Abstract Background context Increasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal ...fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight. Purpose To compare the conclusions regarding the safety and related efficacy published in the original rhBMP-2 industry-sponsored trials with subsequently available Food and Drug Administration (FDA) data summaries, follow-up publications, and administrative and organizational databases. Study design Systematic review. Methods Results and conclusions from original industry-sponsored rhBMP-2 publications regarding safety and related efficacy were compared with available FDA data summaries, follow-up publications, and administrative and organizational database analyses. Results There were 13 original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols. No rhBMP-2–associated adverse events (0%) were reported in any of these studies (99% confidence interval of adverse event rate <0.5%). The study designs of the industry-sponsored rhBMP-2 trials for use in posterolateral fusions and posterior lateral interbody fusion were found to have potential methodological bias against the control group. The reported morbidity of iliac crest donor site pain was also found to have serious potential design bias. Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies. From this review, we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events. After anterior interbody lumbar fusion rates of implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation were higher after using rhBMP-2 than controls. Posterior lumbar interbody fusion use was associated with radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes. In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy. Conclusions Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion. This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications.
BACKGROUND:Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a growth factor known to have in vitro effects on the growth and invasiveness of cancer. It has been approved by the U.S. Food ...and Drug Administration in limited doses for single-level anterior spinal arthrodesis, but it is commonly used off-label and at high doses. The effect of rhBMP-2 on the risk of cancer has been a concern. We sought to evaluate the risk of new cancers in patients receiving high-dose rhBMP-2.
METHODS:We used publicly available data from a pivotal, multicenter, randomized controlled trial of patients with degenerative lumbar spine conditions who underwent a single-level instrumented posterolateral arthrodesis with either high-dose rhBMP-2 in a compression-resistant matrix (CRM) (rhBMP-2/CRM; n = 239) or autogenous bone graft (control group; n = 224). We compared the risks of new cancers in the rhBMP-2/CRM and control groups at two and five years after surgery.
RESULTS:At two years, with 86% follow-up, there were fifteen new cancer events in eleven patients in the rhBMP-2/CRM group compared with two new cancer events in two patients in the control group treated with autogenous bone graft. The incidence rate of new cancer events per 100 person-years was 3.37 (95% confidence interval CI, 1.89 to 5.56) in the rhBMP-2/CRM group at two years compared with 0.50 (95% CI, 0.06 to 1.80) in the control group. The incidence rate ratio was 6.75 (95% CI, 1.57 to 60.83; p = 0.0026) at two years. Calculated in terms of the number of patients with one or more cancer events two years after the surgery, the incidence rate per 100 person-years was 2.54 (95% CI, 1.27 to 4.54) in the rhBMP-2/CRM group compared with 0.50 (95% CI, 0.06 to 1.82) in the control group at two years; the incidence rate ratio was 5.04 (95% CI, 1.10 to 46.82; p = 0.0194). At five years, there was a 37% loss of follow-up, but a significantly greater incidence of cancer events was still observed in the rhBMP-2/CRM group.
CONCLUSIONS:A high dose of 40 mg of rhBMP-2/CRM in lumbar spinal arthrodesis was associated with an increased risk of new cancer.
LEVEL OF EVIDENCE:Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
Systematic review.
To systematically assess benefits and harms of surgery for nonradicular back pain with common degenerative changes, radiculopathy with herniated lumbar disc, and symptomatic spinal ...stenosis.
Although back surgery rates continue to increase, there is uncertainty or controversy about utility of back surgery for various conditions.
Electronic database searches on Ovid MEDLINE and the Cochrane databases were conducted through July 2008 to identify randomized controlled trials and systematic reviews of the above therapies. All relevant studies were methodologically assessed by 2 independent reviewers using criteria developed by the Cochrane Back Review Group (for trials) and Oxman (for systematic reviews). A qualitative synthesis of results was performed using methods adapted from the US Preventive Services Task Force.
