Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.
Sir William Osler
Low back pain (LBP) is a perplexing multidimensional quagmire affecting human beings beyond age, occupation, sex, race, and culture. To date, it has largely resisted diagnostic, procedural, and pharmaceutical advances provided by modern medicine. It has also steadfastly defied attempts at categorization. As far as we know, the incidence and impact of LBP have in fact spread substantially since the advent of organized medicine.
“Low back pain” is a term that lacks specificity, suggesting a homogenous condition sharing among its sufferers only one distinctive feature: pain in the lower back. The term implies a nonspecific condition that lacks specifically identifiable underlying pathology. Although LBP is a symptom, its ramifications have all the manifestations of a disease. It may be time limited and harmless for most; however, for the unlucky others, it can become the bane of their existence-–a life-changing phenomenon.1, 2 However, what have we learned about LBP from more 10,000 and 100,000 or more books and scientific articles, respectively, on LBP?
THE LBP - The Global Burden of Disease
A number of facts about LBP have become common knowledge. For one, LBP is very common, afflicting some 67% to 84% of people in industrialized countries at some point in their lives.3, 4 About one-quarter of adults in the United States report having experienced at least 1 day of LBP in the last 3 months.5 Most patients do not seek medical care because they recover spontaneously within a reasonably short time.6 For patients who suffer enough to require medical attention, the prognosis is very good because pain and disability typically diminish rapidly within the first month, facilitating a return to work.7 Even so, LBP is the most common reason for persons younger than 45 years to limit activities, including work-related activities.8 It is also the single-most costly category of conditions responsible for lost workdays and disability claims.9
Fortunately, LBP does not develop into a chronic, disabling condition for the overwhelming majority. However, by 1 year after an acute episode, approximately one in five patients report persistent back pain resulting in substantial limitations in activity.10 To date, the conversion of acute pain into chronic pain remains an insufficiently understood neurobiologic phenomenon.1,2
“Chronic” LBP has been defined as present for three or more months, which appears to be associated with destruction of frontal and parietal grey matter and has been shown to affect cognitive and emotional abilities.11,12,13 This undoubtedly deleterious condition accounts for substantial socioeconomic and health-care consequences: it is estimated that 5% of patients with LBP account for 75% of the costs.14 Direct and indirect economic losses attributed to LBP in the United States have been estimated to be nearly $90 billion annually.15 In a relatively small country like Switzerland, direct costs of LBP care amount to 2.6 Billion Euro in 2005, or 6.1% of the gross domestic product with indirect productivity losses of 4.6 Billion Euros mainly through absenteeism.16 The future development of CLBP prevalence looks bleak in light of increasing aging of the demographic profile in developed countries, in addition to lack of physical fitness with reduced activity levels, rising body mass indices and a corollary surge of secondary systemic ailments.
WHAT ARE WE DOING ABOUT LBP?
It stands to reason that there are five main driving conceptions of LBP, which have resulted in five corrolary, but distinctly different schools of thought: there is a pain generator driven theorem, which has resulted in the procedural approaches pursued by surgeons and interventionalists; there is the cognitive behavioral therapy school of thought, which concentrates on psychogenic and motivational factors; the rehabilitation model targets muscle dysfunction and postural imbalance, a manipulative school of thought attempts to rebalance a malaligned spinal column and its intervertebral segments through manual applications and in the end there is the opioid analgesic approach based on the thought of a pain dysfunction model (Table 1). All five care entities have largely worked in isolation from one another–-with some attempts at integrated “pain clinics” having come and gone over the years. Most importantly, the synchronous but non-coordinated application of the five core-care concepts-–procedural intervention, cognitive-behavioral care, functional rehabilitation, manipulative care, and pain management—has resulted in serious knowledge gaps with little, if any, room for cross-pollination of thoughts or experiences. From a national perspective, LBP appears likely to be a leading contributor to the “chronic pain epidemic”, which is now being recognized as a leading health-care problem in North America and in other populations, in the same category as cardiac disease, hypertension and cancer related illnesses (Figure 1).17,18 To demonstrate the quantum shift of pain management in LBP, it may help to review the following comparative statistics: in 1998 the National Drug and Therapeutic Index reported 42% of opioid analgesics were prescribed for cancer related pain, 16% for patients with