- Email: [email protected]
Failed Back Surgery Syndrome: Results of a Systematic Review and Meta-Analysis
Vol. 31 No. 4S April 2006
Journal of Pain and Symptom Management S13
Special Article
Spinal Cord Stimulation in Complex Regional Pain Syndrome and Refractory Neuropathic Back and Leg Pain/Failed Back Surgery Syndrome: Results of a Systematic Review and Meta-Analysis Rod S. Taylor, MSc, PhD Department of Public Health & Epidemiology, University of Birmingham, Birmingham, UK
Abstract The drive for good quality evidence has highlighted the importance of well-conducted systematic reviews and meta-analyses that critically evaluate and grade studies for new or existing therapies. A systematic review and meta-analysis was performed to review the efficacy, safety, and cost effectiveness of spinal cord stimulation (SCS) in complex regional pain syndrome (CRPS) and refractory neuropathic back and leg pain/failed back surgery syndrome (FBSS). The results support the use of SCS in patients with refractory neuropathic back and leg pain/FBSS (Grade B evidence) and CRPS type I (Grade A evidence)/type II (Grade D evidence). SCS not only reduces pain, improves quality of life, reduces analgesic consumption, and allows some patients to return to work, with minimal significant adverse events, but may also result in significant cost savings over time. J Pain Symptom Manage 2006;31:S13--S19. Ó 2006 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Spinal cord stimulation, refractory neuropathic pain, complex regional pain syndrome, failed back surgery syndrome, systematic review, meta-analysis
Complex regional pain syndrome (CRPS) and refractory neuropathic back and leg pain and/or failed back surgery syndrome (FBSS) represent a significant unmet medical need and a substantial economic concern. Based
Address reprint requests to: Rod S. Taylor, MSc, PhD Department of Public Health & Epidemiology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: [email protected]. Accepted for publication: November 15, 2005. Ó 2006 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
on epidemiological data, 1500--2000 new cases of CRPS and 30,000--40,000 new cases of FBSS are diagnosed every year in Europe.1,2 FBSS is clinically defined as persistent or recurrent pain, mainly in the lower back and/or legs, even after previous anatomically successful spinal surgery. Although there is good evidence for the treatment of CRPS,3 to date there is a lack of randomized controlled studies in therapy-resistant neuropathic back pain, FBSS, and refractory neuropathic back and leg pain. In clinical practice, drugs that have demonstrated efficacy in 0885-3924/06/$--see front matter doi:10.1016/j.jpainsymman.2005.12.010
S14
Taylor
common indications such as postherpetic neuralgia, painful diabetic neuropathy, and trigeminal neuralgia are often prescribed by physicians for other refractory neuropathic pain conditions such as low back pain, even when there is an absence or scarcity of scientific evidence for efficacy and no indication in the pharmacopoeia.4,5 In a recent review of the literature regarding the management of refractory neuropathic pain, the majority of the systematic reviews identified provided evidence for the use of drugs and spinal cord stimulation (SCS), but little evidence was found for radiofrequency procedures or therapeutic blocks.6 This paper summarizes a series of systematic reviews7--9 that were undertaken to evaluate the evidence for the clinical and cost effectiveness of SCS in the treatment of CRPS and refractory neuropathic back and leg pain/FBSS.
Systematic Reviews, Meta-Analyses, and Grading of the Evidence The increasing drive toward the use of good quality evidence to evaluate new or existing therapies means that well-conducted systematic reviews and meta-analyses are of vital importance. A systematic review is one that strives to comprehensively identify and synthesize all the literature on a topic. Meta-analysis is a statistical technique for assembling the clinical results of several studies, preferably
Vol. 31 No. 4S April 2006
identified by systematic review, into a single numerical estimate. The evidence identified by a systematic review should also be critically evaluated and graded according to its quality, size of effect, and relevance. Until recently, the system for grading guideline recommendations was based on the work of the U.S. Agency for Health Care Research and Quality.10,11 However, experience of guideline development has led to a growing awareness of this system’s weaknesses. To address these problems, the Harbour and Miller12 grading system was developed and it offers several advantages over the older guidelines. It maintains the link between the strength of the available evidence and the grade of the recommendation, while allowing recommendations to be based on the best available evidence and be weighted accordingly. It also incorporates formal assessment of the methodological quality, quantity, consistency, and applicability of the evidence base. Finally, the grading system is presented in a clear and unambiguous way that allows guideline developers and users to understand the link between the strength of the evidence and the grade of recommendation (Table 1).
