According to Wolf et al (1999), NSAID’s are the 15th most common cause of death in the US and in the 30 years preceding, 1999 conservative calculations suggest that 300,000 people in the US alone have died from GI complications.
With the advent of over the counter and easily accessible NSAID’s, these figures are more likely to have risen. In my 20 years of clinical practice, I have seen a significant rise in GI complications and use of protein pump inhibitors. Is increased NSAID use the likely cause or just an anecdotal “thing” that has just happened?
More and more evidence is suggesting that NSAID’s are harmful to cardiovascular health as well as GI health. I have included the references below along with the relevant abstracts; however, long term use is sparse regarding tissue healing. If we accept that the most common reason they are taken is pain use, such as headaches or period pains, let alone the dreaded back aches and pains many of us suffer, are we creating more severe long term issues for ourselves?
There are studies supporting the use of various NSAIDs on patients following soft-tissue injuries (although many of these are somewhat conflicting). Several studies support the use of NSAIDs for back pain (Chung et al 2013, Griffin et al 2002) and many other soft tissue injuries (Jones & Lamdin 2013). However the Cochrane database states that there is insufficient and conflicting evidence to support the use of NSAIDs in treating lateral elbow pain (Pattanittum et al 2013). For back pain however, it’s a go; (Roelfs et al 2008) and as such, people have a propensity to now pop NSAID’s like Smarties at the slightest ache or pain!
The question that has to be asked is, “does the use of NSAIDs for musculoskeletal injuries increase the risk of recurrence due to inadequate tissue healing?”
I’ll leave you to read the abstracts and decide for yourself!
REFERENCES:
Chechik O1, Dolkart O, Mozes G, Rak O, Alhajajra F, Maman E. Timing matters: NSAIDs interfere with the late proliferation stage of a repaired rotator cuff tendon healing in rats. Arch Orthop Trauma Surg. 2014 Apr;134(4):515-20.
Abstract
INTRODUCTION:
Rotator cuff (RC) tear is a common problem that causes pain and can limit shoulder function. Non-steroidal anti-inflammatory drugs (NSAIDs) are often prescribed for musculoskeletal pain, including the pain subsequent to RC repair. NSAIDs have been reported to affect bone metabolism and fracture healing, but there is little evidence about their effect on tendon healing. We investigated the effect of meloxicam (non-steroidal anti-inflammatory drug) on the healing of RC tendons when given immediately after surgical repair.
MATERIALS AND METHODS:
Thirty-nine rats underwent acute RC tear and repair. Group A (n = 13) received daily intraperitoneal (IP) injections of meloxicam for the first 10 postoperative days. Group B (n = 13) received IP injections of meloxicam starting from postoperative day 11. Group C (n = 13, controls) received daily IP injections of saline for 3 weeks. The animals were killed 3 weeks after surgery and the RC was evaluated by gross inspection, biomechanical testing and histological examination.
RESULTS:
Group B displayed a significantly lower mean maximal load at 3 weeks than group C (P = 0.02) and group A (P = 0.05). Stiffness was significantly lower in B group as compared to A group (P = 0.05). Qualitative examination of histology specimens did not disclose any apparent differences with respect to cellularity, vascularity, healing, and collagen orientation.
CONCLUSIONS:
We conclude that meloxicam decreases the biomechanical strength of repaired rat RCs when administered between 11 and 20 days after the repair.
Chen MR1, Dragoo JL. The effect of nonsteroidal anti- inflammatory drugs on tissue healing. Knee Surg Sports Traumatol Arthrosc. 2013 Mar;21(3):540-9.
Abstract
PURPOSE:
Non-selective (NSAIDs) and selective (COX-2) nonsteroidal anti-inflammatory drugs are commonly used for their analgesic and anti-inflammatory effects. Their role after orthopaedic surgery has been infrequently described and remains controversial because of unclear effects on soft tissue and bone healing. This study critically reviews the available literature to describe the effects of NSAIDs and COX-2 inhibitors on soft tissue and bone healing.
METHODS:
A Medline search was performed using NSAIDs or COX-2 inhibitors and tissue healing. The combined search yielded 637 articles. Following exclusion, 44 articles were deemed relevant with 9 articles on soft tissue healing and 35 articles on bone healing. The available evidence is based primarily on animal data (39 studies), with considerable variation in study methods.
RESULTS:
In regard to soft tissue healing, there is insufficient evidence of a detrimental effect when using either NSAIDs or COX-2 inhibitors at standard doses for ≤2 weeks. For soft tissue to bone healing, a limited number of studies demonstrate impairment in healing. However, with respect to bone healing, indomethacin appears to have a clear detrimental effect, with less substantial evidence for other NSAIDs.