LBP. In 2004, the same Register identified opioid analgesics having been prescribed in 18% for cancer related indications, 40% of opioid analgesic prescriptions were for LBP; Figures for other chronic pain, degenerative joint diseases etc were unchanged.19,20 It has been estimated that by now more than 3% of the United States population without cancer are regular users of opioid analgesics, consuming 9.4 billion dosage units/year, that amounts to 25,405 dosage units per capita in the United States assuming a population of 370 million.18,20 The opioid analgesic Vicodin ® has become one of the leading prescription drug in the United States.21 The major burden that LBP and the ramifications of its mistreatment place on societies around the world is unsustainable and requires a rapid comprehensive and encompassing intervention program from affected societies around the globe (Figure 2).22
Unfortunately interventions for spine-related issues have dramatically fallen short on consistently providing lasting pain relief for LBP. A dramatic 2.4 fold (137%) increase in spinal fusions between 1998 and 2008 found in the Healthcare Cost and Utilization Project Nationwide Inpatient Sample was not matched by similar rises in laminectomy (11.3%,), hip replacement (49.1%), and percutaneous coronary angioplasty (38.8%), with coronary artery bypass graft actually decreasing by 40.1% during the same time period.23 As health care utilization and related expenditures continue to rise, providers are increasingly under the microscope to demonstrate the cost-effectiveness of interventions. Spine surgeons, in particular, have recently been characterized by the professional and lay press as either driven by marketing forces to utilize more complex procedures to treat straightforward problems, or worse, as unethical opportunists who recommend dangerous and ineffective procedures to unwitting patients for financial gain.24,25
“Chronic LBP” must be distinguished from other spinal disorders that respond much more reliably to surgery. There is very good evidence that surgery is more efficacious than nonsurgical treatment for neurogenic claudication, radiculopathy, spinal instability, fixed sagittal imbalance, and disabling adult scoliosis.26–29
There remain, however, substantial questions about chronic, non-specific LBP: Is our current phenotypically based approach with its quest to identify and target specific “pain generators” such as disc or facet joint abnormalities really appropriate or are there additional psycho-social or genotypical factors which may play substantive roles in the individual experience of the “suffering” associated with pain?30 When we exclude a number of procedurally treatable causes of LBP, such as neurologically, stability and deformity related conditions within the phenotypical domain, is LBP truly “non-specific”, or are there further subtypes that are more or less amenable to particular treatments (surgical and non-surgical)? By now, most spine-care providers agree that chronic LBP is largely a “mechanical” (i.e., movement-related) problem that may be aggravated by social and psychological factors.31 But beyond this, there is little substantive agreement on etiology. This may partly explain the great deal of variation among care providers in their approach to chronic LBP.32–34 Largely unjustifiable variations in practice patterns, coupled with the significant human and economic costs of this condition, indicate that chronic LBP is a prime target for a more systematic and scientifically based approach.
SYSTEMATIC EVALUATION OF THE BODY OF EVIDENCE
This issue represents the collective efforts of members of the AOSpine community to take a fresh look at the current scientific body of chronic LBP literature in several select areas. Our panel included clinician experts from spine surgery (orthopedics and neurosurgery), chiropractic, rehabilitation medicine, pain management, and physiotherapy as well as epidemiologists and statisticians.
Clinically relevant controversies regarding the evaluation and treatment of chronic LBP were selected after a comprehensive group review process for further critical evaluation and in-depth discussion. Because of the confinements inherent to a Spine Focus issue, several major topics could not be addressed and prioritizations had to be made. For instance, physical examination and interventional diagnostic procedures were set aside as the subject became too extensive for this undertaking. Other important topics such as variance of surgical rates, differences in quality of surgical care delivery, prevalence in chronic LBP among different cultures, and genetic factors were found to be of great interest and, while relevant in many ways, were not analyzed due mainly to the lack of mature data presently available.
The areas for inquiry were further refined into “key questions.” Inclusion and exclusion criteria were used to identify the published studies for each question and a consistent, evidence-based methodology was applied to evaluate the body of evidence. Full descriptions of these methods are discussed in a separate article in this issue.36 The goal was to determine the overall level of evidence for each key question on the basis of the quality, quantity, and consistency of the findings.