Methods Several methods were used to search for relevant evidence, including examination of bibliographic resources (Medline, CINAHL, EMBASE,
Table 1 The Harbour and Miller12 Scale for Grading Recommendations in Evidence-Based Guidelines Levels of evidence 1þþ High-quality meta-analyses, systematic reviews of RCTs, or RCTs of very low risk of bias 1þ Net/conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1 Meta-analyses, systematic reviews of RCTs, or RCTs with high risk of bias 2þþ High-quality systematic reviews of case-control or cohort studies. High-quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal 2þ Well-conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal 2 Case-control or cohort studies with a low risk of confounding, bias, or chance and significant risk that the relationship is not causal 3 Nonanalytic studies, e.g., case reports, case series 4 Expert opinion Grades of recommendation A At least one meta-analysis, systematic review, on RCT rated as 1þþ, and directly applicable to the target population, or a systematic review of RCTs or a body of evidence rated as 1þ, directly applicable to the target population, and demonstrating overall consistency of results B A body of evidence rated as 2þþ, directly applicable to the target population, and demonstrating overall consistency of results or extrapolated evidence from studies rated as 1þþ or 1þ C A body of evidence rated as 2þ, directly applicable to the target population, and demonstrating overall consistency of results or extrapolated evidence from studies rated as 2þþ D Evidence level 3 or 4, or extrapolated evidence from studies rated as 2þ
Vol. 31 No. 4S April 2006
SCS for the Management of Refractory Neuropathic Pain
Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, NHS Center for Reviews & Dissemination (CRD) Health Technology Assessment (HTA) database, UK National Health Service (NHS) Economic Evaluation Database, Health Economics Evaluation Database and registers of current clinical trials), a hand search of reference lists of included studies, and contact with experts and companies. No restrictions were placed on language. Identification/exclusion criteria were as follows: Study design: all designs (excluding case reports) Population: individuals with refractory neuropathic back and leg pain, FBSS, arachnoiditis, and CRPS (type 1/reflex sympathetic dystrophy and type 2/causalgia) Intervention: either unilateral or bilateral SCS as a single therapy or in combination with other therapies (excluding subdural SCS/disaggregated data) Outcomes: pain relief, return to work, functional disability, complications, quality of life, patient satisfaction/preference for intervention, health service utilization, and costs (excluding ‘‘technical outcomes’’) Studies were organized according to the hierarchy of evidence, their quality assessed, and an overall level of evidence grading
S15
applied.12 The quality of comparative studies was assessed using a modified version of the Jadad Scale, a measure of study methodological/ reporting quality (0 being the weakest and 5 being the strongest).13 Studies were also examined for the presence of bias (selection, confounding, performance, detection, attrition). A level and grade of recommendation was applied to the evidence.12
Results One randomized controlled trial (RCT), 25 case series, and one economic evaluation were found for CRPS. One RCT, one cohort study, 72 case series, and four cost studies were found for refractory neuropathic back and leg pain/FBSS (Fig. 1).
Clinical Effectiveness of SCS CRPS. In 2000, an RCT was initiated by Kemler et al.14 to examine whether SCS plus physical therapy (SCS þ PT) (n ¼ 36) was more effective than PT alone (n ¼ 18) in the treatment of therapy-resistant CRPS type I. Parameters assessed included pain intensity (using a visual analogue scale [VAS]), the global perceived effect, functional status,
Fig. 1. Identification and exclusion of studies.
S16
Taylor
health-related quality of life (HRQL), and complications associated with SCS. Patients were followed up for 24 months. The RCT scored 4 out of 5 on the Jadad Scale. A point was lost as patient and care givers were not blinded. After trial stimulation, SCS þ PT was successfully implanted in 24 of the 36 patients. Results showed that treatment with SCS þ PT reduced pain intensity to a significantly greater extent than PT alone, as seen by a reduction of 3.6 cm on the VAS compared with an increase of 0.2 cm in the PT group (P < 0.001). A significantly higher proportion of patients in the SCS þ PT group had a score of 6 (‘‘much improved’’) for the global perceived effect (14 patients, 58%) compared with the PT group (one patient, 6%) (P ¼ 0.01). No significant improvement in functional status was noted. However, only SCS þ PT led to an improvement in the HRQL, with an increase of 11% in the overall score. Significant improvements were seen for patients with an affected hand (P ¼ 0.02) and those with an affected foot (P ¼ 0.008). No improvement in HRQL was seen in the PT group. Four complications associated with SCS were observed: one infection, two generator pockets, and one lead related complication. The VAS and global pain results were maintained at the 24-month follow-up (Fig. 2).15 A total of 25 case series were identified for CRPS that provide a median follow-up time of 33 months postimplant.7 Some biases were noted in these studies, mainly detection (lack
Vol. 31 No. 4S April 2006
of outcome blinding) and attrition (loss to follow-up) bias. It was found that 67% of implanted patients with CRPS type I or II achieved pain relief of 50% or more with SCS. A significant reduction in pain intensity was also observed in the studies that used the VAS score to assess pain; the pooled mean reduction of VAS score was 4.7 with SCS. Significant improvements were noted for HRQL and there was a trend toward an improvement in functional capacity. Data from eight studies indicated that overall, 33% of CRPS patients experienced one or more problems with SCS. However, the majority of these were reversible and were due to lead problems. No serious adverse events were reported and no neurological complications were observed. Using the Harbour and Miller Scale,12 the evidence was classified as Grade A in CRPS type I. Only case series evidence currently exist for the use of SCS in CRPS type II, hence the lower grading of evidence. Refractory Neuropathic Back and Leg Pain/ FBSS. The RCT by North et al.16,17 compared SCS to reoperation in patients with FBSS. A total of 51 surgically remediable FBSS patients with refractory, mainly radicular neuropathic pain (with or without low back pain) were randomly assigned to initial treatment by reoperation (back surgery) or SCS; of these, 15 reoperation and 12 SCS patients reached the 6 month follow-up. Primary outcome measures included patient preference for treatment (frequency of therapy crossover), greater