For nonradicular low back pain with common degenerative changes, we found fair evidence that fusion is no better than intensive rehabilitation with a cognitive-behavioral emphasis for improvement in pain or function, but slightly to moderately superior to standard (nonintensive) nonsurgical therapy. Less than half of patients experience optimal outcomes (defined as no more than sporadic pain, slight restriction of function, and occasional analgesics) following fusion. Clinical benefits of instrumented versus noninstrumented fusion are unclear. For radiculopathy with herniated lumbar disc, we found good evidence that standard open discectomy and microdiscectomy are moderately superior to nonsurgical therapy for improvement in pain and function through 2 to 3 months. For symptomatic spinal stenosis with or without degenerative spondylolisthesis, we found good evidence that decompressive surgery is moderately superior to nonsurgical therapy through 1 to 2 years. For both conditions, patients on average experience improvement either with or without surgery, and benefits associated with surgery decrease with long-term follow-up in some trials. Although there is fair evidence that artificial disc replacement is similarly effective compared to fusion for single level degenerative disc disease and that an interspinous spacer device is superior to nonsurgical therapy for 1- or 2-level spinal stenosis with symptoms relieved with forward flexion, insufficient evidence exists to judge long-term benefits or harms.
Surgery for radiculopathy with herniated lumbar disc and symptomatic spinal stenosis is associated with short-term benefits compared to nonsurgical therapy, though benefits diminish with long-term follow-up in some trials. For nonradicular back pain with common degenerative changes, fusion is no more effective than intensive rehabilitation, but associated with small to moderate benefits compared to standard nonsurgical therapy.
Prospective, match-cohort study of disc degeneration progression over 10 years with and without baseline discography. Objectives. To compare progression of common degenerative findings between lumbar ...discs injected 10 years earlier with those same disc levels in matched subjects not exposed to discography. Summary of Background Data. Experimental disc puncture in animal and in vivo studies have demonstrated accelerated disc degeneration. Whether intradiscal diagnostic or treatment procedures used in clinical practice causes any damage to the punctured discs over time is currently unknown.
Seventy-five subjects without serious low back pain illness underwent a protocol MRI and an L3/4, L4/5, and L5/S1 discography examination in 1997. A matched group was enrolled at the same time and underwent the same protocol MRI examination. Subjects were followed for 10 years. At 7 to 10 years after baseline assessment, eligible discography and controlled subjects underwent another protocol MRI examination. MRI graders, blind to group designation, scored both groups for qualitative findings (Pfirrmann grade, herniations, endplate changes, and high intensity zone). Loss of disc height and loss of disc signal were measured by quantitative methods.
Well matched cohorts, including 50 discography subjects and 52 control subjects, were contacted and met eligibility criteria for follow-up evaluation. In all graded or measured parameters, discs that had been exposed to puncture and injection had greater progression of degenerative findings compared to control (noninjected) discs: progression of disc degeneration, 54 discs (35%) in the discography group compared to 21 (14%) in the control group (P = 0.03); 55 new disc herniations in the discography group compared to 22 in the control group (P = 0.0003). New disc herniations were disproportionately found on the side of the anular puncture (P = 0.0006). The quantitative measures of disc height and disc signal also showed significantly greater loss of disc height (P = 0.05) and signal intensity (P = 0.001) in the discography disc compared to the control disc.
Modern discography techniques using small gauge needle and limited pressurization resulted in accelerated disc degeneration, disc herniation, loss of disc height and signal and the development of reactive endplate changes compared to match-controls. Careful consideration of risk and benefit should be used in recommending procedures involving disc injection.