Our multidisciplinary panel used a modified Delphi technique35,36 to discuss the level of evidence and develop clinical recommendations. For each of these recommendations, we followed the principles outlined by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) Working Group37 and the Agency for Healthcare Research and Quality (AHRQ).38 A detailed description of the GRADE/AHRQ approach can be found elsewhere in this issue.36,39
Of course, it is important for the reader to be aware that this system deliberately separates the quality of the evidence (i.e., high, moderate, low, or inconclusive) from the strength of the clinical recommendation. It is not an automatic one-to-one connection that a high level of evidence for a particular outcome will form the basis for a strong recommendation, or that a low level of evidence will produce a weak recommendation. The famously quoted parachute example illustrates the meaninglessness of demanding a test of the obvious: parachutes reduce the likelihood of mortality after leaping from an airplane; however, their effectiveness has not been proven with randomized controlled trials.40 In the GRADE/AHRQ approach, the strength of clinical recommendations reflects the degree to which we can, across the range of patients for whom the recommendations are intended, be confident that the benefits of a diagnostic or therapeutic intervention outweigh the risks.
BRIEF OVERVIEW OF TOPICS
Our panel decided to approach this issue on CLBP from a categorical approach, beginning with topics of clinical categorization and imaging. We then proceed with an analysis of the major outcome measures for CLBP. This is followed by a review of interventions, both surgical and nonsurgical. We conclude with a section on systems integration of health-care policies in CLBP care. Table 2 provides a comprehensive list of questions addressed by systematic review and the recommendations of our panel.
If chronic LBP indeed is a heterogeneous condition, it logically follows that therapies will be more effective if patients can be categorized into clinically relevant treatment groups.39 In this issue, Fairbank et al41 systematically review the classification systems that have been described for LBP. None were developed specifically for surgical care. However, this is not really a “failure” of these systems as the majority of LBP resolves with nonsurgical care. Given the lack of a clear association between symptoms and magnetic resonance imaging findings, clinical evaluation appears more useful than imaging for directing initial medical and physical treatments.42 An effective classification system has the potential to direct nonsurgical therapies and avoid unnecessary and costly magnetic resonance imaging studies.
The body of evidence for chronic LBP has advanced with the development of reliable, valid patient self-reported outcome measures. However, it is often difficult to make comparisons between published studies because different outcome measures have been utilized to assess pain, function, and quality of life. This is problematic as we progress toward a new era of “comparative effectiveness medicine.” Practicing spine surgeons need to become acquainted with these measures—it is no longer an area of concern only for clinical researchers. Regulatory agencies and payers increasingly demand outcomes information from all care providers. Two studies in this issue that address this issue. Chapman et al43 systematically review the most frequently cited outcome measures and determine which are most reliable and valid. DeVine et al44 compare the responsiveness of measures of pain, physical function, and health-related quality of life after spine surgery.
Recognizing the diverse presentation of chronic LBP, and the varied responsiveness to surgical treatment, four articles investigate the effectiveness of surgical fusion on chronic LBP subpopulations. Randomized trials report average treatment effects, and although estimates of mean effect are useful, some individuals will respond better or worse than the reported average. This disparity is termed heterogeneity of treatment effect (HTE).45 In this issue, the effect of surgical fusion in subgroups of patients defined by certain determinants of health (e.g., smoking), sociological factors (e.g., litigation, sick leave, worker's compensation), and psychological factors (e.g., depression, personality disorder) are explored. Wood et al45 set out to determine whether the presence of isthmic spondylolisthesis modifies the effect of surgical fusion. Each of the studies in this section calculates standardized mean differences and risk differences for outcomes and then uses forest plots to assess potential HTE. Although this type of “post hoc analysis” has potential for bias, the results are interesting—sometimes counterintuitive—and raise questions about some of our assumptions that at very least would seem to merit further study.
The nonsurgical treatment of LBP is evaluated in two articles primarily focusing on the following question: What is the most effective physical treatment for chronic LBP? This long-standing area of controversy is systematically evaluated by Standaert et al46 in a comparative effectiveness analysis of exercise, spinal manipulation, and acupuncture. White et al47 review the commonly prescribed medications for chronic LBP including opioids, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs). Subpopulations are also explored for HTE. While both opioids and nonsteroidals show efficacy, the complications associated with the former class of drugs led our expert panel to recommend that NSAIDs be considered the first-line pharmacological treatment.
The final section of this issue deals with what may be the greatest area of current controversy for chronic LBP: health policy. Cheng et al48 systematically review the quality of evidence underlying current guidelines and payer policies for LBP. The numerous published guidelines are remarkably consistent regarding evaluation but not treatment, specifically the role of surgery. These inconsistencies may produce bias in payer policies. Medical payer policies influence patient care by defining medical necessity for approving treatments. Cheng et al argue that these policies should be held to the same standards as clinical practice guidelines with regard to transparency in the development process and peer review.