Fig. 2. SCS þ PT in CRPS significantly improved the global perceived effect compared to PT alone.15
Vol. 31 No. 4S April 2006
SCS for the Management of Refractory Neuropathic Pain
Fig. 3. SCS in FBSS resulted in significantly greater pain relief and lower analgesic use compared with reoperation.17
than 50% pain relief, and opioid analgesic use at follow-up (6 and 24 months). The RCT scored 4 out of 5 on the Jadad Scale. Although patients and caregivers were not blinded, outcomes were assessed by an individual independent from both the conduct of the trial and delivery of care of the patients in the trial. At the 6-month follow-up, 10 (67%) of the 15 reoperation patients opted for crossover to SCS. In contrast, a significantly lower number of SCS patients (two patients, 17%) opted for crossover to reoperation (P ¼ 0.018). Significantly more patients receiving SCS achieved 50% or more pain relief compared with those who underwent reoperation (P ¼ 0.149). Similarly, patients receiving SCS also required substantially less opiate analgesics than the patients who underwent back surgery (P ¼ 0.0005) (Fig. 3). The 72 case studies in refractory neuropathic back and leg pain/FBSS included studies with follow-up of 10 years (Table 2).8 Across all case studies, results showed that 62% of SCS patients achieved 50% pain relief or more and
S17
53% of patients no longer required analgesics. Functional capacity and HRQL were significantly improved by SCS, and 40% of patients were able to return to work. Furthermore, 70% of SCS patients expressed satisfaction with their treatment. An SCS complication rate of 18% per year18 was observed, most of which were reversible and mainly due to electrode or lead problems. No serious adverse events and no neurological-related complications were reported. Because reoperation was deemed a less relevant comparator for FBSS (at least in the context of current European practice), the evidence for efficacy of SCS in refractory neuropathic back and leg pain/FBSS was classified as Grade B on the Harbour and Miller Scale.12
Cost Effectiveness of SCS In 2002, Kemler and Furnee19 performed a cost-effectiveness analysis based on the above RCT of SCS in CRPS type I. The study found that in the first year, the mean cost per patient was almost twice as high in the SCS þ PT group (V9,805) compared with the PT alone group (V5,741). This cost was mainly due to the implantation procedure, which formed 83% of the expenditure. However, after initial treatment, mean annual routine CRPS I costs declined significantly in the SCS þ PT group (P < 0.003)dmainly due to a diminished requirement for medical caredbut remained constant in the PT group. Thus, after 3 years the cost differences were permanently reversed, resulting in a lifetime cost saving of V58,471 per patient with SCS þ PT (Fig. 4). A cost-utility analysis of this trial, which investigated the additional cost and the additional net economic cost gained per quality-adjusted life-years (QALY), indicated a cost of V22,500 per QALY. This cost per QALY for SCS is consistent with a level of cost effectiveness that is
Table 2 Meta-Analysis of Pooled Outcomes with SCS for Refractory Neuropathic Back and Leg Pain/FBSS Case Series Median Follow-Up 18 Months (reproduced with permission from Taylor et al.)8 Outcome Pain relief $50% Tested patients Implanted patients No analgesics Return to work Patient satisfaction
No. of Studies
Cases/Sample Size
20 65 16 15 6
624/1165 1992/3313 324/681 405/1133 147/220
Pooled Estimate (95% CI) 48% 62% 53% 40% 70%
(43%--53%) (56%--69%) (48%--56%) (28%--50%) (62%--85%)
Heterogeneity P value <0.0001 <0.0001 <0.0001 <0.0001 0.003
S18
Taylor
Vol. 31 No. 4S April 2006
surgery (CAD$7,291). Although for 2 years postimplant the cumulative costs of SCS were in excess of those associated with non-SCS patients (as a result of high acquisition costs), the pattern reversed after about 2.5 years. In some centers, the time to cost neutrality (‘‘payback’’ period) was as little as 15 months postimplant (but ranged up to 5 years). The ‘‘payback’’ period was sensitive to a variety of factors, including the efficacy of SCS, battery/electrode life, and the level of SCS usage by patients. Fig. 4. SCS þ PT in CRPS resulted in an estimated lifetime cost saving of V58,471 (25% reduction) per patient compared with PT alone.19
commonly regarded as representing good value and appropriate use of the resources of society and the health care systemsdanything less than V60,000 per QALY is generally funded by the health care system. No economic evaluation of SCS for refractory neuropathic back and leg pain/FBSS was identified. However, four studies have examined the costs of SCS. These studies consistently report that over time SCS is potentially cost saving to the health care system. This is illustrated in Fig. 5, comparing the costs of SCS to best medical treatment/conventional pain therapy (CPT) for FBSS reported by Kumar et al.20 It was found that annual maintenance health care costs of SCS-treated patients (CAD$1,094) were considerably less than the costs associated with patients treated without
Conclusions The literature has shown that although there is little controlled evidence for the management of refractory neuropathic pain conditions such as FBSS, systematic reviews provide good evidence for the use of SCS.6 This systematic review and meta-analysis support the efficacy and safety of SCS in patients with refractory neuropathic back and leg pain/ FBSS (Grade B evidence) or CRPS type I (Grade A evidence) or type II (Grade D evidence). Furthermore, SCS has been shown to be a cost effective treatment for CRPS type I. In the medium to long term (beyond 2--3 years), SCS is likely to be cost saving compared with alternative therapy strategies for patients with FBSS. Evidence of the cost effectiveness of SCS in refractory neuropathic back and leg pain/FBSS is required.