CONCLUSIONS:
Short-term, low-dose use of NSAIDs and COX-2 inhibitors does not appear to have a detrimental effect following soft tissue injury, but is inhibitory in cases involving bony healing. However, additional well-controlled human studies are necessary to draw more definitive conclusions regarding their role. Clinically, the prudent use of anti-inflammatory medications following sports medicine injuries and surgeries appears to be a reasonable option in clinical practice unless bone healing is required.
Chung JW1, Zeng Y, Wong TK. Drug therapy for the treatment of chronic nonspecific low back pain: systematic review and meta-analysis. Pain Physician. 2013 Nov-Dec;16(6):E685-704.
Abstract
BACKGROUND:
Low back pain (LBP) is one of the most common health problems in adults. The impact of LBP on the individual can cause loss of health status in the form of symptoms and loss of function related to pain in the back; limitation of daily, leisure, and/or strenuous activities, and disability. LBP also poses an economic burden to society, mainly in terms of one of the most common reasons for seeking medical care (direct treatment costs), and accounts for the large number of work days lost (indirect costs). To reduce the impact of LBP on adults, drug therapy is the most frequently recommended intervention. Over the last decade, a substantial number of randomized clinical trials of drug therapy for LBP have been published.
OBJECTIVE:
To determine the effectiveness of drug therapy for the treatment of chronic nonspecific low back pain (CNLBP).
STUDY DESIGN:
Systematic review
METHODS:
A systematic review and meta-analysis of randomized controlled trials was conducted. Five databases (Medline, CINAHL, Science Direct, CAJ Full-text Database, and Cochrane databases) were searched for articles published from 2002 to 2012. The eligibility criteria were randomized trials and double-blind controlled trials of oral or injection drug therapy for CNLBP in subjects who were aged at least 18 years old, published in English or Chinese. Two independent reviewers extracted the data.
RESULTS:
A total of 25 drug therapy trials were included. cyclo-oxygenase-2 (COX-2) nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol, and opioids were commonly used. Only 5 trials studied the efficacy of adjuvant analgesics of antiepileptics (n = 1) and antidepressants (n = 4) for CNLBP. The standardized mean difference (SMD) for COX-2 NSAIDs in pain relief was -12.03 (95% confidence interval [CI]: -15.00 to -9.06). The SMD for tramadol in pain relief was -1.72 (95% CI: -3.45 to 0.01). As the 95% CI crossed 0, this effect size was not considered statistically significant. The SMD for the overall effects of opioids in pain relief was -5.18 (95% CI: -8.30 to -2.05). The SMD for the partial opioid agonist drug in pain relief was -7.46 (95% CI: -11.87 to -3.04).
LIMITATIONS:
The follow-up periods of these included trials in the meta-analysis ranged from 4 to 24 weeks. The difference of follow-up periods influenced how study outcomes were recorded. These included trials also had significant differences in patient selections. Some trials may actually include CNLBP patients with neuropathic pain, as not having focal neurological findings or signs does not mean that the pain is not neuropathic. Consequently, different pain conditions may influence patients who responded to the same drug and then influence pooled estimates of treatment effect size.
CONCLUSION:
This review endorses the use of COX-2 NSAIDs as the first-line drugs for CNLBP. Tramadol shows no statistically significant effect on pain relief, but has small effect sizes in improving functioning. Among included opioid therapy studies, the overall effects of opioids and the partial opioids agonist drug had statistically significant treatment effects in pain relief for CNLBP patients.
Cohen DB1, Kawamura S, Ehteshami JR, Rodeo SA. Indomethacin and celecoxib impair rotator cuff tendon- to-bone healing. Am J Sports Med. 2006 Mar;34(3):362- 9.
Abstract
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.
Dahners LE1, Mullis BH. Effects of nonsteroidal anti- inflammatory drugs on bone formation and soft-tissue healing. J Am Acad Orthop Surg. 2004 May- Jun;12(3):139-43.
Abstract
Nonsteroidal anti-inflammatory drugs continue to be prescribed as analgesics for patients with healing fractures even though these drugs diminish bone formation, healing, and remodeling. Inhibition of bone formation can be clinically useful in preventing heterotopic ossification in selected clinical situations. In this regard, naproxen may be more efficacious than the traditional indomethacin, and short-term administration is as effective as long-term. When fracture healing or spine fusion is desired, nonsteroidal anti-inflammatory drugs should be avoided. Some nonsteroidal anti-inflammatory drugs have a positive effect on soft-tissue healing; they stimulate collagen synthesis and can increase strength in the early phases of repair during skin and ligament healing. Cyclooxygenase-2 inhibitors have an adverse effect on bone healing and may have an adverse effect on ligament healing. Therefore, further investigation is necessary to confirm that traditional nonsteroidal anti-inflammatory drugs may be preferable for the healing of collagenous tissues.
Dimmen S1, Engebretsen L, Nordsletten L, Madsen JE. Negative effects of parecoxib and indomethacin on tendon healing: an experimental study in rats. Knee Surg Sports Traumatol Arthrosc. 2009 Jul;17(7):835-9.
