male New Zealand White rabbits were subjected to a standardized trauma (tenetomy + repair) on the left hindlimb. Half of the animals were subsequently treated with indomethacin, 10 mg/kg per day orally, and the other half with placebo. After 2 and 4 weeks the rabbits were injected intravenously with 3H-proline and killed 18 h later. Indomethacin affected the collagen metabolism differently depending on whether the tendons were involved in wound healing or not. In intact tendons the drug caused a small general inhibition of collagen synthesis. In the healing tendon there was a shift towards the synthesis of more insoluble collagen with little effect on the total synthesis. After 4 weeks there was also a slight but significant decrease in the amount of hydroxyproline in the most soluble collagen fraction from the tenotomized, indomethacin treated tendons.

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Carlstedt, C. A., K. Madsen, et al. (1986). "The influence of indomethacin on tendon healing. A biomechanical and biochemical study." Arch Orthop Trauma Surg 105(6): 332-6.

The influence of indomethacin on the biomechanical and biochemical properties of tendons during their healing was investigated. In 68 New Zealand White rabbits a transverse tenotomy followed by repair with a criss-cross suture was performed in the plantaris longus tendon of the left hind limb. The leg was immobilized for 4 weeks postoperatively in a long-leg plastic splint. Half of the animals were treated with indomethacin, 10 mg/kg/day orally, and the other half with placebo. After 4, 8, and 16 weeks of treatment the animals were killed and biomechanical and biochemical parameters were measured. After 16 weeks there was a significant increase in tensile strength in the indomethacin group. There were only small biochemical differences between the groups. However, there was a slight but significant decrease in the amount of soluble collagen in the indomethacin group. This may indicate a higher degree of cross-linkage following indomethacin treatment, which might explain the increased tensile strength.

Carlstedt, C. A., K. Madsen, et al. (1987). "The influence of indomethacin on biomechanical and biochemical properties of the plantaris longus tendon in the rabbit." Arch Orthop Trauma Surg106(3): 157-60.

It has previously been reported that indomethacin inhibits fracture healing and heterotopic bone formation. Stimulated by these reports, we undertook the present investigation to study the influence of indomethacin on biomechanical and biochemical properties of the plantaris longus tendon in the rabbit. Sixty-eight New Zealand White rabbits were used for the experiment. Half of them were treated with indomethacin, 10 mg/kg orally a day, and the other half with placebo. After 4, 8, and 16 weeks of treatment biomechanical and biochemical variables were determined and compared between the two groups. After 16 weeks there was a significant increase in tensile strength in the group treated with indomethacin. There was no certain concomitant change in the total collagen content, the amounts of soluble and insoluble collagen, or the water content. Further investigations concerning the influence of indomethacin on tendon healing are indicated.

Dimar, J. R., W. A. Ante, et al. (1996). "The effects of nonsteroidal anti-inflammatory drugs on posterior spinal fusions in the rat." Spine 21(16): 1870-6.

STUDY DESIGN: This was a prospective study to determine the potential effects of indomethacin on spinal fusions in the rat. OBJECTIVES: To determine if indomethacin exerts a deleterious effect on spinal fusions in the rat model. SUMMARY OF BACKGROUND DATA: Nonsteroidal anti- inflammatory drugs are a class of compound that affect bone osteogenesis during fracture healing and heterotopic ossification. Spinal fusion is a process that occurs via osteogenesis and, therefore, may be similarly affected. METHODS: Thirty-nine adult, Sprague-Dawley rats underwent a three-level posterior spinal fusion. Fusion was performed using morselized autogenous vertebral bone graft obtained via caudectomy and stabilized using a cerclage wiring technique. The 39 rats were divided into two groups consisting of 17 study animals and 22 control animals. The control group was injected with 1.5 cc of 0.9 normal saline subcutaneously for 12 weeks, whereas the test animals were injected on an identical schedule using 3 mg/kg of indomethacin sodium salt. Two control animals died, and three animals in the treatment group died of drug-related complications. Twelve weeks after surgery, all animals were killed, and the involved spinal segments were evaluated by direct manual examination. A fusion was probable if the spinal segments exhibited decreased scaled micromotion. RESULTS: Sixty segmental levels in 20 control animals were assessed. Overall, 27 of 60 levels (45%) achieved fusion. In the indomethacin-treated group, 42 levels in 14 animals were evaluated. Overall, four of 42 levels (10%) achieved a fusion. Chi-square analysis demonstrated a significant difference (P < 0.001) between the control and indomethacin-treated groups. CONCLUSIONS: This study raises serious questions about the inhibitory effects of nonsteroidal anti-inflammatory drugs on spinal fusion. Clinically, the widespread use of nonsteroidal anti- inflammatory drugs in the postoperative period after spinal fusion may need to be avoided.