References 1. Schofferman J, Reynolds J, Herzog R, et al. Failed back surgery: etiology and diagnostic evaluation. Spine J 2003;3:400--403. 2. Sandroni P, Burned-Larsen LM, McClelland RL, Low PA. Complex reflex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003;103:199--207. 3. Stanton-Hicks MD, Burton AW, Bruehl SP, et al. An updated interdisciplinary clinical pathway for CRPS: report of an expert panel. Pain Pract 2002; 2(1):1--16. 4. Hansson PT, Dickenson AH. Pharmacological treatment of peripheral neuropathic pain conditions based on shared commonalities despite multiple etiologies. Pain 2005;113:251--254.
Fig. 5. SCS in FBSS resulted in a cost saving after 2.5 years compared with conventional medical care.20
5. Backonja M-M, Serra J. Pharmacologic management Part 2: lesser-studied neuropathic pain diseases. Pain Med 2004;5(S1):S48--S59.
Vol. 31 No. 4S April 2006
SCS for the Management of Refractory Neuropathic Pain
6. Taylor RS, Niv D, Raj PP. Management of refractory neuropathic pain: exploration of the evidence. Pain Pract, submitted for publication. 7. Taylor RS, Van Buyten J-P, Buchser E. Spinal cord stimulation for complex regional pain syndrome: a systematic review of the clinical and cost-effectiveness literature and assessment of prognostic factors. Eur J Pain 2006;10(2):91--101. 8. Taylor RS, Van Buyten JP, Buchser E. Spinal cord stimulation for chronic back and leg pain and failed back surgery syndrome: a systematic review and analysis of prognostic factors. Spine 2005; 30(1):152--160. 9. Taylor RS, Taylor RJ, Van Buyten JP, et al. The cost effectiveness of spinal cord stimulation in the treatment of pain: a systematic review of the literature. J Pain Symptom Manage 2004;27:370--378. 10. United States Department of Health and Human Services, Agency for Health Care Policy and Research. Acute pain management: Operative or medical procedures and trauma. Rockville, MD: AHCPR, 1993: 107. (Clinical practice guideline No. 1, AHCPR Publication No. 92-0023.). 11. Hadorn DC, Baker D, Hodges JS, Hicks N. Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 1996;49:749--754. 12. Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001;323:334--336. 13. Jadad AR, Cook DJ, Jones A, et al. Methodology and reports of systematic reviews and meta-analyses: a comparison of Cochrane reviews with articles
S19
published in paper-based journals. JAMA 1998;280: 278--280. 14. Kemler MA, Barendse GAM, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 2000; 343:618--624. 15. Kemler MA, De Vet HCW, Barendse GAM, et al. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann Neurol 2004;55:13--18. 16. North RB, Kidd DH, Lee MS, et al. A prospective, randomised study of spinal cord stimulation versus reoperation for failed back surgery syndrome: initial results. Stereotact Funct Neurosurg 1994;62:267--272. 17. North RB, Kidd DH, Farrokhi F, Piantadosi SA. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: a randomized, controlled trial. Neurosurgery 2005;56:98--106. 18. Taylor RJ, Taylor RS. Spinal cord stimulation for failed back surgery syndrome: a decision-analytic model and cost-effectiveness analysis. Int J Technol Assess Health Care 2005;21(3):351--358. 19. Kemler A, Furnee CA. Economic evaluation of spinal cord stimulation for chronic reflex sympathetic dystrophy. Neurology 2002;59:1203--1209. 20. Kumar K, Malik S, Demeria D. Treatment of chronic pain with spinal cord stimulation versus alternative therapies: cost-effectiveness analysis. Neurosurgery 2002;51(1):106--116.