Abstract
Conventional non-steroidal anti-inflammatory drugs (NSAIDs) and newer specific cyclooxygenase-2 (cox-2) inhibitors are commonly used in muscular skeletal trauma and in relation to orthopedic surgery to reduce the inflammatory response and pain. Studies have indicated that these drugs can have a negative effect on tendon healing in the early proliferative phase, but might be beneficial in the remodeling phase when inflammation might impede healing. Our study was designed to investigate if short-term administration of cox inhibitors after injury or postoperatively might have negative effects on the tendon healing. The right Achilles tendon of 60 rats was cut transversely, a 3 mm long segment of the tendon was removed and left unrepaired. The animals were then given parecoxib, indomethacin or saline intraperitoneally twice daily for 7 days. After 14 days, the animals were euthanized. The transverse and sagittal diameters in the healing area were measured and mechanical testing of the tensile strength of the tendons was performed. We found a significantly lower tensile strength in rats given both parecoxib and indomethacin compared to the control group. Stiffness in the healing tendons was significantly lower in the parecoxib group compared to both the placebo and the indomethacin groups. The transverse and sagittal diameters of the tendons were reduced in both the parecoxib and indomethacin groups. Both parecoxib and indomethacin impaired tendon healing; the negative effect was most pronounced with parecoxib.
Ferry ST, Dahners LE, Afshari HM, Weinhold PS. The effects of common anti-inflammatory drugs on the healing rat patellar tendon. Am J Sports Med. 2007 Aug;35(8):1326-33.
Abstract
BACKGROUND:
Tendon injuries that occur at the osteotendinous junction are commonly seen in clinical practice and range from acute strain to rupture. Nonsteroidal anti-inflammatory drugs are often prescribed in the treatment of these conditions, but the effect that these agents may have on the healing response at the bone-tendon junction is unclear.
HYPOTHESIS:
In response to an acute injury at the osteotendinous junction, the healing patellar tendon will have inferior biomechanical properties with administration of anti-inflammatory drugs as compared with acetaminophen and control.
STUDY DESIGN:
Controlled laboratory study.
METHODS:
A total of 215 Sprague-Dawley rats underwent transection of the patellar tendon at the inferior pole of the patella, which was subsequently stabilized with a cerclage suture. The animals were then randomized into 7 groups and administered 1 of the following analgesics for 14 days: ibuprofen, acetaminophen, naproxen, piroxicam, celecoxib, valdecoxib, or control. At 14 days, all animals were sacrificed, and the extensor mechanism was isolated and loaded to failure. Biochemical analysis of the repair site tissue was performed. Animal activity throughout the study was monitored using a photoelectric sensor system.
RESULTS:
The control group demonstrated greater maximum load compared with the celecoxib, valdecoxib, and piroxicam groups (P < .05). The acetaminophen and ibuprofen groups were also significantly stronger than the celecoxib group (P < .05) but not statistically different than the control group. A total of 23 specimens had failure of the cerclage suture with the following distribution: control (0/23), ibuprofen (0/23), acetaminophen (0/24), naproxen (3/24), piroxicam (4/24), celecoxib (6/22), and valdecoxib (10/24). The difference in distribution of the failures was significant (P < .001).
CONCLUSIONS:
Anti-inflammatory drugs, with the exception of ibuprofen, had a detrimental effect on healing strength at the bone-tendon junction as demonstrated by decreased failure loads and increased failures of the cerclage suture. Acetaminophen had no effect on healing strength. The biomechanical properties paralleled closely with the total collagen content at the injury site, suggesting that these agents may alter healing strength by decreasing collagen content.
CLINICAL RELEVANCE:
Selective and nonselective cyclooxygenase (COX) inhibitors should be used judiciously in the acute period after injury or surgical repair at the bone-tendon junction.