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Diwan, P. V. and D. R. Kulkarni (1986). "Effects of nonsteroidal antiinflammatory agents (NSAIAs) on wound healing." Indian J Exp Biol 24(10): 640-3.


Dong, Y. L., R. Y. Fleming, et al. (1993). "Effect of ibuprofen on the inflammatory response to surgical wounds." J Trauma 35(3): 340-3.

Patients suffering severe trauma frequently become immunosuppressed following injury. This can predispose patients to infectious sequelae. Biochemically, these patients synthesize excessive quantities of cyclooxygenase products (prostaglandins). It has been hypothesized that the prostaglandins cause the immunosuppression and that inhibition of the cyclooxygenase enzyme could thus prevent the immunosuppression. We investigated the effect of the cyclooxygenase inhibitor ibuprofen on the inflammatory response. Rats were subjected to a 30% total body surface area burn and were administered either ibuprofen for a period of 7 days or 14 days, or were administered the carrier for 14 days. The rats were then killed and multiple immunologic variables were measured. Ibuprofen was found to decrease neutrophil chemiluminescence, lymphocyte blastogenesis, and helper/inducer T-lymphocyte infiltration of a sponge matrix model. The same ibuprofen protocol decreased survival in a cecal ligation and puncture model. In conclusion, the cyclooxygenase enzyme system appears to produce metabolites essential for optimal survival following traumatic injury.

Durant, S., D. Duval, et al. (1989). "Effect of exogenous prostaglandins and nonsteroidal anti-inflammatory agents on prostaglandin secretion and proliferation of mouse embryo fibroblasts in culture." Prostaglandins Leukot Essent Fatty Acids 38(1): 1-8.

During wound healing, the positive and negative modulation of fibroblast proliferation may be due, in part, to the high prostaglandin concentration of the inflammatory exudates. In vitro, PGF2 alpha has been shown to stimulate, whereas PGE2 inhibits, the growth of different fibroblast cell lines. Therefore, we have investigated the effect of exogenous prostaglandins (PGs) and of various nonsteroidal anti- inflammatory drugs (NSAIDs) on the proliferation and the prostaglandin (PG) synthesis of normal mouse embryo fibroblasts. PGF2 alpha, 6-keto PGF1 alpha and PGE2 increase fibroblast proliferation. On the other hand, PGF2 alpha increases the synthesis of PGE2 and 6-keto PGF1 alpha while 6-keto PGF1 alpha solely inhibits PGF2 alpha release, PGE2 being inactive. The mouse embryo fibroblasts partially transform the prodrug sulindac sulfoxide in the sulfide form, which completely inhibits PG synthesis, as does indomethacin. In contrast, ibuprofen exerts a differential action, according to the type of PG measured. Among the NSAIDs tested, only sulindac (sulfoxide or sulfide) stimulates fibroblast proliferation and this effect appears independent of an alteration of PG synthesis. Therefore, in this model of normal mouse embryo fibroblasts, while endogenous prostaglandins are not involved in the control of cell proliferation, exogenous PGs have the ability to alter fibroblast growth and PG synthesis.

Dvivedi, S., S. M. Tiwari, et al. (1997). "Effect of ibuprofen and diclofenac sodium on experimental would healing." Indian J Exp Biol 35(11): 1243-5.

