Many animal studies have investigated the impact of nonselective NSAIDs and selective COX-2 inhibitors on fracture healing. Nearly all those experiments focused on chronic drug administration following simulated long-bone fractures. One concern regarding the clinical relevance of those animal studies is that the “fractures” are often created by open means, which results in cortical devascularization and which may not accurately simulate the most common long-bone fracture pathophysiology in humans. Nevertheless, many orthopaedic surgeons have used the results of those animal studies to limit—or even stop—their use of NSAIDs to treat postfracture pain.
In the July 15, 2020 issue of The Journal, George et al. use a large private-insurance database to investigate the association between postfracture prescriptions filled for NSAIDS (both selective COX-2 inhibitors and nonselective types) and the subsequent diagnosis of a nonunion at 1 year postinjury. Administrative database research is more useful for generating hypotheses than for proving or disproving them, and these authors (along with Commentary writer Willem-Jan Metsemakers, MD, PhD) rightly point out that adequately powered randomized trials are needed to more fully address this issue.
Still, I was a bit surprised by the finding that nonselective NSAIDs were not associated with the diagnosis of nonunion while selective COX-2 inhibitors were. It seems to me that, given the sparse and conflicting clinical evidence today, a brief course of NSAIDs for fracture-related pain management should be included for patients while we await answers from studies with more robust research designs.
Marc Swiontkowski, MD
OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from Eric Secrist, MD in response to a recent study in Arthritis Research & Therapy.
There has been a proliferation of research regarding postoperative opioid usage after joint arthroplasty due to the widespread opioid epidemic. But Rajamäki and colleagues from Tampere University in Finland took the unique approach of also analyzing acetaminophen and NSAID usage in addition to opioids. The authors used robust data from Finland’s nationwide Drug Prescription Register, which contains reliable information on all medications dispensed from pharmacies, including over-the-counter drugs.
After excluding patients who underwent revision surgery or had their knee or hip replaced for a diagnosis other than osteoarthritis, the authors analyzed 6,238 hip replacements in 5,657 patients and 7,501 knee replacements in 6,791 patients, all performed between 2002 and 2013. The mean patient age was 68.7 years and the mean BMI was 29.
One year postoperatively, 26.1% of patients were still filling prescriptions for one or more analgesics, including NSAIDs (15.5%), acetaminophen (10.1%), and opioids (6.7%). Obesity and preoperative analgesic use were the strongest predictors of prolonged analgesic medication usage 1 year following total joint arthroplasty. Other predictors of ongoing analgesic usage included older age, female gender, and higher number of comorbidities. Patients who underwent knee replacement used the 3 analgesics more often than those who underwent hip replacement.
This study had all of the limitations inherent in retrospective database analyses. Additionally, it was not possible for the authors to determine whether patients took analgesic medications for postoperative knee or hip pain or for pain elsewhere in their body. Finally, the authors utilized antidepressant reimbursement data as a surrogate marker for depression and other medications as a surrogate for a Charlson Comorbidity Index.
Figure 2 from this study (shown below) reveals 2 important findings. First, total joint arthroplasty resulted in a significant decrease in the proportion of patients taking an analgesic medication, regardless of BMI. Second, patients in lower BMI categories were less likely to use analgesics both preoperatively and postoperatively.
The findings from this study may be most useful during preoperative counseling for obese patients, who often present with severe joint pain but are frequently told they need to delay surgery to lose weight and improve their complication-risk profile. Based on this study, those patients can be counseled that losing weight will not only decrease their complication risk, but also decrease their reliance on medications for the pain that led them to seek surgery in the first place.
Eric Secrist, MD is a fourth-year orthopaedic resident at Atrium Health in Charlotte, North Carolina.
In November 2019, OrthoBuzz promised readers more details from the Pain Management Research Symposium held that month (see related post), which was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Those details are now available in the form of a JBJS Supplement containing 12 articles generated from that convening of > 30 orthopaedic researchers and journal editors. The Symposium focused on the unique challenges of designing studies that will answer pressing questions about pain management related to musculoskeletal conditions and procedures.