Hauser RA, E.E. Dolan, H.J. Phillips, A.C. Newlin, R.E. Moore and B.A. Bentham Ligament Injury and Healing: A Review of Current Clinical Diagnostics and Therapeutics The Open Rehabilitation Journal, 2013, 6, 1-20
Ligament injuries are among the most common causes of musculoskeletal joint pain and disability encountered in primary practice today. Ligament injures create disruptions in the balance between joint mobility and joint stability, causing abnormal force transmission through the joint, which results in damage to other structures in and around the joint. The long-term consequence of nonhealed ligament injury is osteoarthritis, the most common joint disorder in the world today. Ligaments heal through a distinct sequence of cellular events that take place in three consecutive stages: an acute inflammatory phase, a proliferative or regenerative phase, and a tissue remodeling phase. The process can take months to resolve itself, and despite advances in therapeutics, many ligaments do not regain their normal tensile strength. Various diagnostic procedures have been used to determine and assess ligament injury. Traditionally, MRI and X-rays have been the most utilized techniques; however, because ligaments do not show up clearly with these devices, there have been many false positives and negatives reported due to inconclusive or inaccurate readings. Newer technologies, such as ultrasound and digital motion X-ray, are able to provide a more detailed image of a ligament’s structure and function. Numerous strategies have been employed over the years attempting to improve ligament healing after injury or surgery. One of the most important of these is based on the understanding that monitoring early resumption of activity can stimulate repair and restoration of function and that prolonging rest may actually delay recovery and adversely affect the tissue’s response to repair. Likewise, there is a shift away from the use of steroid injections and nonsteroidal anti-inflammatory medications. Although these compounds have been shown effective in decreasing the inflammation and pain of ligament injuries for up to six to eight weeks, their use has been shown to inhibit the histological, biochemical, and biomechanical properties of ligament healing. For this reason their use is cautioned against in athletes who have ligament injuries. Such products are no longer recommended for chronic soft tissue injuries or for acute ligament injuries, except for the shortest possible time, if at all. Regenerative medicine techniques, such as prolotherapy, have been shown, in both case series and clinical studies, to resolve ligament injuries of the spine and peripheral joints. More research and additional studies are needed to better assess ligament injuries and healing properties.
Hunt RH1, Choquette D, Craig BN, De Angelis C, Habal F, Fulthorpe G, Stewart JI, Turpie AG, Davis P. Approach to managing musculoskeletal pain: acetaminophen, cyclooxygenase-2 inhibitors, or traditional NSAIDs? Can Fam Physician. 2007 Jul;53(7):1177-84.
Abstract
OBJECTIVE:
To provide family physicians and pharmacists with practical, evidence- and expertise-based guidance on choosing the safest approach to using analgesics to manage patients with musculoskeletal pain.
SOURCES OF INFORMATION:
Health care providers from family practice, rheumatology, gastroenterology, hepatology, internal medicine, and pharmacy participated in an educational needs assessment regarding the management of pain and the safety of commonly used analgesics. Feedback from one-on-one interviews was compiled and distributed to participants who selected key topics. Topics chosen formed the basis for the discussions of this multidisciplinary panel that reviewed data on the safety of analgesics, particularly in regard to comorbidity and concurrent use with other therapies.
MAIN MESSAGE:
Treatment should begin with an effective analgesic with the best safety profile at the lowest dose and escalate to higher doses and different analgesics as required. Acetaminophen is a safe medication that should be considered first-line therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with potential adverse gastrointestinal, renal, hepatic, and cardiovascular effects. Physicians should not prescribe NSAIDs before taking a careful history and doing a physical examination so they have the information they need to weigh the risks (adverse effects and potential drug interactions) and benefits for individual patients.
CONCLUSION:
Taking a complete and accurate history and doing a physical examination are essential for choosing the safest analgesic for a particular patient.
Jones P1, Lamdin R. Oral cyclo-oxygenase 2 inhibitors versus other oral analgesics for acute soft tissue injury: systematic review and meta-analysis. Clin Drug Investig. 2010;30(7):419-37.
Abstract
BACKGROUND:
Acute soft tissue injuries are common and carry significant societal costs. Cyclo-oxygenase 2 (COX-2) inhibitors (coxibs), non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics are used to treat acute soft tissue injuries, with ongoing debate about their analgesic efficacy, effects on tissue healing and adverse effects (AEs).
OBJECTIVES:
To systematically review the evidence comparing oral coxibs with other oral analgesics for acute soft tissue injuries, using the outcomes: pain, swelling, function and AEs.
METHODS:
The following databases were searched: MEDLINE, EMBASE, Cochrane CENTRAL, CINAHL, AMED, PEDro and SPORTDiscus. Further studies were sought through clinical trials registries, dissertations, correspondence with pharmaceutical companies and manual searches of relevant journals. There was no language restriction.
DEFINITIONS:
‘Coxibs’ were defined as drugs that inhibit COX-2 >5-fold more than COX-1; ‘acute’ was defined as injury occurring within 48 hours of enrollment; ‘soft tissue injury’ was defined as closed injuries to upper or lower limb soft tissues (ligaments, muscles or tendons).
STUDY SELECTION:
Randomized controlled trials in humans comparing a coxib to a different class of oral analgesic agent for the treatment of acute soft tissue injuries for <30 days, and in which >or=80% of participants met the definition of acute soft tissue injury, were included. Studies were excluded if >20% of participants enrolled had back pain, cervical spine injury, repetitive strain injuries, delayed-onset muscle soreness, fractures, cartilage injury, penetrating wounds or primary inflammatory conditions (tendonitis, bursitis and arthritis). Nine out of 23 (39.1%) potentially relevant studies met the selection criteria.
DATA EXTRACTION:
A standard form was used to extract data. Included studies were screened by the authors for risk of bias using the Cochrane risk of bias tool and evidence was graded for quality using the GRADE tool.