Effects of frequently used anti-inflammatory drugs ibuprofen and diclofenac was studied on experimental wound healing in rats. These drugs impede tissue repair by virtue of retarding inflammation. There was 16-36% reduction in wound strength measured in terms of tensile strength in experimental rats. The detrimental effect of anti- inflammatory drugs was confirmed by histological examination of wound and by measuring dry granuloma weight.

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Engesaeter, L. B., B. Sudmann, et al. (1992). "Fracture healing in rats inhibited by locally administered indomethacin." Acta Orthop Scand 63(3): 330-3.

We studied the inhibitory effect of indomethacin on fracture healing in 135 young, male rats after oral administration compared with local application into the fracture. A closed mid-diaphyseal fracture of the left femur was performed in all the rats. The fractures were not immobilized. In one experiment, half of the animals received indomethacin via a stomach tube (2 mg/kg/day) for 10 days; the controls received only the vehicle. In another experiment, 0.5 mg of indomethacin, contained in a bioerodible polyorthoester gel, was injected into the fracture area in half the rats; in the controls, only the gel was injected. In both experiments, random animals were killed on Days 0, 5, 10, and 20. As assessed by radiographs and manual testing, the same inhibition of fracture healing was found regardless of whether indomethacin was given orally or locally. However, the amount of indomethacin that was applied locally was only one fourth of the total dose given orally; no indomethacin was detected in the serum.

Fang, C., J. W. Alexander, et al. (1983). "Failure of topical prostaglandin inhibitors to improve wound healing following deep partial-thickness burns." J Trauma 23(4): 300-4.

The present study was designed to determine the efficacy of topical inhibitors of prostaglandins on wound healing. Two uniform deep partial- thickness burns were inflicted on mirror-image areas of guinea pig backs by an aluminum template heated to 75 degrees C and applied for 10 seconds. Indomethacin was tested extensively in a wide range of concentrations in groups of six or more animals each. The healing rates measured at 21 days postburn showed that topical indomethacin at each concentration tested was not effective for improving wound healing. In fact, the treated sites were consistently worse than the control sites. Moreover, the drug adversely affected the healing process proportional to the concentration and was associated with death, which was related to perforations of the GI tract. Also, the India ink filling in the dermal microcirculation was no better in the experimental wounds than in the controls. The evaluations for hair growth were definitely in favor of the controls. The other tested inhibitors, ibuprofen, flurbiprofen, tolmetin, zomepirac, piroxicam, and dipyridamole, also failed to show any benefit.

Giannoudis, P. V., D. A. MacDonald, et al. (2000). "Nonunion of the femoral diaphysis. The influence of reaming and non- steroidal anti-inflammatory drugs." J Bone Joint Surg Br 82(5): 655-8.

We assessed factors which may affect union in 32 patients with nonunion of a fracture of the diaphysis of the femur and 67 comparable patients whose fracture had united. These included gender, age, smoking habit, the use of non-steroidal anti-inflammatory drugs (NSAIDs) the type of fracture (AO classification), soft-tissue injury (open or closed), the type of nail, the mode of locking, reaming nu non-reaming, infection, failure of the implant, distraction at the fracture site, and the time to full weight-bearing. Patients with severe head injuries were excluded. Both groups were comparable with regard to gender, Injury Severity Score and soft-tissue injury. There was no relationship between the rate of union and the type of implant, mode of locking, reaming, distraction or smoking. There were fewer cases of nonunion in more comminuted fractures (type C) and in patients who were able to bear weight early. There was a marked association between nonunion and the use of NSAIDs after injury (p = 0.000001) and delayed healing was noted in patients who took NSAIDs and whose fractures had united.

Hogevold, H. E., B. Grogaard, et al. (1992). "Effects of short-term treatment with corticosteroids and indomethacin on bone healing. A mechanical study of osteotomies in rats." Acta Orthop Scand63(6): 607-11.

We studied the effects of short-term therapy with methylprednisolone and indomethacin on healing of intramedullary pinned osteotomies of the femur in rats. When the osteotomy was complete and healing occurred under unstable conditions with callus formation, indomethacin inhibited healing when estimated by mechanical tests of bending moment, energy expenditure before refracture, and bending rigidity 6 weeks after surgery. No inhibitory effects were seen following corticosteroid treatment. When the osteotomy was incomplete and healing occurred under stable conditions, similar tendencies were observed. Thus, short-term medication with indomethacin inhibits fracture healing. This was not the case with short-term methylprednisolone.