In the final article, Fourney et al49 discuss the “translation gap” between guidelines and clinical practice for LBP. Clinical pathways for spine care are systematically reviewed to determine whether they promote guidelines-concordant care, improve outcomes, or reduce waste (unnecessary tests or ineffective treatments). A clinical pathway for LBP that has been implemented in a Canadian province is described. The Saskatchewan Spine Pathway utilizes a classification system to guide evidence-based care. Its features includes an online course for primary care education and triage clinics for referrals to imaging and spine surgery, and it has several built-in features to encourage compliance.
CONCLUSIONS: FROM “EVIDENCE-BASED MEDICINE” TO “RESULTS-BASED MEDICINE”
The articles presented in this issue discuss several current controversies in the management of chronic LBP. Increasing patient and payer demands for quality, effectiveness, and cost containment are driving a new paradigm in evidence-based management of this condition.
A consistent finding of our systematic reviews on most of our topics studied was the possible influence of HTE. The implications of HTE for future research cannot be overstated. Identifying characteristics that modify treatment effects is critical to patient-centered, individualized care. In the future, investigators conducting randomized controlled trials may wish to consider characteristics that plausibly modify the effect of spine treatment, plan to conduct subgroup analyses on those characteristics, and prestate that intention in their protocol.51–54 Considerations may need to be given to increase the sample size so that there is sufficient power to detect differences in subgroup analyses. While it is important not to overinterpret the results of subgroup analyses, it is necessary to recognize that HTE analysis assists in hypothesis generation and aids in the design of future confirmatory studies.55–57
As quality randomized trials of appropriately large scale are exceedingly expensive to run and may run counter to unanticipated influences, such as emerging patient preferences or technology shifts, the time may have come to reevaluate the role of registries on a national, regional, or statewide basis. Undoubtedly, most—if not all—attempts at unstructured large-scale spine data gathering have consumed vast quantities of funding and produced little in credible research, perhaps because of unrealistic attempts at data gathering, selection bias, and inconsistent follow-up rates. A major notable exception may be the Swedish Spine Registry (SweSpine), which started in 1993 with eight contributing centers and has since grown to a major nationwide comprehensive data-gathering tool encompassing 45 centers. SweSpine is actively used to review results and trends in a collaborative fashion between practitioners, patient representatives, and health-system administrators following the principles of transparency and accountability.58,59
As a group, AOSpine sees an urgent need for starting to use national, regional, or statewide collaborative quality registries free of secondary gain interests. The goal of these registries would be to cover sociodemographic, surgical, and result-oriented data in a cost-conscientious fashion. Registries should be an ideal instrument to capture substantial loads of meaningful data in a comparably short-time period and would be useful to define normative values and to identify subgroups. Studies designed to confirm differences in treatment effects for subpopulations could help set the stage for this new era of understanding and treating CLBP. We need to understand three main issues:
- When will LBP become chronic?
- Improve our risk assessment, screening, prognostication sophistication and coordinated available of various treatment options applied in a timely fashion
- Identify “whom to treat”. Who will respond to treatment, who won't - thereby avoiding or minimizing health care costs and avoid unnecessary procedures.
There has been evidence mounting that pain genes may be instrumental in the development of pain etc, or the outcome following spine surgery.60 If we can identify specific genetic factors that may influence sensitivity, perception, tolerance, and memory of pain, the realm of targeted therapy for CLPB may be near. Large patient cohorts available for subanalyses will be incredibly valuable for future directions of research and the formulation of a new era of “results-based medicine,” going beyond the principles formulated for the current era of “evidence-based medicine.”
Converging the five main treatment spheres (procedural interventions, functional rehabilitation, cognitive-behavioral care, manipulative treatment, and pain management) into one conjoined effort could provide a quantum leap for research, knowledge, and most importantly patient care.
These efforts would move us beyond the currently “inconclusive” results from so many chronic LBP studies. It is hoped that this issue will provide a small impetus toward the realization of Sir William Osler's aptly phrased mandate quoted in the introduction, challenging us to recognize the individuality of our patients beyond the diagnosis of a disease.61
- Current low back pain management is fragmented into five major management spheres, which have little or no interactions with one another.
- Chronic LBP is a heterogeneous condition and this affects the way it is diagnosed, classified, treated, and studied.
- While nonoperative approaches are the mainstay of management of LBP, surgery offers improved outcomes in carefully selected patients.
- There is an urgent need for large national registries to track the natural history and outcomes of treatments for chronic LBP.