DATA SYNTHESIS:
Clinical heterogeneity was minimized by application of strict selection criteria. Statistical heterogeneity was assessed using the I2 statistic and meta-analysis was undertaken if appropriate. Weighted mean difference (WMD) was used to assess pain, relative risk (RR) to assess AEs, and Peto odds ratio (OR) to assess return to function.
RESULTS:
The nine RCTs evaluated in the meta-analysis included 3060 patients. Coxibs were found to be equal to NSAIDs (day 7+, n = 1884, 100 mm visual analogue scale [VAS]), WMD = 0.18 mm (95% CI -1.76, 2.13), p = 0.85 and tramadol (day 7+, n = 706, 100 mm VAS), WMD = -6.6 mm (95% CI -9.63, -3.47) [single study, difference clinically insignificant] for treating pain after soft tissue injuries. Coxibs had fewer gastrointestinal AEs than NSAIDs, even with short-term use (RR 0.59 [95% CI 0.41, 0.85], p = 0.004) [low quality evidence]. Swelling was measured in two studies with no difference being found between groups, but the presentation of the data was not sufficient to allow further analysis. Coxibs were found to be unlikely to be different to NSAIDs in helping patients return to function (OR 1.0 [95% CI 0.77, 1.3], p = 0.99); however, a single study suggested they may improve time to return to function (moderate quality evidence) and may have fewer AEs than tramadol (very low quality evidence). The risk of serious AEs with both coxibs and NSAIDs in this setting was low (but incompletely defined).
CONCLUSIONS:
More studies comparing coxibs with NSAIDs and other analgesics in the setting of acute soft tissue injuries are necessary. A different review methodology would be required to answer the question of cardiovascular risk associated with short-term use of coxibs and NSAIDs.
Klenerman L, et al The prediction of chronicity in patients with an acute attack of low back pain in a general practice setting. Spine. 1995 Feb 15;20(4):478- 84.
Abstract
STUDY DESIGN:
Three hundred patients, attending their general practitioners with attacks of acute low back pain, formed the subject population for a study of fear avoidance and other variables in the prediction of chronicity. Follow-up was at 2 and 12 months.
OBJECTIVE:
The hypothesis to be tested was that evidence of psychological morbidity, particularly fear-avoidance behavior, would be manifest from the outset of the presenting attack in susceptible subjects.
SUMMARY OF BACKGROUND DATA:
While back pain is an almost universal human experience, only about 5% of sufferers seek medical advice. Most of these respond to conservative treatment. However, approximately 10% of those who experience an acute attack of low back pain go on to become chronic sufferers.
METHODS:
Psychosocial and physiological data (including fear-avoidance measures) were collected from a sample of 300 acute low back pain patients within 1 week of presentation and at 2 months, to try to predict 12 month outcome.
RESULTS:
Data analysis showed that subjects who had not recovered by 2 months were those who went on to become chronic low back pain patients (7.3%). Using multiple regression analyses, fear-avoidance variables were the most successful in predicting outcome. Using multiple discriminant function analyses, the results suggest that the outcome in terms of the future course of low back pain can be correctly classified in 66% from fear-avoidance variables alone and in 88% of patients from all variables.
CONCLUSIONS:
The results suggest that, at the earliest stage of low back pain, fear of pain should be identified by clinicians and, where this is severe, pain confrontation should arguably form part of the approach to treatment.
McGettigan P1, Henry D. Use of non-steroidal anti- inflammatory drugs that elevate cardiovascular risk: an examination of sales and essential medicines lists in low-, middle-, and high-income countries. PLoS Med. 2013;10(2):e1001388.
Abstract
BACKGROUND:
Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries.
METHODS AND FINDINGS:
Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7-58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%.
CONCLUSIONS:
Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs.
Mishra DK1, Fridén J, Schmitz MC, Lieber RL. Anti- inflammatory medication after muscle injury. A treatment resulting in short-term improvement but subsequent loss of muscle function. J Bone Joint Surg Am. 1995 Oct;77(10):1510-9.