The content of this open-access Supplement ranges from subspecialty-specific considerations in pain management to “complementary medicine” approaches. It culminates in 7 key “Recommendations for Pain Management Research,” all targeted to identifying effective pain-management strategies, not just elimination of opioids. Among those recommendations are the following:
- Define all terms (such as “long-term opioid use”) precisely.
- Quantify opioid use in morphine milligram equivalents (MMEs), and state how MMEs were calculated.
- Precisely define the study population (including age, sex, and socioeconomic and cultural characteristics).
- Mental/emotional risk factors–including depression, catastrophizing, expectations, and coping ability–should be studied.
- Outcome measures should be patient-related, not just the number of pills taken.
JBJS would again like to thank NIAMS for its support and all Symposium participants and Supplement authors for their time and energy.
Designing studies to answer questions about surgical procedures takes a lot of thought, effort, and experience. Creating robust study designs to investigate pain management related to musculoskeletal conditions and procedures presents additional, unique challenges.
On November 19, 2019, more than 30 orthopaedic researchers and journal editors convened to identify—and propose solutions for—those challenges. The one-of-a-kind Pain Management Research Symposium was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS award number 1R13AR076879-01) and hosted by The Journal of Bone & Joint Surgery.
Several themes emerged from the daylong discussions and presentations:
- Despite the fact that 80% of opioid prescriptions worldwide originate in the US, outcome measures going forward should focus on effective pain management rather than reduced or “zero” opioids.
- The wide variability of definitions of key research terms such as “opioid naïve” and “persistent opioid use” makes it difficult to reach robust conclusions from prior opioid/pain management research.
- Beware false equations/assumptions. For example, opioid prescription filling is not the same as opioid consumption, and persistent opioid use after surgery does not equal iatrogenic opioid dependence.
- Surgeons and other physicians must maintain a biopsychosocial perspective on pain management. Risk factors for persistent use of opioids include mental/emotional states such as depression and catastrophizing.
- Despite some equivocal reports in the orthopaedic literature, there is no convincing evidence that NSAIDs negatively affect fracture healing. Therefore, absent specific patient contraindications, NSAIDs can be considered for pain management in trauma cases.
Many more details from the Pain Management Research Symposium will appear in a special JBJS supplement, scheduled for publication in the first half of 2020.
The Journal would again like to thank all the participants for their time and energy and NIAMS for its support.
Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all such OrthoBuzz summaries.
This month, co-author Nitin B. Jain, MD, MSPH selected the most clinically compelling findings from the 40 studies summarized in the November 20, 2019 “What’s New in Orthopaedic Rehabilitation.”
–A randomized controlled trial compared pain-related function, pain intensity, and adverse effects among 240 patients with chronic back, hip, or knee pain who were randomized to receive opioids or non-opioid medication.1 After 12 months, there were no between-group differences in pain-related function. Statistically, the pain intensity score was significantly lower in the non-opioid group, although the difference is probably not clinically meaningful. Adverse events were significantly more frequent in the opioid group.
–A series of nested case-control studies found that the use of the NSAID diclofenac was associated with an increase in the risk of myocardial infarction in patients with spondyloarthritis and osteoarthritis, relative to those taking the NSAID naproxen.2
–Intra-articular injections of corticosteroids or hyaluronic acid are often used for pain relief prior to an eventual total knee arthroplasty (TKA). An analysis of insurance data found that patients who had either type of injection within three months of a TKA had a higher risk of periprosthetic joint infection (PJI) after the operation than those who had injections >3 months prior to TKA.
Partial-Thickness Rotator Cuff Tears
–A randomized controlled trial of 78 patients with a partial-thickness rotator cuff compared outcomes of those who underwent immediate arthroscopic repair with outcomes among those who delayed operative repair until completing 6 months of nonoperative treatment, which included activity modification, PT, corticosteroid injections, and NSAIDs.3 At 2 and 12 months post-repair, both groups demonstrated improved function relative to initial evaluations. At the final follow-up, there were no significant between-group differences in range of motion, VAS, Constant score, or ASES score. Ten (29.4%) of the patients in the delayed group dropped out of the study due to symptom improvement.