Journal of Pain and Symptom Management S13
Special Article
Spinal Cord Stimulation in Complex Regional Pain Syndrome and Refractory Neuropathic Back and Leg Pain/Failed Back Surgery Syndrome: Results of a Systematic Review and Meta-Analysis Rod S. Taylor, MSc, PhD Department of Public Health & Epidemiology, University of Birmingham, Birmingham, UK
Abstract The drive for good quality evidence has highlighted the importance of well-conducted systematic reviews and meta-analyses that critically evaluate and grade studies for new or existing therapies. A systematic review and meta-analysis was performed to review the efficacy, safety, and cost effectiveness of spinal cord stimulation (SCS) in complex regional pain syndrome (CRPS) and refractory neuropathic back and leg pain/failed back surgery syndrome (FBSS). The results support the use of SCS in patients with refractory neuropathic back and leg pain/FBSS (Grade B evidence) and CRPS type I (Grade A evidence)/type II (Grade D evidence). SCS not only reduces pain, improves quality of life, reduces analgesic consumption, and allows some patients to return to work, with minimal significant adverse events, but may also result in significant cost savings over time. J Pain Symptom Manage 2006;31:S13--S19. Ó 2006 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Spinal cord stimulation, refractory neuropathic pain, complex regional pain syndrome, failed back surgery syndrome, systematic review, meta-analysis
Complex regional pain syndrome (CRPS) and refractory neuropathic back and leg pain and/or failed back surgery syndrome (FBSS) represent a significant unmet medical need and a substantial economic concern. Based
Address reprint requests to: Rod S. Taylor, MSc, PhD Department of Public Health & Epidemiology, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. E-mail: [email protected]. Accepted for publication: November 15, 2005. Ó 2006 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved.
on epidemiological data, 1500--2000 new cases of CRPS and 30,000--40,000 new cases of FBSS are diagnosed every year in Europe.1,2 FBSS is clinically defined as persistent or recurrent pain, mainly in the lower back and/or legs, even after previous anatomically successful spinal surgery. Although there is good evidence for the treatment of CRPS,3 to date there is a lack of randomized controlled studies in therapy-resistant neuropathic back pain, FBSS, and refractory neuropathic back and leg pain. In clinical practice, drugs that have demonstrated efficacy in 0885-3924/06/$--see front matter doi:10.1016/j.jpainsymman.2005.12.010
S14
Taylor
common indications such as postherpetic neuralgia, painful diabetic neuropathy, and trigeminal neuralgia are often prescribed by physicians for other refractory neuropathic pain conditions such as low back pain, even when there is an absence or scarcity of scientific evidence for efficacy and no indication in the pharmacopoeia.4,5 In a recent review of the literature regarding the management of refractory neuropathic pain, the majority of the systematic reviews identified provided evidence for the use of drugs and spinal cord stimulation (SCS), but little evidence was found for radiofrequency procedures or therapeutic blocks.6 This paper summarizes a series of systematic reviews7--9 that were undertaken to evaluate the evidence for the clinical and cost effectiveness of SCS in the treatment of CRPS and refractory neuropathic back and leg pain/FBSS.
Systematic Reviews, Meta-Analyses, and Grading of the Evidence The increasing drive toward the use of good quality evidence to evaluate new or existing therapies means that well-conducted systematic reviews and meta-analyses are of vital importance. A systematic review is one that strives to comprehensively identify and synthesize all the literature on a topic. Meta-analysis is a statistical technique for assembling the clinical results of several studies, preferably
Vol. 31 No. 4S April 2006
identified by systematic review, into a single numerical estimate. The evidence identified by a systematic review should also be critically evaluated and graded according to its quality, size of effect, and relevance. Until recently, the system for grading guideline recommendations was based on the work of the U.S. Agency for Health Care Research and Quality.10,11 However, experience of guideline development has led to a growing awareness of this system’s weaknesses. To address these problems, the Harbour and Miller12 grading system was developed and it offers several advantages over the older guidelines. It maintains the link between the strength of the available evidence and the grade of the recommendation, while allowing recommendations to be based on the best available evidence and be weighted accordingly. It also incorporates formal assessment of the methodological quality, quantity, consistency, and applicability of the evidence base. Finally, the grading system is presented in a clear and unambiguous way that allows guideline developers and users to understand the link between the strength of the evidence and the grade of recommendation (Table 1).