Abstract
We studied the effect of flurbiprofen, a non-steroidal anti-inflammatory drug, on muscles that had been subjected to exercise-induced injury. The muscles of the anterior compartment in the limbs of rabbits were cyclically activated as the ankle was simultaneously moved through passive plantar flexion every two seconds for thirty minutes. This treatment imposed acute passive lengthening (eccentric contractions) of the maximally contracted muscles of the anterior compartment. After the eccentric contraction-induced muscle injury, one group of rabbits was treated with oral administration of flurbiprofen, two times a day for six days, while the other group of rabbits served as untreated controls. The contractile, histological, and ultrastructural properties of the muscles were measured before the initial exercise and at three, seven, and twenty-eight days afterward. The group that was treated with flurbiprofen demonstrated a more complete functional recovery than the untreated controls at three and seven days but had a deficit in torque and force generation at twenty-eight days. The administration of flurbiprofen also resulted in a dramatic preservation of the intermediate filament protein desmin. After three days, the proportion of fibers of the extensor digitorum longus that lost desmin-staining was significantly greater in the untreated controls than in the treated animals (34 +/- 4.1 compared with 2.9 +/- 1.7 per cent) (p < 0.001), a finding that supports the concept of a short-term protective effect. However, the muscles in the treated animals still mounted a dramatic regenerative response, as indicated by the expression of embryonic myosin. Early in the recovery period (at three days), significantly fewer fibers of the extensor digitorum longus (2.2 +/- 1.4 per cent) expressed embryonic myosin in the treated animals than in the untreated controls (11.8 +/- 1.9 per cent) (p < 0.001). However, at seven days, the expression of embryonic myosin by the muscles from the treated animals (19.5 +/- 11.9 per cent) actually exceeded that of the muscles from the untreated controls (16.2 +/- 4.1 per cent). This finding suggests either a delayed or an ineffectual regenerative response by the muscles in the treated animals.
O’Connor JP1, Capo JT, Tan V, Cottrell JA, Manigrasso MB, Bontempo N, Parsons JR. A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing. Acta Orthop. 2009 Oct;80(5):597- 605.
Abstract
BACKGROUND AND PURPOSE:
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity, which is the rate-limiting enzyme in the synthesis of prostaglandins. Previous studies have indicated that NSAID therapy, and in particular NSAIDs that specifically target the inflammatory cyclooxygenase (COX-2), impair bone healing. We compared the effects of ibuprofen and rofecoxib on fibula osteotomy healing in rabbits to determine whether nominal, continuous inhibition of COX-2 with rofecoxib would differentially affect fracture healing more than cyclical inhibition of COX-2 using ibuprofen, which inhibits COX-1 and COX-2 and has a short half-life in vivo.
METHODS:
Bilateral fibula osteotomies were done in 67 skeletally mature male New Zealand white rabbits. The rabbits were treated with placebo, rofecoxib (12.5 mg once a day), or ibuprofen (50 mg 3 times a day) for 28 days after surgery. Plasma ibuprofen levels were measured by HPLC analysis. Bone healing was assessed by histomorphometry at 3 and 6 weeks after osteotomy, and at 6 and 12 weeks by torsional mechanical testing.
RESULTS:
Plasma ibuprofen levels peaked and declined between successive doses. Fracture callus morphology was abnormal in the rofecoxib-treated rabbits and torsional mechanical testing showed that fracture healing was impaired. Ibuprofen treatment caused persistence of cartilage within the fracture callus and reduced peak torque at 6 weeks after osteotomy as compared to the fibulas from the placebo-treated rabbits. In the specimens allowed to progress to possible healing, non-union was seen in 5 of the 26 fibulas from the rofecoxib-treated animals as compared to 1 of 24 in the placebo group and 1 of 30 in the ibuprofen treatment group.
INTERPRETATION:
Continuous COX-2 inhibition as modeled by rofecoxib treatment appears to be more deleterious to fracture repair than cyclical cyclooxygenase inhibition as modeled by ibuprofen treatment. Ibuprofen treatment appeared to delay bone healing based upon the persistence of cartilage within the fracture callus and diminished shear modulus. Despite the ibuprofen-induced delay, rofecoxib treatment produced worse fracture (osteotomy) healing than ibuprofen treatment.
Pattanittum P1, Turner T, Green S, Buchbinder R. Non- steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults. Cochrane Database Syst Rev. 2013 May 31;5:
Abstract
BACKGROUND:
Lateral elbow pain, or tennis elbow, is a common condition that causes pain in the elbow and forearm. Although self-limiting, it can be associated with significant disability and often results in work absence. It is often treated with topical and oral non-steroidal anti-inflammatory drugs (NSAIDs). This is an update of a review first published in 2002 (search date October 11, 2012).
OBJECTIVES:
To assess the benefits and harms of topical and oral NSAIDs for treating people with lateral elbow pain.
SEARCH METHODS:
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, EMBASE and SciSearch up to October 11, 2012. No language restriction was applied.
SELECTION CRITERIA:
Studies were included if they were randomised or quasi-randomised controlled trials (RCTs or CCTs) that compared topical or oral NSAIDs with placebo or another intervention, or compared two NSAIDs in adults with lateral elbow pain. Outcomes of interest were pain, function, quality of life, pain-free grip strength, overall treatment success, work loss and adverse effects.
DATA COLLECTION AND ANALYSIS:
Two review authors independently selected the studies for inclusion, extracted the data, and performed a risk of bias assessment.