Jones, M. K., H. Wang, et al. (1999). "Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing." Nat Med5(12): 1418-23.

Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.

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Jones, P. G. (1999). "Analgesia in soft-tissue injury: current practice in Auckland is not supported by the available evidence." N Z Med J 112(1097): 376-9.

AIMS: To document current prescribing habits and attitudes of doctors in the Auckland region towards analgesic medication for soft-tissue injury and determine whether the available evidence supports this practice. METHOD: A survey of 573 doctors in the Auckland region was conducted. There was a 71.4% response rate. The clinical and experimental evidence concerning non-steroidal, anti-inflammatory (NSAID) use in soft-tissue injury was reviewed. The side-effect profiles of NSAIDs were reviewed, with emphasis on the incidence of gastrointestinal side-effects when NSAIDs are prescribed for short periods and evidence implicating adverse renal effects on healthy exercising adults. RESULTS: Most doctors ranked NSAIDs more effective than paracetamol (70.4%, p<0.01). NSAIDs were the most prescribed single analgesic agents (47.8%, p<0.0001). Diclofenac was the NSAID of choice for 69.8% of doctors, who used NSAIDs (p<0.001). The incidence of gastrointestinal side-effects for short-term use of NSAIDs in acute soft tissue was 11%. CONCLUSION: The available evidence does not support the belief by the doctors surveyed that NSAIDs are more effective than paracetamol in soft-tissue injury. NSAIDs delay, but do not prevent the inflammatory response in injured tissue and may expose athletes to an increased risk of re-injury by delaying healing. Significant adverse effects do occur in previously healthy patients who receive NSAIDs.

Keller, J. (1996). "Effects of indomethacin and local prostaglandin E2 on fracture healing in rabbits."Dan Med Bull 43(4): 317-29.


Keller, J., C. Bunger, et al. (1987). "Bone repair inhibited by indomethacin. Effects on bone metabolism and strength of rabbit osteotomies." Acta Orthop Scand 58(4): 379-83.

We measured mineral content, maximum bending strength, and regional blood flow after tibial osteotomy fixed with a small metal plate in 38 rabbits. Half of the animals were treated with indomethacin (10 mg/kg/day) while the other half served as controls. After 2 and 6 weeks, the bone mineral content and maximum bending strength were lower in the indomethacin group when compared with the controls. Compared with the controls, the blood flow at the osteotomy site was decreased after 2 weeks and increased after 6 weeks in the indomethacin-treated animals. Inhibition of blood flow increase by indomethacin medication in the early period following osteotomy, as well as retarded bone healing, are probably caused by inhibition of the inflammatory reaction.

Keller, J., P. Kjaersgaard-Andersen, et al. (1990). "Indomethacin and bone trauma. Effects on remodeling of rabbit bone." Acta Orthop Scand 61(1): 66-9.

The influence of indomethacin on remodeling activity in normal trabecular and cortical bone and its influence on cortical bone close to a midtibial drill hole, 2 mm in diameter were histomorphometrically evaluated. Eight rabbits were treated with indomethacin (12.5 mg/kg/day), and another 8 rabbits served as controls. After 3 days, the mean plasma indomethacin level was 542 ng/mL, resulting in an almost complete inhibition of prostaglandin synthesis as reflected by the serum levels. In the control rabbits the remodeling activity after 6 weeks was increased 1 mm away from the drill hole but not at 3 and 8 mm. In conclusion, indomethacin had no effect on the activated remodeling process in cortical bone neighboring a small drill hole or on remodeling in nontraumatized cortical and cancellous bone. This suggests that the inhibitory effect of indomethacin on the remodeling process following local trauma to bone depends on the extent of the trauma.

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Khan, M. I. (1997). "Fracture healing: role of NSAIDs." Am J Orthop 26(6): 413.


Kumar, A., M. Rao, et al. (1988). "Zinc incorporation reverses suppressant effect of ibuprofen on wound healing." Indian J Exp Biol 26(6): 483-5.