Methods Several methods were used to search for relevant evidence, including examination of bibliographic resources (Medline, CINAHL, EMBASE,
Table 1 The Harbour and Miller12 Scale for Grading Recommendations in Evidence-Based Guidelines Levels of evidence 1þþ High-quality meta-analyses, systematic reviews of RCTs, or RCTs of very low risk of bias 1þ Net/conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1 Meta-analyses, systematic reviews of RCTs, or RCTs with high risk of bias 2þþ High-quality systematic reviews of case-control or cohort studies. High-quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal 2þ Well-conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal 2 Case-control or cohort studies with a low risk of confounding, bias, or chance and significant risk that the relationship is not causal 3 Nonanalytic studies, e.g., case reports, case series 4 Expert opinion Grades of recommendation A At least one meta-analysis, systematic review, on RCT rated as 1þþ, and directly applicable to the target population, or a systematic review of RCTs or a body of evidence rated as 1þ, directly applicable to the target population, and demonstrating overall consistency of results B A body of evidence rated as 2þþ, directly applicable to the target population, and demonstrating overall consistency of results or extrapolated evidence from studies rated as 1þþ or 1þ C A body of evidence rated as 2þ, directly applicable to the target population, and demonstrating overall consistency of results or extrapolated evidence from studies rated as 2þþ D Evidence level 3 or 4, or extrapolated evidence from studies rated as 2þ
Vol. 31 No. 4S April 2006
SCS for the Management of Refractory Neuropathic Pain
Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, NHS Center for Reviews & Dissemination (CRD) Health Technology Assessment (HTA) database, UK National Health Service (NHS) Economic Evaluation Database, Health Economics Evaluation Database and registers of current clinical trials), a hand search of reference lists of included studies, and contact with experts and companies. No restrictions were placed on language. Identification/exclusion criteria were as follows: Study design: all designs (excluding case reports) Population: individuals with refractory neuropathic back and leg pain, FBSS, arachnoiditis, and CRPS (type 1/reflex sympathetic dystrophy and type 2/causalgia) Intervention: either unilateral or bilateral SCS as a single therapy or in combination with other therapies (excluding subdural SCS/disaggregated data) Outcomes: pain relief, return to work, functional disability, complications, quality of life, patient satisfaction/preference for intervention, health service utilization, and costs (excluding ‘‘technical outcomes’’) Studies were organized according to the hierarchy of evidence, their quality assessed, and an overall level of evidence grading
S15
applied.12 The quality of comparative studies was assessed using a modified version of the Jadad Scale, a measure of study methodological/ reporting quality (0 being the weakest and 5 being the strongest).13 Studies were also examined for the presence of bias (selection, confounding, performance, detection, attrition). A level and grade of recommendation was applied to the evidence.12
Results One randomized controlled trial (RCT), 25 case series, and one economic evaluation were found for CRPS. One RCT, one cohort study, 72 case series, and four cost studies were found for refractory neuropathic back and leg pain/FBSS (Fig. 1).
Clinical Effectiveness of SCS CRPS. In 2000, an RCT was initiated by Kemler et al.14 to examine whether SCS plus physical therapy (SCS þ PT) (n ¼ 36) was more effective than PT alone (n ¼ 18) in the treatment of therapy-resistant CRPS type I. Parameters assessed included pain intensity (using a visual analogue scale [VAS]), the global perceived effect, functional status,
Fig. 1. Identification and exclusion of studies.
S16
Taylor
health-related quality of life (HRQL), and complications associated with SCS. Patients were followed up for 24 months. The RCT scored 4 out of 5 on the Jadad Scale. A point was lost as patient and care givers were not blinded. After trial stimulation, SCS þ PT was successfully implanted in 24 of the 36 patients. Results showed that treatment with SCS þ PT reduced pain intensity to a significantly greater extent than PT alone, as seen by a reduction of 3.6 cm on the VAS compared with an increase of 0.2 cm in the PT group (P < 0.001). A significantly higher proportion of patients in the SCS þ PT group had a score of 6 (‘‘much improved’’) for the global perceived effect (14 patients, 58%) compared with the PT group (one patient, 6%) (P ¼ 0.01). No significant improvement in functional status was noted. However, only SCS þ PT led to an improvement in the HRQL, with an increase of 11% in the overall score. Significant improvements were seen for patients with an affected hand (P ¼ 0.02) and those with an affected foot (P ¼ 0.008). No improvement in HRQL was seen in the PT group. Four complications associated with SCS were observed: one infection, two generator pockets, and one lead related complication. The VAS and global pain results were maintained at the 24-month follow-up (Fig. 2).15 A total of 25 case series were identified for CRPS that provide a median follow-up time of 33 months postimplant.7 Some biases were noted in these studies, mainly detection (lack
Vol. 31 No. 4S April 2006
of outcome blinding) and attrition (loss to follow-up) bias. It was found that 67% of implanted patients with CRPS type I or II achieved pain relief of 50% or more with SCS. A significant reduction in pain intensity was also observed in the studies that used the VAS score to assess pain; the pooled mean reduction of VAS score was 4.7 with SCS. Significant improvements were noted for HRQL and there was a trend toward an improvement in functional capacity. Data from eight studies indicated that overall, 33% of CRPS patients experienced one or more problems with SCS. However, the majority of these were reversible and were due to lead problems. No serious adverse events were reported and no neurological complications were observed. Using the Harbour and Miller Scale,12 the evidence was classified as Grade A in CRPS type I. Only case series evidence currently exist for the use of SCS in CRPS type II, hence the lower grading of evidence. Refractory Neuropathic Back and Leg Pain/ FBSS. The RCT by North et al.16,17 compared SCS to reoperation in patients with FBSS. A total of 51 surgically remediable FBSS patients with refractory, mainly radicular neuropathic pain (with or without low back pain) were randomly assigned to initial treatment by reoperation (back surgery) or SCS; of these, 15 reoperation and 12 SCS patients reached the 6 month follow-up. Primary outcome measures included patient preference for treatment (frequency of therapy crossover), greater