MAIN RESULTS:
Fifteen trials, involving 759 participants and reporting 17 comparisons, were included in the review. Four new trials identified from the updated search were included, along with 11 of 14 trials included in the original review (three trials included in the previous review were found not to meet inclusion criteria). Of eight trials that studied topical NSAIDs (301 participants), five compared topical NSAIDs with placebo, one compared manipulative therapy and topical NSAIDs with manipulative therapy alone, one compared leech therapy with topical NSAIDs and one compared two different topical NSAIDs. Of seven trials that investigated oral NSAIDs (437 participants), two compared oral NSAIDs with placebo, one compared oral NSAIDs and bandaging with bandaging alone, three compared oral NSAIDs with glucocorticoid injection, one compared oral NSAIDs with a vasodilator and two compared two different oral NSAIDs. No trials directly compared topical NSAIDs with oral NSAIDs. Few trials used intention-to-treat analysis, and the sample size of most was small. The median follow-up was 2 weeks (range 1 week to 1 year).Low-quality evidence was obtained from three trials (153 participants) suggesting that topical NSAIDs were significantly more effective than placebo with respect to pain in the short term (mean difference -1.64, 95% confidence interval (CI) -2.42 to -0.86) and number needed to treat to benefit (7 (95% CI 3 to 21) on a 0 to 10 scale). Low-quality evidence was obtained from one trial (85 participants) indicating that significantly more participants report fair, good or excellent effectiveness with topical NSAIDs versus placebo at 28 days (14 days of therapy) (risk ratio (RR) 1.49, 95% CI 1.04 to 2.14). No participants withdrew as the result of adverse events, but some studies reported mild adverse effects such as rash in 2.5% of those exposed to topical NSAIDs compared with 1.3% of those exposed to placebo.Low-quality and conflicting evidence regarding the benefits of oral NSAIDs obtained from two trials could not be pooled. One trial found significantly greater improvement in pain compared with placebo, and the other trial found no between-group differences; neither trial found differences in function. One trial reported a withdrawal due to adverse effects for a participant in the NSAIDs group. Use of oral NSAIDs was associated with increased risk of gastrointestinal side effects compared with placebo in one trial in the review. Another trial reported discontinuation of treatment due to gastrointestinal side effects in four participants taking NSAIDs, and another participant developed an allergic reaction in response to oral NSAIDs.Very scant and conflicting evidence regarding the comparative effects of oral NSAIDs and glucocorticoid injection was obtained. One trial reported a significant improvement in pain with glucocorticoid injection, and another found no between-group differences; treatment success was similar between groups (RR of fair, good or excellent effectiveness 0.74; 95% CI 0.43 to 1.26). Transient pain may occur following injection.
AUTHORS’ CONCLUSIONS:
There remains limited evidence from which to draw firm conclusions about the benefits or harms of topical or oral NSAIDs in treating lateral elbow pain. Although data from five placebo-controlled trials suggest that topical NSAIDs may be beneficial in improving pain (for up to 4 weeks), non-normal distribution of data and other methodological issues precluded firm conclusions. Some people may expect a mild transient skin rash. Evidence about the benefits of oral NSAIDs has been conflicting, although oral NSAID use may result in gastrointestinal adverse effects in some people. No direct comparisons between oral and topical NSAIDs were available. Some trials demonstrated greater benefit from glucocorticoid injection than from NSAIDs in the short term, but this was not apparent in all studies and was not apparent by 6 months in the only study that included longer-term outcomes.
Singh Gurkirpal, MD, “Recent Considerations in Nonsteroidal Anti-Inflammatory Drug Gastropathy”, The American Journal of Medicine, July 27, 1998, p. 31S
Abstract
Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications and at least 16,500 NSAID-related deaths occur each year among arthritis patients alone. The figures for all NSAID users would be overwhelming, yet the scope of this problem is generally under-appreciated. The Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) Post-Marketing Surveillance Program (PMS) has prospectively followed patient status and outcomes, drug side effects, and the economic impact of illness for >11,000 arthritis patients at 8 participating institutions in the United States and Canada. Analysis of these data indicates that: (1) osteoarthritis (OA) and rheumatoid arthritis (RA) patients are 2.5-5.5 times more likely than the general population to be hospitalized for NSAID-related GI events; (2) the absolute risk for serious NSAID-related GI toxicity remains constant and the cumulative risk increases over time; (3) there are no reliable warning signals- >80% of patients with serious GI complications had no prior GI symptoms; (4) independent risk factors for serious GI events were age, prednisone use, NSAID dose, disability level, and previous NSAID-induced GI symptoms; and (5) antacids and H2 antagonists do not prevent NSAID-induced gastric ulcers, and high-risk NSAID users who take gastro-protective drugs are more likely to have serious GI complications than patients not taking such medications. Currently, limiting NSAID use is the only way to decrease the risk of NSAID-related GI events. Ongoing ARAMIS research is aimed at developing a simple point-score system for estimating individual risks of developing serious NSAID-related GI complications.