Lane, N., T. Coble, et al. (1990). "Effect of naproxen on cancellous bone in ovariectomized rats." J Bone Miner Res 5(10): 1029-35.

Nonsteroidal anti-inflammatory drugs (NSAIDs) affect bone metabolism in vitro and in vivo. They delay but do not alter the outcome of healing processes in bone. In some bone loss models, they block bone resorption and slow the rate of loss. We studied the effect of naproxen, a potent NSAID, on cancellous bone of the proximal tibial metaphysis of 6-month- old adult female ovariectomized rats. Animals were ovariectomized, divided into groups, and fed standard diets differing only in naproxen content for 42 days. The rats of the groups ate 2.0, 5.5, 12.7, and 32 mg naproxen per kg body weight per day, respectively. Serum levels of naproxen were determined. Bone volume, mineralizing surface, osteoblast activity, osteoclast surface, and bone resorption rate were determined by bone histomorphometric techniques. The rats' dose-related serum naproxen levels ranged from 4 to 28 micrograms/ml. Naproxen inhibited up to 70% of the bone loss occurring after ovariectomy at a serum level of 4 micrograms/ml. We deduced that naproxen blocked bone resorption in ovariectomized rats by slowing osteoclast activity at all doses. In contrast, naproxen slowed bone formation only at serum levels greater than 20 micrograms/ml in ovariectomized rats. These findings may have clinical relevance in helping to prevent postmenopausal bone loss in women.

Moorman, C. T., U. Kukreti, et al. (1999). "The early effect of ibuprofen on the mechanical properties of healing medial collateral ligament." Am J Sports Med 27(6): 738-41.

We tested the hypothesis that injured ligaments in rabbits treated with ibuprofen would have decreased values of mechanical properties compared with the values of those treated with a placebo. In 24 New Zealand White rabbits, the medial collateral ligament of one hindlimb was ruptured; the contralateral ligament served as an internal control. The rabbits were treated orally, twice daily, with a 14-day course of either 35 mg of ibuprofen per kilogram of body weight or a placebo. The rabbits were sacrificed at 14 or 28 days, and the ligaments were tested in tension to failure at 0.15 mm/sec. There was no statistically significant difference in the values of mechanical properties of ligaments from rabbits treated with ibuprofen versus those treated with placebo at either 14 or 28 days after injury. Our findings suggest that there is no early deleterious effect of a short course of ibuprofen on the mechanical behavior of medial collateral ligaments.

Muscara, M. N., W. McKnight, et al. (2000). "Wound collagen deposition in rats: effects of an NO-NSAID and a selective COX-2 inhibitor." Br J Pharmacol 129(4): 681-6.

Selective cyclo-oxygenase (COX)-2 inhibitors and nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) exhibit reduced toxicity in the gastrointestinal tract, but may affect wound healing in other tissues. In this study, we have compared the effects of a selective COX- 2 inhibitor (celecoxib), a nitric-oxide releasing derivative of naproxen (HCT-3012) and naproxen in a model of wound collagen deposition in the rat. Polyvinyl alcohol sponges were implanted subcutaneously in rats. The rats were treated daily for 5 days with the test drugs at equieffective anti-inflammatory doses. Naproxen (10 mg kg(-1)) significantly decreased (45%) collagen deposition at the wound site relative to the vehicle-treated control group. In contrast, HCT- 3012 (14.5 mg kg(-1)) significantly increased (62%) collagen deposition, while celecoxib (10 mg kg(-1)) had no effect. Naproxen and HCT-3012 suppressed prostaglandin (PG) E(2) levels at the wound site and whole blood thromboxane synthesis to similar degrees. Celecoxib had no significant effect on wound fluid PGE(2) levels, but slightly reduced whole blood thromboxane synthesis (by 17%). COX-1 mRNA and protein were expressed in the wound exudate, the skin surrounding the wound and in normal skin. In contrast, COX-2 mRNA, but not protein, was expressed in wound and normal skin. These results demonstrate that HCT- 3012 can significantly enhance collagen deposition at a wound site, despite inhibiting prostaglandin synthesis to the same extent as the parent drug. Nitric oxide-releasing NSAIDs may represent a safer alternative to standard NSAIDs for use as anti-inflammatory and analgesic agents by post-surgery patients.

