Long-term data on the effectiveness of spinal cord stimulation (SCS) for CRPS has recently been published. While the authors conclude that SCS has no durable statistically significant effect on pain relief for chronic CRPS Type I patients, there are limi-tations with regard to the analysis and a more comprehensive evaluation and interpretation of the data is warranted.

What is Complex Regional Pain Syndrome (CRPS)?

CRPS is a neuropathic pain syndrome precipitated most com-monly by minor limb trauma.1-4 Continuous, severe pain, dis-proportionate to the inciting event, occurs in the limb and may be accompanied by allodynia, hyperalgesia, skin color changes, edema, joint stiffness, and bone demineralization.1,4,5 The second most common use of spinal cord stimulation (SCS) in the United States is for the symptomatic management of CRPS.

Clinical evidence supports the use of spinal cord stimulation (SCS) using current technology as safe, effective, and cost-effec-tive for the treatment of complex regional pain syndrome/reflex sympathetic dystrophy (CRPS/RSD).4-14

Studies have shown that SCS provides significant pain relief4,5,8,9,13 and has been associated with substantial long-term success as measured by global perceived effect.5,8,13 One study demonstrated that SCS led to a reduction in medication use.4 Two studies have shown improvements in function and daily living4,13 and enabled patients to return to work.4 SCS can significantly enhance CRPS treatment by providing sufficient pain relief such that patients can engage in physical therapy as part of their rehabilitation process.16 Cost studies show that the mean first-year cost of SCS becomes substantially less in the second year.14,15

Background on the Kemler study for CRPS: previously reported six- and 24-month results

Patients selected for the Kemler study were enrolled between March of 1997 and July of 1998 and were randomized 2:1 to either SCS plus physical therapy (SCS+PT) (n = 36) or PT alone (n = 18). Of the 36 patients randomized to SCS+PT, 24 (67%) were implanted.

At six months, in an intention-to-treat (ITT) analysis, the mean VAS score for SCS+PT patients decreased by 2.4 cm, while it increased by 0.2 cm for PT-only patients (p < 0.001). In an as-treated analysis, the mean VAS score for SCS+PT implanted

patients decreased by 3.6 cm, while it increased by 0.2 cm for PT-only patients (p < 0.001). (Figure 1). In the as-treated analysis, global perceived effect (GPE) was much improved in 14 (58%) of the 24 SCS+PT implanted patients, as compared to one of the 18 (6%) PT-only patients (p < 0.001). SCS+PT also resulted in significant improvements in health-related quality of life (HRQoL) both for patients with an affected hand (p = 0.02) or foot (p = 0.008).7

At the two-year follow-up, in an ITT analysis, mean pain inten-sity (VAS) decreased by 2.1 cm for SCS+PT patients compared to 0 cm for PT-only patients (p < 0.001). In the as-treated analy-sis, mean VAS score decreased by 3.0 cm for SCS+PT implanted patients compared to 0 cm for PT-only patients (p < 0.001). In the as-treated analysis, GPE was much improved in 15 of the 24 (63%) SCS+PT implanted patients, as compared to 1 of 11 (9%) PT-only patients (p < 0.001) (Figure 2). HRQoL benefits remained the same.8

Figure 1. Change in VAS (cm) at six months: SCS+PT implanted versus PT-only 7

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Spinal Cord Stimulation for Complex Regional Pain Syndrome (CRPS): Better Pain Relief than Conventional Medical Care After 5 YearsMedtronic’s Response to the Kemler Journal of Neurosurgery Article (2008;108:292-298)

Kemler study for CRPS: five-year results

After five years, in the main analysis the mean pain intensity for the patients randomized to SCS+PT (n = 31) was reduced by 1.7 cm versus 1.0 cm for the patient randomized to PT only (n = 13) (p = 0.25). Twenty-three percent (23%) of the SCS+PT patients reported much improvement on the GPE scale, while 15% of PT-only patients reported much improvement (p = 0.24). HRQoL changes were not statistically different between groups.18

In the subgroup analysis of permanently implanted patients (n = 20) versus PT-only patients (n = 13), the average pain relief (VAS) was 2.5 cm compared to 1.0 cm (p = 0.06). Thirty-five percent (35%) of the SCS+PT implanted patients reported much improvement on the GPE scale, while 15% of PT-only patients reported much improvement (p = 0.02). HRQoL measures were not significantly different between groups. Patient satisfaction in SCS implanted patients was also very high. After five years, 90% of SCS implanted patients indicated that they had positively responded to SCS, and 95% reported that they would undergo treatment again for the same result.18

Pain scores at five years likely moderate for SCS-implanted patients and severe for PT-only patients

In the as-treated analysis of SCS+PT implanted patients ver-sus PT-only patients, the difference in VAS pain score change approached statistical significance (p = 0.06) in favor of SCS and that difference was likely clinically meaningful to patients. As Figure 3 demonstrates, the mean VAS score for SCS implanted patients was relatively steady over years 3-5 and was still nearly two points lower than PT-only patients at year five.18 Further, the average VAS score for SCS implanted patients was in the range of scores considered to equate to moderate pain, while the average score for PT-only patients was in the range of scores considered to equate to severe pain.19

The nature of the analysis was unconventional

Kemler’s main analysis should have employed ITT analysis whereby comparisons would be made between the patients ran-domized to SCS+PT versus the patients randomized to PT only, regardless of what actually happened with their treatment. In fact, Kemler excludes one SCS+PT randomized patient due to a special implant and excludes four PT-only randomized patients

due to SCS implant. ITT analysis is valuable because it allows the balance of known and unknown patients’ characteristics to remain equal between the two treatment groups as a result of randomization. As ITT was not employed, we cannot be sure that the two treatment groups are directly comparable or if selection bias exists.

