Eugene J. Carragee

A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned

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 Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies.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.

The burden and determinants of neck pain in the general population: results of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders.

Study Design. Best evidence synthesis. Objective. To undertake a best evidence synthesis of the published evidence on the burden and determinants of neck pain and its associated disorders in the general population. Summary of Background Data. The evidence on burden and determinants of neck has not previously been summarized. Methods. The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and Its Associated Disorders performed a systematic search and critical review of literature published between 1980 and 2006 to assemble the best evidence on neck pain. Studies meeting criteria for scientific validity were included in a best evidence synthesis. Results. We identified 469 studies on burden and determinants of neck pain, and judged 249 to be scientifically admissible; 101 articles related to the burden and determinants of neck pain in the general population. Incidence ranged from 0.055 per 1000 person years (disc herniation with radiculopathy) to 213 per 1000 persons (self-reported neck pain). Incidence of neck injuries during competitive sports ranged from 0.02 to 21 per 1000 exposures. The 12-month prevalence of pain typically ranged between 30% and 50%; the 12-month prevalence of activity-limiting pain was 1.7% to 11.5%. Neck pain was more prevalent among women and prevalence peaked in middle age. Risk factors for neck pain included genetics, poor psychological health, and exposure to tobacco. Disc degeneration was not identified as a risk factor. The use of sporting gear (helmets, face shields) to prevent other types of injury was not associated with increased neck injuries in bicycling, hockey, or skiing. Conclusion. Neck pain is common. Nonmodifiable risk factors for neck pain included age, gender, and genetics. Modifiable factors included smoking, exposure to tobacco, and psychological health. Disc degeneration was not identified as a risk factor. Future research should concentrate on longitudinal designs exploring preventive strategies and modifiable risk factors for neck pain.

Course and prognostic factors for neck pain in whiplash-associated disorders (WAD): results of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders.

Study Design. Best evidence synthesis. Objective. To perform a best evidence synthesis on the course and prognostic factors for neck pain and its associated disorders in Grades I–III whiplash-associated disorders (WAD). Summary of Background Data. Knowledge of the course of recovery of WAD guides expectations for recovery. Identifying prognostic factors assists in planning management and intervention strategies and effective compensation policies to decrease the burden of WAD. Methods. The Bone and Joint Decade 2000–2010 Task Force on Neck Pain and its Associated Disorders (Neck Pain Task Force) conducted a critical review of the literature published between 1980 and 2006 to assemble the best evidence on neck pain and its associated disorders. Studies meeting criteria for scientific validity were included in a best evidence synthesis. Results. We found 226 articles related to course and prognostic factors in neck pain and its associated disorders. After a critical review, 70 (31%) were accepted on scientific merit; 47 of these studies related to course and prognostic factors in WAD. The evidence suggests that approximately 50% of those with WAD will report neck pain symptoms 1 year after their injuries. Greater initial pain, more symptoms, and greater initial disability predicted slower recovery. Few factors related to the collision itself (for example, direction of the collision, headrest type) were prognostic; however, postinjury psychological factors such as passive coping style, depressed mood, and fear of movement were prognostic for slower or less complete recovery. There is also preliminary evidence that the prevailing compensation system is prognostic for recovery in WAD. Conclusion. The Neck Pain Task Force undertook a best evidence synthesis to establish a baseline of the current best evidence on the course and prognosis for WAD. Recovery of WAD seems to be multifactorial.

Interventional therapies, surgery, and interdisciplinary rehabilitation for low back pain: an evidence-based clinical practice guideline from the American Pain Society.

Study Design. Clinical practice guideline. Objective. 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. Summary of Background Data. 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. Methods. 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. Results. 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. Conclusion. 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.