Stem Cell Therapy
–A systematic review that assessed 46 studies investigating stem cell therapy for articular cartilage repair4 found low mean methodology scores, indicating overall poor-quality research. Only 1 of the 46 studies was classified as excellent, prompting the authors to conclude that evidence to support the use of stem cell therapy for cartilage repair is limited by a lack of high-quality studies and heterogeneity in the cell lines studied.
- Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, Kroenke K, Bair MJ, Noorbaloochi S. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA. 2018 Mar 6;319(9):872-82.
- Dubreuil M, Louie-Gao Q, Peloquin CE, Choi HK, Zhang Y, Neogi T. Risk ofcmyocardial infarction with use of selected non-steroidal anti-inflammatory drugs incpatients with spondyloarthritis and osteoarthritis. Ann Rheum Dis. 2018 Aug;77(8): 1137-42. Epub 2018 Apr 19.
- Kim YS, Lee HJ, Kim JH, Noh DY. When should we repair partial-thickness rotator cuff tears? Outcome comparison between immediate surgical repair versus delayed repair after 6-month period of nonsurgical treatment. Am J Sports Med. 2018 Apr;46(5):1091-6. Epub 2018 Mar 5.
- Park YB, Ha CW, Rhim JH, Lee HJ. Stem cell therapy for articular cartilage repair: review of the entity of cell populations used and the result of the clinical application of each entity. Am J Sports Med. 2018 Aug;46(10):2540-52. Epub 2017 Oct 12.
Orthopaedists are seeing an increasing number of active, young patients with hip pain. A study by May et al. in the March 20, 2019 issue of The Journal of Bone & Joint Surgery strongly suggests that osteoid osteoma (OO)—a small, benign tumor characterized by dense sclerotic bone tissue—should not be overlooked in the differential diagnosis when working up these patients.
The authors identified and reviewed the records of 50 children and adolescents (mean age of 12.4 years) at their tertiary-care pediatric center who had received a diagnosis of OO within or around the hip between 2003 and 2015. Nighttime hip and/or thigh pain (90%) and symptom relief with NSAIDs (88%) were common clinical findings.
Sclerosis/cortical thickening was visible in 58% of the radiographs. Perilesional edema and a radiolucent nidus was found on all 43 of the available CT scans, leading the authors to conclude that “CT scans provide definitive diagnosis” of OO.
Unfortunately, 46% of these patients initially received an alternative diagnosis, the most common of which was femoroacetabular impingement (FAI), and a delay in diagnosis of >6 months occurred in 43% of patients. The authors note that concerns regarding radiation exposure have led some clinicians to order MRI rather than CT when evaluating pediatric hip disorders, but this study found that identifying an OO nidus with MRI was not as accurate as doing so with CT.
Regarding treatment, among the 41 patients who ultimately underwent percutaneous radiofrequency ablation (RFA) to treat OO, 93% achieved complete post-RFA symptom resolution. Complications from RFA occurred in 7% of patients who underwent the procedure.
I congratulate Vannabouathong et al. for the well-performed and relevant systematic review. In Germany, the Association of Scientific Medical Societies (AWMF) just published a guideline on the medical treatment of knee osteoarthritis (see: https://www.awmf.org/uploads/tx_szleitlinien/033-004l_S2k_Gonarthrose_2018-01_1.pdf), which comes to very similar conclusions as those presented in this systematic review.
The new German guideline suggests a four-stage algorithm starting with topical NSAIDs and escalating to oral NSAIDs (according to individual risks), then followed either by glucosamine, hyaluronic acid (HA), or corticosteroids, and ends finally with opioids. It was very useful that Vannabouathong et al. used the AAOS description for clinical significance, and it was elegant of them to include the effect of intra-articular placebo in their analysis of intra-articular treatments. This review compares treatment-group differences (not within-patient improvements) and considers that the placebo effect in osteoarthritis trials is typically large, particularly in the case of intra-articular injections. Consequently, the measured effect size would underestimate the clinical benefits for patients1, 2. It is valuable that this systematic review calculated the intra-articular placebo versus the oral placebo effect and added the resulting difference of 0.29 standard deviation (SD) units to the respective effect sizes of the intra-articular treatments.