Fig. 2. SCS þ PT in CRPS significantly improved the global perceived effect compared to PT alone.15
Vol. 31 No. 4S April 2006
SCS for the Management of Refractory Neuropathic Pain
Fig. 3. SCS in FBSS resulted in significantly greater pain relief and lower analgesic use compared with reoperation.17
than 50% pain relief, and opioid analgesic use at follow-up (6 and 24 months). The RCT scored 4 out of 5 on the Jadad Scale. Although patients and caregivers were not blinded, outcomes were assessed by an individual independent from both the conduct of the trial and delivery of care of the patients in the trial. At the 6-month follow-up, 10 (67%) of the 15 reoperation patients opted for crossover to SCS. In contrast, a significantly lower number of SCS patients (two patients, 17%) opted for crossover to reoperation (P ¼ 0.018). Significantly more patients receiving SCS achieved 50% or more pain relief compared with those who underwent reoperation (P ¼ 0.149). Similarly, patients receiving SCS also required substantially less opiate analgesics than the patients who underwent back surgery (P ¼ 0.0005) (Fig. 3). The 72 case studies in refractory neuropathic back and leg pain/FBSS included studies with follow-up of 10 years (Table 2).8 Across all case studies, results showed that 62% of SCS patients achieved 50% pain relief or more and
S17
53% of patients no longer required analgesics. Functional capacity and HRQL were significantly improved by SCS, and 40% of patients were able to return to work. Furthermore, 70% of SCS patients expressed satisfaction with their treatment. An SCS complication rate of 18% per year18 was observed, most of which were reversible and mainly due to electrode or lead problems. No serious adverse events and no neurological-related complications were reported. Because reoperation was deemed a less relevant comparator for FBSS (at least in the context of current European practice), the evidence for efficacy of SCS in refractory neuropathic back and leg pain/FBSS was classified as Grade B on the Harbour and Miller Scale.12
Cost Effectiveness of SCS In 2002, Kemler and Furnee19 performed a cost-effectiveness analysis based on the above RCT of SCS in CRPS type I. The study found that in the first year, the mean cost per patient was almost twice as high in the SCS þ PT group (V9,805) compared with the PT alone group (V5,741). This cost was mainly due to the implantation procedure, which formed 83% of the expenditure. However, after initial treatment, mean annual routine CRPS I costs declined significantly in the SCS þ PT group (P < 0.003)dmainly due to a diminished requirement for medical caredbut remained constant in the PT group. Thus, after 3 years the cost differences were permanently reversed, resulting in a lifetime cost saving of V58,471 per patient with SCS þ PT (Fig. 4). A cost-utility analysis of this trial, which investigated the additional cost and the additional net economic cost gained per quality-adjusted life-years (QALY), indicated a cost of V22,500 per QALY. This cost per QALY for SCS is consistent with a level of cost effectiveness that is
Table 2 Meta-Analysis of Pooled Outcomes with SCS for Refractory Neuropathic Back and Leg Pain/FBSS Case Series Median Follow-Up 18 Months (reproduced with permission from Taylor et al.)8 Outcome Pain relief $50% Tested patients Implanted patients No analgesics Return to work Patient satisfaction
No. of Studies
Cases/Sample Size
20 65 16 15 6
624/1165 1992/3313 324/681 405/1133 147/220
Pooled Estimate (95% CI) 48% 62% 53% 40% 70%
(43%--53%) (56%--69%) (48%--56%) (28%--50%) (62%--85%)
Heterogeneity P value <0.0001 <0.0001 <0.0001 <0.0001 0.003
S18
Taylor
Vol. 31 No. 4S April 2006
surgery (CAD$7,291). Although for 2 years postimplant the cumulative costs of SCS were in excess of those associated with non-SCS patients (as a result of high acquisition costs), the pattern reversed after about 2.5 years. In some centers, the time to cost neutrality (‘‘payback’’ period) was as little as 15 months postimplant (but ranged up to 5 years). The ‘‘payback’’ period was sensitive to a variety of factors, including the efficacy of SCS, battery/electrode life, and the level of SCS usage by patients. Fig. 4. SCS þ PT in CRPS resulted in an estimated lifetime cost saving of V58,471 (25% reduction) per patient compared with PT alone.19
commonly regarded as representing good value and appropriate use of the resources of society and the health care systemsdanything less than V60,000 per QALY is generally funded by the health care system. No economic evaluation of SCS for refractory neuropathic back and leg pain/FBSS was identified. However, four studies have examined the costs of SCS. These studies consistently report that over time SCS is potentially cost saving to the health care system. This is illustrated in Fig. 5, comparing the costs of SCS to best medical treatment/conventional pain therapy (CPT) for FBSS reported by Kumar et al.20 It was found that annual maintenance health care costs of SCS-treated patients (CAD$1,094) were considerably less than the costs associated with patients treated without
Conclusions The literature has shown that although there is little controlled evidence for the management of refractory neuropathic pain conditions such as FBSS, systematic reviews provide good evidence for the use of SCS.6 This systematic review and meta-analysis support the efficacy and safety of SCS in patients with refractory neuropathic back and leg pain/ FBSS (Grade B evidence) or CRPS type I (Grade A evidence) or type II (Grade D evidence). Furthermore, SCS has been shown to be a cost effective treatment for CRPS type I. In the medium to long term (beyond 2--3 years), SCS is likely to be cost saving compared with alternative therapy strategies for patients with FBSS. Evidence of the cost effectiveness of SCS in refractory neuropathic back and leg pain/FBSS is required.