Pyogenic Vertebral Osteomyelitis

I retrospectively reviewed the records of 111 patients who had pyogenic vertebral osteomyelitis unrelated to an open procedure on the spine. The mean age at the time of the diagnosis was sixty years (range, eighteen to eighty-four years); sixty-one patients (55 per cent) were sixty years old or more. Forty-four patients (40 per cent) had an impaired immune system secondary to diabetes mellitus, the use of corticosteroids, chemotherapy for cancer, rheumatic or immunological disease, renal or hepatic failure, malnutrition, or myelodysplasia. Magnetic resonance imaging, critical for the determination of an early diagnosis, was performed for 103 patients (93 per cent). The infection in sixty-eight patients (61 per cent) was diagnosed within one month after the onset of symptoms. The most frequent infecting organism was Staphylococcus aureus (forty patients; 36 per cent). The infection in forty-one patients (37 per cent) was caused by organisms, such as Staphylococcus epidermidis, Propionibacterium acnes, and diphtheroid species, that are traditionally considered to be of low virulence. The urinary tract was the most frequent source of infection (confirmed in thirteen patients and suspected in twenty-one). The success of non-operative treatment was predicted by four independent variables: an age of less than sixty years, the immune status, infection with Staphylococcus aureus, and a decreasing erythrocyte sedimentation rate. Forty-two patients were managed with débridement and arthrodesis. Fourteen of these patients also had instrumentation of the spine, in the presence of infection, without compromise of the outcome. Eighteen patients died by the time of the latest follow-up evaluation at a mean of four years (range, two years and two months to six years and six months): seven who had been managed non-operatively died in the first month after the diagnosis was made, three died in the acute postoperative period, three died of late complications of paraplegia, and five died of unrelated causes. None of the eighty-nine patients who were seen at a minimum of two years postoperatively had had late recurrence of infection. Chronic, severe back pain was noted in only seven patients.

Clinical outcomes after lumbar discectomy for sciatica: the effects of fragment type and anular competence.

Background: The surgical treatment of sciatica with discectomy is ineffective in a sizable percentage of patients, and reherniation occurs after 5% to 15% of such procedures. The purpose of the present study was to determine if competence of the disc anulus and the type of herniation could be used to predict postoperative clinical outcomes following lumbar discectomy.Methods: A prospective observational study of 187 consecutive patients undergoing single-level primary lumbar discectomy was conducted. A single surgeon performed all of the procedures, and an independent examiner evaluated 180 of the patients clinically at a minimum of two and a median of six years after surgery. The extent of anular deficiency and the presence of disc fragments were determined. On the basis of these intraoperative findings, disc herniations were classified into four categories: (1) Fragment-Fissure herniations (eighty-nine patients), (2) Fragment-Defect herniations (thirty-three patients), (3) Fragment-Contained herniations (forty-two patients), and (4) No Fragment-Contained herniations (sixteen patients). The effects of disc herniation morphology and preoperative variables on subsequent clinical outcome were determined with the Student t test for continuous variables and chi-square analysis for categorical variables.Results: Patients in the Fragment-Fissure group, who had disc fragments and a small anular defect, had the best overall outcomes and the lowest rates of reherniation (1%) and reoperation (1%). Patients in the Fragment-Contained group had a 10% rate of reherniation and a 5% rate of reoperation. Patients in the Fragment-Defect group, who had extruded fragments and massive posterior anular loss, had a 27% rate of reherniation and a 21% rate of reoperation. Patients in the No Fragment-Contained group did poorly: 38% had recurrent or persistent sciatica, and the standard outcomes scores were less improved compared with those in the other groups (p < 0.001).Conclusion: Intraoperative findings, as described in the present study, were more clearly associated with outcomes than were demographic, socioeconomic, or clinical variables. The degree of anular competence after discectomy and the type of herniation appear to have value for the prediction of the recurrence of sciatica, reoperation, and clinical outcome following lumbar discectomy.Level of Evidence: Prognostic study, Level I-1 (prospective study). See p. 2 for complete description of levels of evidence.

Surgery for low back pain: A review of the evidence for an American pain society clinical practice guideline

Study Design. Systematic review. Objective. 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. Summary of Background Data. Although back surgery rates continue to increase, there is uncertainty or controversy about utility of back surgery for various conditions. Methods. 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. Results. 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. Conclusion. 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.

2009 Issls Prize Winner: Does Discography Cause Accelerated Progression of Degeneration Changes in the Lumbar Disc: A Ten-year Matched Cohort Study

Study Design. 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. Methods. 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. Results. 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. Conclusion. 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.

2000 Volvo Award winner in clinical studies: Lumbar high-intensity zone and discography in subjects without low back problems.