Abstract Background Context Defining success after spinal surgery remains problematic. The minimal clinically important difference (MCID) in pain or functional outcomes is a common metric often ...calculated independent of perceived risk and morbidity, which is an important consideration in large procedures such as spinal fusion and instrumentation. Purpose The purpose of this study was to describe a method of assessing treatment success based on prospective, patient-reported “minimum acceptable” outcome for which they would undergo a procedure. These goals can then be compared at follow-up to gauge how frequently patient goals are met and determine correlation with patient satisfaction. Study Design This is a clinical descriptive study of the patient-reported minimum acceptable outcomes for spinal fusion surgery. Outcome Measures Minimum acceptable outcomes were determined by patients on preoperatively administered standard questionnaires regarding ultimate pain intensity, functional outcome (Oswestry Disability Index ODI), medication usage, and work status. Satisfaction with outcomes was assessed at 2-year follow-up. Methods One hundred sixty-five consecutive patients undergoing lumbar fusion for either isthmic spondylolisthesis or disc degeneration were asked to preoperatively define on standard questionnaires their minimum acceptable outcomes after surgery. Two-year outcomes and satisfaction were subsequently reported and compared with the preoperatively determined minimum acceptable outcomes. Results Both the spondylolisthesis and the degenerative disc disease (DDD) groups reported that a high degree of improvement was the minimum acceptable threshold for considering spinal fusion. A large majority indicated that the minimum acceptable outcomes included at least a decrease in pain intensity to 3/10 or less, an improvement in ODI of 20 or more, discontinuing opioid medications, and return to some occupational activity. Achieving the minimum acceptable outcome was strongly associated with satisfaction at 2 years after surgery. Patients with compensation claims, psychological distress, and other psychosocial stressors were more likely to report satisfaction in the absence of achieving their minimum acceptable outcome. Conclusions Patients with spondylolisthesis and DDD both have relatively high minimum acceptable outcomes for spinal fusion. In these cohorts, few subjects considered more commonly proposed MCIDs for pain and function as an acceptable outcome and report that they would not have surgery if they did not expect to achieve more than those marginal improvements. Although there was good concordance between achieving the minimum acceptable outcomes and ultimate satisfaction, patients with significant psychosocial factors (compensation claims, psychological distress, and others) are less likely to associate satisfaction with outcomes with actually achieving these improvements.
Clinical practice guideline.
To develop evidence-based recommendations on use of interventional diagnostic tests and therapies, surgeries, and interdisciplinary rehabilitation for low back pain of ...any duration, with or without leg pain.
Management of patients with persistent and disabling low back pain remains a clinical challenge. A number of interventional diagnostic tests and therapies and surgery are available and their use is increasing, but in some cases their utility remains uncertain or controversial. Interdisciplinary rehabilitation has also been proposed as a potentially effective noninvasive intervention for persistent and disabling low back pain.
A multidisciplinary panel was convened by the American Pain Society. Its recommendations were based on a systematic review that focused on evidence from randomized controlled trials. Recommendations were graded using methods adapted from the US Preventive Services Task Force and the Grading of Recommendations, Assessment, Development, and Evaluation Working Group.
Investigators reviewed 3348 abstracts. A total of 161 randomized trials were deemed relevant to the recommendations in this guideline. The panel developed a total of 8 recommendations.
Recommendations on use of interventional diagnostic tests and therapies, surgery, and interdisciplinary rehabilitation are presented. Due to important trade-offs between potential benefits, harms, costs, and burdens of alternative therapies, shared decision-making is an important component of a number of the recommendations.
Persistent Low Back Pain Carragee, Eugene J
The New England journal of medicine,
05/2005, Letnik:
352, Številka:
18
Journal Article
Recenzirano
A 49-year-old maintenance worker with a history of depression and previous reports of minor back pain is seen during four months of continuing low back pain. He has remained out of work for fear of ...worsening the injury. Magnetic resonance imaging two weeks after the onset of pain showed only mild degenerative changes in the lumbar region without spinal stenosis or disk collapse or extrusion. How should this patient be evaluated and treated?
A 49-year-old maintenance worker with a history of depression is seen during four months of continuing low back pain. Magnetic resonance imaging showed only mild degenerative changes in the lumbar region.
Foreword
This
Journal
feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.
Stage
A 49-year-old maintenance worker with a history of depression and previous reports of minor back pain is seen after four months of continuing low back pain. He has remained out of work for fear of worsening the injury. Magnetic resonance imaging (MRI) two weeks after the onset of pain showed only mild degenerative changes in the lumbar region without spinal stenosis or disk collapse or extrusion. How should this patient be evaluated and treated?
The Clinical Problem
Low back pain without sciatica, stenosis, or severe spinal deformity is common, with a reported point prevalence as high as 33 percent . . .