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Obeid, G., X. Zhang, et al. (1992). "Effect of ibuprofen on the healing and remodeling of bone and articular cartilage in the rabbit temporomandibular joint." J Oral Maxillofac Surg 50(8): 843-9; discussion 849-50.

The purpose of this study was to determine the effect of ibuprofen on the healing and remodeling of bone and cartilage in the temporomandibular joint of the rabbit. Forty-two rabbits were operated on to create a groove and a hole in the articular surface of both the right and left mandibular condyles. Following surgery, the animals were divided into three groups. Group A (12 rabbits) was used as a control and the animals did not receive any medication. Group B (15 rabbits) was given a daily dose of 17 mg/kg of ibuprofen. Group C (15 rabbits) was given a daily dose of 34 mg/kg of ibuprofen. All animals were killed after 4 weeks. The 84 condyles were examined clinically and histologically. Statistical analysis showed a highly significant difference in the healing of bone and cartilage between groups A and C (P less than .01) and a significant difference between groups A and B (P less than .05). The results of this study indicate that ibuprofen has an adverse effect on the healing of bone and cartilage in the temporomandibular joint of the rabbit.

Reynolds, J. F., T. D. Noakes, et al. (1995). "Non-steroidal anti-inflammatory drugs fail to enhance healing of acute hamstring injuries treated with physiotherapy." S Afr Med J 85(6): 517-22.

The effects of two non-steroidal anti-inflammatory drugs (NSAIDs), meclofenamate and diclofenac, in combination with physiotherapy modalities on the rate of healing of acute hamstring muscle tears were studied in a double-blind, placebo-controlled trial. Fourty-four of the 75 patients with this injury recruited were assessed and randomly allocated to one of three treatment groups: meclofenamate (100 mg 3 times a day), diclofenac (50 mg 3 times a day) and placebo. All patients received the same intensive physiotherapy treatment over the 7- day treatment period. Patient assessments were performed on days 1, 3 and 7 of the 7-day study period and included pain assessment (visual analogue scale), swelling measurement (thigh circumference measurement at the site of the muscle tear) and isokinetic muscle performance testing. Treatment produced a significant improvement in all measurements in all groups, but there was no difference in any measurement between groups. However, when only the more severe injuries were analysed, the reported pain score at day 7 was significantly lower in the placebo group than in either the meclofenamate group or the diclofenac group (P < 0.05). Hence this study did not find any additive effect on the healing of acute muscle injuries when meclofenamate or diclofenac was added to standard physiotherapeutic modalities. The study therefore does not support the use of NSAIDs in the treatment of acute hamstring muscle injuries.

Tornkvist, H. and T. S. Lindholm (1980). "Effect of ibuprofen on mass and composition of fracture callus and bone. An experimental study on adult rat." Scand J Rheumatol 9(3): 167-71.

Sixty adult male rats were used to study the effect of the anti- inflammatory drug Ibuprofen on fracture callus and perpendicular skeleton. After experimental periods of 3 and 9 weeks, fracture callus and both fractured and unfractured tibiae were examined with respect to bone mass and composition and 45Ca metabolism. No significant changes were found in the composition of fracture callus during treatment. Significantly diminished parameters of both fractured and unfractured tibia were observed for wet and dry weights, ash content, and organic matter after 3 weeks but the bone mass had become almost restored and the changes were non-significant during treatment 9 weeks following fracturing. The 45Ca activity was elevated significantly in fracture callus and fractured tibia 3 weeks after fracturing but had definitely declined to physiological levels at 9 weeks. Serum 45Ca activity was significantly elevated during Ibuprofen treatment. The findings support the concept that Ibuprofen lessens the bone mass and composition of both fractured and unfractured tibia and also activates the calcium metabolism in fracture callus. In the long run, however, this effect is weakened and the bone changes are become almost normal. Some explanations regarding these short-term effects of Ibuprofen are discussed.

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FAQs: Prof. Tim Watson

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