This review concludes that the intra-articular injection of HA has the most concise effect estimate and exceeds the defined threshold of clinical importance of 0.5 SD units. Thus the clinical usefulness of HA is boosted from “possibly clinically important” to “clinically important” according to the AAOS definitions. This review also investigates HA formulations in terms of different molecular weights. It illustrates clearly the effect sizes of high-molecular-weight HA formulations between 1,500 kDa and 6,000 kDa, as well as those above 6,000 kDa.
One point requiring further discussion is that many patients have contraindications to NSAIDs due to comorbidities or comedications. Our new German guideline points out that NSAIDs are contraindicated for elderly patients (>60 years old) and those with existing ulcers, GI bleeding, or infections with H. pylori. Additional contraindicated factors are comedications such as corticosteroids, anticoagulants, or aspirin. In addition, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) reasons that oral NSAIDs have a moderate effect on pain relief, but they are associated with a 3- to 5-fold increase in the risk of upper GI complications, including peptic ulcer perforation, obstruction, and bleeding3.
Another analysis from the Coxib and Traditional NSAID Trialists (CNT) Collaboration shows that 2 to 4 out of 1,000 patients face GI complications after the daily intake of 150 mg of diclofenac. The same applies for 6 to 16 out of 1,000 patients taking 1,000 mg of ibuprofen per day4. An announcement of the Medicines Commission of the German Medical Profession also mentions high relative risks for GI complications associated with NSAIDs. The German guideline recommends intra-articular HA injections especially for individuals at risk for adverse NSAID side effects and for those for whom NSAIDs are not sufficiently effective.
The German guideline also discusses potentially beneficial effects of combining corticosteroids with HA. This should be a topic for a future systematic review.
Prof Joerg Jerosch is a professor of orthopaedic surgery at Johanna-Etienne Hospital in Neuss, Germany.
1. Bannuru RR et al., Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis e meta-analysis, Osteoarthritis Cartilage. 2011 Jun;19(6):611-9. doi: 10.1016/j.joca.2010.09.014.
2. Bannuru RR et al., Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis, Ann Intern Med. 2015 Jan 6;162(1):46-54. doi: 10.7326/M14-1231
3. Bruyere O et al. A consensus statement on the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) algorithm for the management of knee osteoarthritis-From evidence-based medicine to the real-life setting. Semin Arthritis Rheum, 2016. 45(4 Suppl): p. S3-11
4. Bhala N et al., Coxib and traditional NSAID Trialists’ (CNT) Collaboration, Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013; 382(9894): 769-779
European investigators recently reported on a trial comparing the efficacy of pharmaceutical-grade chondroitin sulfate (CS) (800 mg/day) with the NSAID celecoxib (CX) (200 mg/day) and placebo in more than 600 patients with painful knee osteoarthritis (OA).
In this well-designed, well-executed, double-blinded, 3-armed trial, investigators tracked patient pain scores at baseline and at 1-month, 3-month and 6-month intervals. This trial was characterized by strict adherence to blinded protocols, high levels of patient adherence, and meticulous review of patient diaries and adverse-event reports.
Patients in both the CS and CX groups experienced significantly greater pain relief when compared to those in the placebo group at every follow-up time point. In addition to tracking pain via the visual analogue scale (VAS), the investigators included the Lequesene index (LI)—which integrates both pain and function—along with the Minimal-Clinically Important Improvement (MCII) scale. While CX and CS were not superior/inferior to one another, both active treatments provided significant pain improvements relative to placebo according to all three measurements at all time points.
These findings showing the efficacy of pharmaceutical-grade CS are important for orthopaedic surgeons, rheumatologists, and general practitioners. Nonoperative management of knee OA remains an important modality that requires a multimodal approach, typically including NSAIDs and/or acetaminophen. These results suggest that there’s another safe medication that may prove especially helpful for OA patients who cannot tolerate NSAIDs or acetaminophen due to kidney, gastrointestinal, cardiovascular, and/or liver issues.