The authors would like to thank Dean Chou, MD, Theodore J. Choma, MD, Peter Fritzell, MD, PhD, Jeremy Fairbank, MD, FRCS, and Nancy Holmes, R.N. for their invaluable insights, help and guidance in the preparation of this manuscript.
1. Jayson MI. Why does acute back pain become chronic? BMJ 1997;314:1639–40.
2. Chanda ML, Alvin MD, Schnitzer TJ, et al. Pain characteristic differences between subacute and chronic back pain. J Pain 2011;12:792–800.
3. Jarvik JG, Hollingworth W, Heagerty PJ, et al. Three-year incidence of low back pain in an initially asymptomatic cohort: clinical and imaging risk factors. Spine (Phila Pa 1976) 2005;30:1541–8; discussion 1549.
4. Walker BF. The prevalence of low back pain: a systematic review of the literature from 1966 to 1998. J Spinal Disord 2000;13:205–17.
5. Deyo RA, Mirza SK, Martin BI. Back pain prevalence and visit rates: estimates from U.S. national surveys, 2002. Spine (Phila Pa 1976) 2006;31:2724–7.
6. Carey TS, Evans AT, Hadler NM, et al. Acute severe low back pain. A population-based study of prevalence and care-seeking. Spine (Phila Pa 1976) 1996;21:339–44.
7. Pengel LH, Herbert RD, Maher CG, et al. Acute low back pain: systematic review of its prognosis. BMJ 2003;327:323.
8. Andersson GB. Epidemiological features of chronic low-back pain. Lancet 1999;354:581–5.
9. Frank JW, Kerr MS, Brooker AS, et al. Disability resulting from occupational low back pain. Part I: What do we know about primary prevention? A review of the scientific evidence on prevention before disability begins. Spine (Phila Pa 1976) 1996;21:2908–17.
10. Von Korff M, Saunders K. The course of back pain in primary care. Spine (Phila Pa 1976) 1996;21:2833–7; discussion 8–9.
11. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007;147:478–91.
12. Baliki MN, Geha PY, Apkarian AV, et al. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci 2008;28:1398–403.
13. Apkarian AV, Sosa Y, Sonty S, et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 2004;24:10410–5.
14. Frymoyer JW, Cats-Baril WL. An overview of the incidences and costs of low back pain. Orthop Clin North Am 1991;22:263–71.
15. Dagenais S, Caro J, Haldeman S. A systematic review of low back pain cost of illness studies in the United States and internationally. Spine J 2008;8:8–20.
16. Wieser S, Horisberger B, Schmidhauser S, et al. Cost of low back pain in Switzerland in 2005. Eur J Health Econ 2011;12:455–67.
17. National Research Council. Musculoskeletal Disorders and the Workplace. Washington DC: National Academy Press; 2001.
18. Okie S. A flood of opiods, a rising tide of deaths. N Engl J Med 2010;363:1981–5.
19. IMS National Drug and Therapeutic index NDT.
20. IMS Health Survey 2003–2004.
21. Rx List: The Internet Drug Index. The Top 300 Prescriptions for 2005 by number of US prescriptions dispensed. Available at: rxlist.com/top200htm
22. Sullivan MD, Edlund MJ, Steffick D, et al. Regular use of prescribed opioids: association with common psychiatric disorders. Pain 2005;119:95–103.
24. Carragee EJ. The increasing morbidity of elective spinal stenosis surgery: is it necessary? JAMA 2010;303:1309–10.
25. Deyo RA, Mirza SK, Martin BI, et al. Trends, major medical complications, and charges associated with surgery for lumbar spinal stenosis in older adults. JAMA 2010;303:1259–65.
26. Weinstein JN, Lurie JD, Tosteson TD, et al. Surgical versus nonoperative treatment for lumbar disc herniation: four-year results for the Spine Patient Outcomes Research Trial (SPORT). Spine (Phila Pa 1976) 2008;33:2789–800.
27. Weinstein JN, Lurie JD, Tosteson TD, et al. Surgical compared with nonoperative treatment for lumbar degenerative spondylolisthesis. four-year results in the Spine Patient Outcomes Research Trial (SPORT) randomized and observational cohorts. J Bone Joint Surg Am 2009;91:1295–304.
28. Weinstein JN, Tosteson TD, Lurie JD, et al. Surgical versus nonoperative treatment for lumbar spinal stenosis four-year results of the Spine Patient Outcomes Research Trial. Spine (Phila Pa 1976) 2010;35:1329–38.