Slatyer MA1, Hensley MJ, Lopert R. A randomized controlled trial of piroxicam in the management of acute ankle sprain in Australian Regular Army recruits. The Kapooka Ankle Sprain Study. Am J Sports Med. 1997 Jul-Aug;25(4):544-53.
Abstract
Three hundred sixty-four Australian Regular Army recruits with acute ankle sprains sustained during training were randomized to treatment with either piroxicam or placebo. Compared with the placebo group, subjects treated with piroxicam had less pain, were able to resume training more rapidly, were treated at lower cost, and were found to have increased exercise endurance on resumption of activity. Nausea was the only side effect reported significantly more often in the treatment group than in the placebo group (6.8% versus 0.3%). Interestingly, subjects treated with piroxicam showed some evidence of local abnormalities such as instability and reduced range of movement. We conclude that nonsteroidal antiinflammatory agents should form an integral part of the treatment of acute ankle sprains.
Warden SJ1, Avin KG, Beck EM, DeWolf ME, Hagemeier MA, Martin KM. Low-intensity pulsed ultrasound accelerates and a nonsteroidal anti- inflammatory drug delays knee ligament healing. Am J Sports Med. 2006 Jul;34(7):1094-102.
Abstract
BACKGROUND:
Low-intensity pulsed ultrasound and nonsteroidal anti-inflammatory drugs are used to treat ligament injuries; however, their individual and combined effects are not established.
HYPOTHESES:
Low-intensity pulsed ultrasound accelerates ligament healing, a nonsteroidal anti-inflammatory drug delays healing, and the nonsteroidal anti-inflammatory drug inhibits the beneficial effect of low-intensity pulsed ultrasound.
STUDY DESIGN:
Controlled laboratory study.
METHODS:
Sixty adult rats underwent bilateral transection of their knee medial collateral ligaments. Animals were divided into 2 drug groups and treated 5 d/wk with celecoxib (5 mg/kg) mixed in a vehicle solution (NSAID group) or vehicle alone (VEH group). One to 3 hours after drug administration, all animals were treated with unilateral active low-intensity pulsed ultrasound and contralateral inactive low-intensity pulsed ultrasound. Equal numbers of animals from each drug group were mechanically tested at 2 weeks (n = 14/group), 4 weeks (n = 8/group), and 12 weeks (n = 8/group) after injury.
RESULTS:
Ultrasound and drug intervention did not interact to influence ligament mechanical properties at any time point. After 2 weeks of intervention, ligaments treated with active low-intensity pulsed ultrasound were 34.2% stronger, 27.0% stiffer, and could absorb 54.4% more energy before failure than could ligaments treated with inactive low-intensity pulsed ultrasound, whereas ligaments from the NSAID group could absorb 33.3% less energy than could ligaments from the VEH group. There were no ultrasound or drug effects after 4 and 12 weeks of intervention.
CONCLUSIONS:
Low-intensity pulsed ultrasound accelerated but did not improve ligament healing, whereas the nonsteroidal anti-inflammatory drug delayed but did not impair healing. When used in combination, the beneficial low-intensity pulsed ultrasound effect was cancelled by the detrimental nonsteroidal anti-inflammatory drug effect.
CLINICAL RELEVANCE:
Low-intensity pulsed ultrasound after ligament injury may facilitate earlier return to activity, whereas non-steroidal anti-inflammatory drugs may elevate early reinjury risk.
Wolfe M. MD, Lichtenstein D. MD, and Singh Gurkirpal, MD, “Gastrointestinal Toxicity of Nonsteroidal Anti-inflammatory Drugs”, The New England Journal of Medicine, June 17, 1999, Vol. 340, No. 24, pp. 1888-1889.
“If deaths from the toxic effects from NSAID’s were tabulated separately, they would constitute the 15th most common cause of death in the United States. Yet these toxic effect remain a “silent epidemic,” with many physicians and most patients unaware of the magnitude of the problem. Furthermore the mortality statistics do not include deaths ascribed to the use of over-the-counter NSAIDS.”
Ziltener JL1, Leal S, Fournier PE.Non-steroidal anti- inflammatory drugs for athletes: an update. Ann Phys Rehabil Med. 2010 May;53(4):278-82, 282-8
Abstract
Sports medicine physicians often treat athletes in pain with non-steroidal anti-inflammatory drugs (NSAIDs). However, there is a lack of high-quality evidence to guide NSAID use. Their adverse effects have clinical relevance, and their possible negative consequences on the long-term healing process are slowly becoming more obvious. This article provides some practical management guidelines for the use of NSAIDs, developed to help sports medicine physicians deal with frequent sports-related injuries. We do not recommend their use for muscle injuries, bone fractures (also stress fractures) or chronic tendinopathy. In all cases, if chosen, NSAID treatments should always be kept as short as possible and should take into account the specific type of injury, the level of dysfunction and pain.