Richard Yoon, MD is a fellow in orthopaedic traumatology and complex adult reconstruction at Orlando Regional Medical Center.
Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.
This month, Nitin Jain, MD, MSPH, a co-author of the November 16, 2016 Specialty Update on Orthopaedic Rehabilitation, selected the five most clinically compelling findings from among the more than 40 studies summarized in the Specialty Update.
–A prospective cohort study1 evaluating the benefit of early imaging (within 6 weeks of index visit) for patients ≥65 years old with new-onset back pain found that those with early imaging had significantly higher resource utilization and expenditures compared with matched controls who did not undergo early imaging. One year after the index visit, authors found no significant between-group differences in patient-reported pain or disability. They concluded that “early imaging should not be performed routinely for older adults with acute back pain.”
–A randomized clinical trial2 comparing 10 days of NSAID monotherapy with 10 days of NSAIDs + muscle relaxants or opioids for acute nonradicular low back pain found no significant differences across the groups for pain, functional impairment, or use of health care resources. The authors said these findings suggest that combination therapy is not better than monotherapy in this situation, and that the use of opioids in such patients is not indicated.
Rotator Cuff Tears
–A two year follow-up of a randomized trial comparing three treatments for supraspinatus tears (physiotherapy, physiotherapy + acromioplasty, and rotator cuff repair + acromioplasty +physiotherapy) found no significant pain or function differences among the three groups. However, mean tear size was significantly smaller in the cuff-repair group than in the other two.
–A meta-analysis3 investigating the use of cannabinoids for managing chronic pain and spasticity concluded that those substances reduced pain and spasticity more than placebo, but the benefits came with an increased risk of side effects such as dizziness, nausea, confusion, and loss of balance.
–A randomized controlled trial4 comparing a phone-based cognitive-behavioral/physical therapy (CBPT) program to standard education following lumbar spine surgery found that patients in the CBPT group had greater decreases in pain and disability and increases in general health and physical performance.
- Jarvik JG, Gold LS, Comstock BA, Heagerty PJ, Rundell SD, Turner JA, Avins AL, Bauer Z, Bresnahan BW,Friedly JL, James K, Kessler L, Nedeljkovic SS, Nerenz DR, Shi X, Sullivan SD, Chan L, Schwalb JM, Deyo RA. Association of early imaging for back pain with clinical outcomes in older adults. JAMA. 2015 Mar17;313(11):1143-53.
- Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D, Bijur PE, Gallagher EJ. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. JAMA. 2015 Oct 20;314(15):1572-80.
- Whiting PF, Wolff RF, Deshpande S, DiNisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73.
- Skolasky RL, Maggard AM, Li D, Riley LH 3rd., Wegener ST. Health behavior change counseling in surgery for degenerative lumbar spinal stenosis. Part I: improvement in rehabilitation engagement and functional outcomes. Arch Phys Med Rehabil. 2015 Jul;96(7):1200-7. Epub 2015 Mar 28.
Late last summer, JBJS began offering KUDOS as a free service to authors. KUDOS is an easy-to-use tool that helps authors boost and measure the impact of their published work.To date, 159 JBJS authors have registered with KUDOS.
Recently, KUDOS applauded Dr. Alejandro Marquez-Lara, co-author of a JBJS Reviews article about the effects of NSAIDs on bone healing, for his exemplary job summarizing and explaining the importance of his study.
On KUDOS, Dr. Marquez-Lara said the article “provides insight into the disconnect between basic science and clinical literature” on this controversial topic. He explained the predicament this way: “There is no clear evidence to support that NSAIDs inhibit bone healing in the clinical setting…but there is also no good evidence confirming the safety of NSAIDs with regards to bone healing.” He concluded by encouraging orthopaedists “to read this review to improve the quality of ongoing and future clinical studies.”
Click here to learn more about how KUDOS works and how it can help JBJS authors enhance the visibility and influence of their published research.