Surgical treatment of older patients with severe and protracted symptoms from neurogenic claudication or radicular pain syndromes can provide rapid improvement. The most common clinical presentation, ...spinal stenosis with primary radicular pain, can be effectively treated with lumbar decompression alone. The use of the operative microscope, minimal dissection, and rapid postoperative mobilization, as developed over the last 20 years, has decreased surgical morbidity. Large observational and controlled studies have shown that most patients with spinal stenosis can realize large and durable gains in pain relief and functional improvement with this procedure, despite multilevel vertebral involvement, advanced age, and common comorbid medical conditions. Here, Carragee comments on an article by Deyo et all reporting that the rate of spinal stenosis surgery in the Medicare population has remained more or less stable, but the rate of complex surgery for this disease has increased from negligible levels in 2002 to nearly 15% of all spinal stenosis surgeries in 2007. These more complex surgeries are also reported to be independently associated with increased perioperative mortality, major complications, rehospitalization, and cost.
This is a prospective study of the validity of a positive test result in provocative lumbar discography for the diagnosis of "discogenic pain."
To investigate the hypothesis that provocative ...discography by strict criteria accurately identifies a low back pain illness due to a primary disc lesion.
According to the Sackett and Haynes criteria for establishing diagnostic test validity, no test without a gold standard external standard can be meaningfully applied. Provocative discography as a test for determining "discogenic pain" has, to date, not been compared against a gold standard. Absent a gold standard reference, there can be no validity assessment or systematic improvement of test accuracy. This is the first study to apply an external gold standard evaluation of the diagnostic validity of discography in any manner.
Over a 5-year period using a strict enrollment protocol, 32 patients with low back pain and a positive single-level low-pressure provocative discogram, underwent spinal fusion. Subjects with known patient selection comorbidities were excluded. Generic surgical limitations/morbidity were controlled by comparison to the clinical outcomes of a strictly-matched cohort of 34 patients having a well-accepted single-level lumbar pathology (unstable spondylolisthesis). Treatment success was compared between groups.
In the control-spondylolisthesis group, 23 of 32 patients (72%) met the highly effective success criteria compared with 8 of 30 in the presumed discogenic pain cohort (27%). The proportion of patients who met the "minimal acceptable outcome" was 29 of 32 (91%) in the spondylolisthesis group and 13 of 30 (43%) in the presumed discogenic pain group. Adjusting for surgical morbidity and dropout failure, by either criteria of success, the best-case positive predictive value of discography was calculated to be 50% to 60%.
Positive discography was not highly predictive in identifying bona fide isolated intradiscal lesions primarily causing chronic serious LBP illness in this first study comparing discography results to a gold standard.
Systematic review and best evidence synthesis.
To describe the prevalence and incidence of neck pain and disability in workers; to identify risk factors for neck pain in workers; to propose an ...etiological diagram; and to make recommendations for future research.
Previous reviews of the etiology of neck pain in workers relied on cross-sectional evidence. Recently published cohorts and randomized trials warrant a re-analysis of this body of research.
We systematically searched Medline for literature published from 1980-2006. Retrieved articles were reviewed for relevance. Relevant articles were critically appraised. Articles judged to have adequate internal validity were included in our best evidence synthesis.
One hundred and nine papers on the burden and determinants of neck pain in workers were scientifically admissible. The annual prevalence of neck pain varied from 27.1% in Norway to 47.8% in Québec, Canada. Each year, between 11% and 14.1% of workers were limited in their activities because of neck pain. Risk factors associated with neck pain in workers include age, previous musculoskeletal pain, high quantitative job demands, low social support at work, job insecurity, low physical capacity, poor computer workstation design and work posture, sedentary work position, repetitive work and precision work. We found preliminary evidence that gender, occupation, headaches, emotional problems, smoking, poor job satisfaction, awkward work postures, poor physical work environment, and workers' ethnicity may be associated with neck pain. There is evidence that interventions aimed at modifying workstations and worker posture are not effective in reducing the incidence of neck pain in workers.
Neck disorders are a significant source of pain and activity limitations in workers. Most neck pain results from complex relationships between individual and workplace risk factors. No prevention strategies have been shown to reduce the incidence of neck pain in workers.