References 1. Schofferman J, Reynolds J, Herzog R, et al. Failed back surgery: etiology and diagnostic evaluation. Spine J 2003;3:400--403. 2. Sandroni P, Burned-Larsen LM, McClelland RL, Low PA. Complex reflex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003;103:199--207. 3. Stanton-Hicks MD, Burton AW, Bruehl SP, et al. An updated interdisciplinary clinical pathway for CRPS: report of an expert panel. Pain Pract 2002; 2(1):1--16. 4. Hansson PT, Dickenson AH. Pharmacological treatment of peripheral neuropathic pain conditions based on shared commonalities despite multiple etiologies. Pain 2005;113:251--254.
Fig. 5. SCS in FBSS resulted in a cost saving after 2.5 years compared with conventional medical care.20
5. Backonja M-M, Serra J. Pharmacologic management Part 2: lesser-studied neuropathic pain diseases. Pain Med 2004;5(S1):S48--S59.
Vol. 31 No. 4S April 2006
SCS for the Management of Refractory Neuropathic Pain
6. Taylor RS, Niv D, Raj PP. Management of refractory neuropathic pain: exploration of the evidence. Pain Pract, submitted for publication. 7. Taylor RS, Van Buyten J-P, Buchser E. Spinal cord stimulation for complex regional pain syndrome: a systematic review of the clinical and cost-effectiveness literature and assessment of prognostic factors. Eur J Pain 2006;10(2):91--101. 8. Taylor RS, Van Buyten JP, Buchser E. Spinal cord stimulation for chronic back and leg pain and failed back surgery syndrome: a systematic review and analysis of prognostic factors. Spine 2005; 30(1):152--160. 9. Taylor RS, Taylor RJ, Van Buyten JP, et al. The cost effectiveness of spinal cord stimulation in the treatment of pain: a systematic review of the literature. J Pain Symptom Manage 2004;27:370--378. 10. United States Department of Health and Human Services, Agency for Health Care Policy and Research. Acute pain management: Operative or medical procedures and trauma. Rockville, MD: AHCPR, 1993: 107. (Clinical practice guideline No. 1, AHCPR Publication No. 92-0023.). 11. Hadorn DC, Baker D, Hodges JS, Hicks N. Rating the quality of evidence for clinical practice guidelines. J Clin Epidemiol 1996;49:749--754. 12. Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001;323:334--336. 13. Jadad AR, Cook DJ, Jones A, et al. Methodology and reports of systematic reviews and meta-analyses: a comparison of Cochrane reviews with articles
S19
published in paper-based journals. JAMA 1998;280: 278--280. 14. Kemler MA, Barendse GAM, van Kleef M, et al. Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. N Engl J Med 2000; 343:618--624. 15. Kemler MA, De Vet HCW, Barendse GAM, et al. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann Neurol 2004;55:13--18. 16. North RB, Kidd DH, Lee MS, et al. A prospective, randomised study of spinal cord stimulation versus reoperation for failed back surgery syndrome: initial results. Stereotact Funct Neurosurg 1994;62:267--272. 17. North RB, Kidd DH, Farrokhi F, Piantadosi SA. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: a randomized, controlled trial. Neurosurgery 2005;56:98--106. 18. Taylor RJ, Taylor RS. Spinal cord stimulation for failed back surgery syndrome: a decision-analytic model and cost-effectiveness analysis. Int J Technol Assess Health Care 2005;21(3):351--358. 19. Kemler A, Furnee CA. Economic evaluation of spinal cord stimulation for chronic reflex sympathetic dystrophy. Neurology 2002;59:1203--1209. 20. Kumar K, Malik S, Demeria D. Treatment of chronic pain with spinal cord stimulation versus alternative therapies: cost-effectiveness analysis. Neurosurgery 2002;51(1):106--116.