Study Design. A prospective observational study of patients with low back pain and those without was performed. Objective. To investigate the prevalence and significance of a high-intensity zone in a group of patients asymptomatic for low back pain, but who had known risk factors for lumbar disc degeneration. This asymptomatic group was compared with a symptomatic group of patients with respect to the presence of anular high-intensity zone and the pain response with discography. Summary of Background Data. Some authors have estimated the prevalence of a high-intensity zone in a group of symptomatic patients to be 86%. They have reported a strong correlation between a high-intensity zone and positive discography in patients with low back pain. Other investigators have reported evidence either supporting or discounting these findings. Methods. Patients with low back pain and those without underwent physical examination, psychometric testing, plain radiograph, magnetic resonance imaging, and discography. The presence of a high-intensity zone, anular disruption, and positive discographic pain then were compared between the two groups. There were strict inclusion criteria for both groups. A total of 109 discs in 42 patients were evaluated in the symptomatic group and compared with 143 discs in 54 patients in the asymptomatic group. The presence of a high-intensity zone was determined by a standardized criteria on T2-weighted magnetic resonance images. Psychometric testing also was administered to each patient before discography. Standard discography was performed on all the patients, and the pain response was recorded using a visual analog scale according to the Walsh et al criteria. Results. The prevalence of a high-intensity zone in the patient populations was 59% in the symptomatic group and 24% in the asymptomatic group. In the symptomatic group, 33 (30.2%) of 109 discs were found to have a high-intensity zone. In the asymptomatic group, 13 of 143 discs were found to have a high-intensity zone. In the symptomatic group, 72.7% of the discs with a high-intensity zone were positive on discography, whereas 38.2% of the discs without a high-intensity zone were positive. In the asymptomatic group, 69.2% of the discs with a high-intensity zone were positive on discography, whereas 10% of the discs without a high-intensity zone were positive. In the patients with normal psychometric testing, 50% of the discs with a high-intensity zone were positive on discography, as compared with 100% positive discography results in patients with abnormal psychometric testing or chronic pain. Conclusions. The presence of a high-intensity zonedoes not reliably indicate the presence of symptomaticinternal disc disruption. Although higher in symptomaticpatients, the prevalence of a high-intensity zone inasymptomatic individuals with degenerative disc disease (25%) is too high for meaningful clinical use. When injected during discography, the same percentage of asymptomatic and symptomatic discs with a high-intensity zone were shown to be painful.

The rates of false-positive lumbar discography in select patients without low back symptoms.

STUDY DESIGN Experimental disc injections in subjects with no history of low back symptoms. OBJECTIVE To determine in an experimental setting the relative pain response and pain-related behavior in selected subjects without a history of low back pain undergoing lumbar discography. This study aimed to select a study population that more closely represented patients undergoing discography in clinical practice. SUMMARY OF BACKGROUND DATA Previous work has shown that in young, healthy men with little degenerative disc disease and no history of low back problems, discographic injections usually did not cause significant pain. This group differed from the patients who usually undergo discographic evaluation in clinical practice. Most clinical patients are older, have significant degenerative disc disease, have behavioral changes associated with chronic pain, and often have confounding psychosocial troubles. The authors undertook to study discography in subjects without low back pain but with clinical profiles similar to patients undergoing discography in clinical practice. METHODS Twenty-six individuals, mean age 43 years, with no history of low back pain had lumber discography according to the strict protocol of Walsh et al. Of these, 10 were pain-free; 10 had chronic neck and arm pain, but no low back symptoms; and 6 had primary somatization disorders without low back symptoms.- RESULTS Significant positive pain response and pain-related behavior with discography were found in 10% of the pain-free group, in 40% of the chronic cervical pain group, and in 83% of the somatization disorder group completing the injections. Twenty-four subjects had negative control discs. Discs with annular disruption were more likely to be painful on injection, particularly in those individuals with ongoing compensation issues, chronic pain, or abnormal psychological testing.- CONCLUSION If strict criteria are applied, the rate of false-positive discography may be low in subjects with normal psychometric profiles and without chronic pain. Significantly painful injections were very common in subjects with annular disruption and chronic pain or abnormal psychometric testing.