29. Danon-Hersch N, Samartzis D, Wietlisbach V, et al. Appropriateness Criteria for Surgery Improve Clinical Outcomes in Patients With Low Back Pain and/or Sciatica [published online ahead of print February 4, 2010]. Spine (Phila Pa 1976)
30. Cahana A. New Approaches in Selecting Patients for Pain Management. Washington DC: American Academy of Pain Medicine; 2011
31. Weiner BK. Spine update: the biopsychosocial model and spine care. Spine (Phila Pa 1976) 2008;33:219–23.
32. Bishop PB, Wing PC. Compliance with clinical practice guidelines in family physicians managing worker's compensation board patients with acute lower back pain. Spine J 2003;3:442–50.
33. Deyo RA, Phillips WR. Low back pain. A primary care challenge. Spine (Phila Pa 1976) 1996;21:2826–32.
34. Klein BJ, Radecki RT, Foris MP, et al. Bridging the gap between science and practice in managing low back pain. A comprehensive spine care system in a health maintenance organization setting. Spine (Phila Pa 1976) 2000;25:738–40.
35. Stewart J, O'Halloran C, Harrigan P, et al. Identifying appropriate tasks for the preregistration year: modified Delphi technique. BMJ 1999;319:224–9.
36. Norvell DC. Methodology for the systematic reviews on an evidence based approach for the management of chronic LBP. Spine 2011;36:S10–S18.
37. Listone H, Turoff M. The Delphi Method. Boston: Addison-Wesley; 1975.
38. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490.
39. West S, King V, Carey T. Systems to Rate the Strength of Scientific Evidence. Rockville, MD: Agency for Healthcare Research and Quality; 2002. Evidence Report/Technology Assessment 47 [Prepared by the Research Triangle Institute-University of North Carolina Evidence-based Practice Center, Contract No. 290-97-0011].
40. Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003;327:1459–61.
41. Fairbank J. The role of classification of chronic low back pain. Spine 2011;36:S19–S42.
42. Chou D. Degenerative MRI changes in patients with chronic low back pain: a systematic review. Spine 2011;36:S43–S53.
43. Chapman R, Norvell C, Hermsmeyer T, et al. Evaluating common outcomes for measuring treatment success for chronic low back pain. Spine 2011;36:S54–S68.
44. DeVine JG. Evaluating the correlation and responsiveness of patient reported pain with function and quality of life outcomes after spine surgery. Spine 2011;36:S69–S74.
45. Wood KB, Fritzell P, Detorri J. Effectiveness of spinal fusion versus structured rehabilitation in chronic low back pain patients with and without isthmic spondylolisthesis. Spine 2011:36:S110–S119.
46. Standaert C. Comparative effectiveness of exercise, acupuncture, and spinal manipulation for low back pain. Spine 2011;36:S120–S130.
47. White AP. Pharmacologic management of chronic low back pain: synthesis of the evidence. Spine 2011;36:S131–S143.
48. Cheng JS. Clinical guidelines and payer policies on fusion for the treatment of chronic low back pain. Spine 2011;36:S144–S163.
49. Fourney DR. A systematic review of clinical pathways for lower back pain and introduction of the Saskatchewan Spine Pathway. Spine 2011;36:S164–S171.
50. Norvell Detorri J. Heterogenity treatment Effect. EBSJ 3/2011
51. Scientific approach to the assessment and management of activity-related spinal disorders. A monograph for clinicians. Report of the Quebec Task Force on Spinal Disorders. Spine (Phila Pa 1976) 1987;12:S1–59.
52. Kravitz RL, Duan N, Braslow J. Evidence-based medicine, heterogeneity of treatment effects, and the trouble with averages. Milbank Q 2004;82:661–87.
53. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 2010;63:e1–37.
54. Gabler NB, Duan N, Liao D, et al. Dealing with heterogeneity of treatment effects: is the literature up to the challenge? Trials 2009;10:43.
55. Wang R, Lagakos SW, Ware JH, et al. Statistics in medicine–reporting of subgroup analyses in clinical trials. N Engl J Med 2007;357:2189–94.
56. Brookes ST, Whitely E, Egger M, et al. Subgroup analyses in randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test. J Clin Epidemiol 2004;57:229–36.
57. Brookes ST, Whitley E, Peters TJ, et al. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol Assess 2001;5:1–56.
60. Dai I, Belfer CE, Schwartz R, et al. Association of catechol-O-methyltransferase genetic variants with outcome in patients undergoing surgical treatment for lumbar degenerative disc disease. Spine J 2010;10:949–57.