Kemler’s subgroup analysis should have employed an as-treated approach whereby comparisons would be made between all patients who actually received an SCS implant (n = 27) versus all patients receiving PT only (n = 22). In fact, Kemler excludes one SCS+PT randomized patient who received a special implant, four PT-only randomized patients who received an SCS implant, and nine SCS+PT randomized patients who received PT only due to a failed SCS trial.18 As-treated analysis allows you to analyze the patients based upon the treatment they actually received. In the case of this study, as-treated analysis offers value because sev-eral patients randomized to SCS never received the therapy and several patients randomized to PT-only received stimulation.

The use of a post-randomization baseline pain measure raises concern. As the study was not blinded, the patients’ perceived baseline pain intensity may have been influenced by knowing which treatment they were about to receive.

Analyzing five-year outcomes versus baseline values may no lon-ger be a valid comparison for two reasons. First, patients may reframe their pain, meaning that the patient considers his or her pain experience from a new reference point. Treatment may allow them to increase their level of functioning. This enhanced level of activity might then become their new normal. As they push their bodies to do more, they may perceive their pain as being worse, when in fact they are performing an activity that previously was difficult or impossible due to pain. Second, their disease may have progressed or changed over time to involve additional painful regions or different painful regions.

CRPS responds to treatment best when it is diagnosed and treated early

A clinical treatment pathway for patients who have not responded to conservative therapy (Figure 4), developed under the auspices of the International Association for the Study of Pain (IASP), rec-ommends SCS at 12-16 weeks. This guideline was developed by a panel of internationally recognized experts in the care of CRPS

Figure 3. Mean VAS Scores over Time18

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Bar graph demonstrating the mean (± SD) VAS pain scores in patients with complex CRPS-I. The groups in the main analysis are represented by the gray and dark blue bars, whereas the subgroup of patients with an implant at the final follow-up is represented by light blue bars.

patients.16 Patients in the Kemler study at enrollment had CRPS on average for more than three years.7

Figure 4. Treatment Pathway for CRPS 16

Motor changes

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CRPS symptoms are heterogeneous and dynamic17

The character of CRPS pain evolves over time, and in 10% of patients spreads to a new region or limb.16 As Kemler notes, the pain may, on occasion, even resolve.18 Whether programming was adjusted to treat the changing nature of the patients’ pain in Kemler’s study is unknown. Further, the ability to adjust programming was limited for patients with the Itrel 3 and quadripolar leads compared to the systems and software avail-able today. Significant differences in pain relief and the ability to recapture pain relief without reintervention have been reported in retrospective analysis for patients with dual lead octapolar systems versus single lead quadripolar systems.9

SCS technology in the Kemler study now outdatedPatients were implanted with the Itrel® 3 Model 7425 neurostimulator and Model 3487A leads, which are quadripolar with four electrodes.7 This is a single lead system providing uni-lateral stimulation designed for simple neuropathic pain, the only therapy available at the time. Today’s therapy provides bilateral stimulation using up to 16 electrodes and powers multiple lead arrays with rechargeable neurostimulators and advanced pro-gramming features to handle the complex and high-power needs of CRPS patients. Neurostimulation can be adjusted to address the changing nature of CRPS pain over time. A physician can give patients the ability to adjust their therapy to accommodate fluctuations in day-to-day pain.

Complications should be interpreted with caution

Over five years of treatment, 10 (42%) of 24 SCS+PT implanted patients underwent reoperation as a result of complications.17 The most common complication was lead migration. Today’s 16-electrode systems may reduce the number of interventions required to correct lead migration as reprogramming may recap-ture the loss of or shift in paresthesia coverage or the change in pain patterns. Finally, the stimulator replacements were listed in the complications table of the article, which is misleading. Appropriately, they were not counted as complications in the Kemler study. The typical high-power needs of CRPS patients routinely exhausted the natural battery life sooner in older generation technology. Today’s rechargeable neurostimulators can minimize the number of stimulator replacements for CRPS patients with high-power needs.

SCS for CRPS is a cost-effective therapy

CRPS is a serious, debilitating medical condition and patients are often refractory to more conservative treatments.20-21 Spi-nal cord stimulation offers these patients a chance to achieve significant pain relief. While the pain relief may diminish over time, as the authors note, two to three years of significant pain reduction must be considered an important achievement.18 Finally, spinal cord stimulation remains a cost-effective ther-apy. Despite a higher cost in the first year, due largely to trial and implant costs, economic analysis has demonstrated that the mean first-year cost becomes substantially less in the sec-ond year14,15 and lifetime costs for SCS+PT patients are lower compared to costs for PT-only patients (Figure 5).14 Regard-less of the figure selected, discount rate, implantation rate, and complication rate, the costs of conventional treatment exceed those of spinal cord stimulation.14 Similarly, SCS for failed back surgery syndrome (FBSS) patients has been shown to be cost-effective versus conventional treatment22-25 and this has been reported to occur approximately two years following implant.24,25

Figure 5. Mean cost from first year to death14

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References1 Kumar K, Hunter G, Demeria D. Spinal cord stimulation in treatment of chronic benign pain: challenges in treatment planning and present status, a 22-year experience. Neurosurgery. 2006;58(3):481-496.2 Wasner G, Schattschneider J, Binder A, Baron R. Complex regional pain syndrome—diagnostic, mechanisms, CNS involvement and therapy. Spinal Cord. 2003;41(2):61-75.3 Baron R, Levine JD, Fields HL. Causalgia and reflex sympathetic dystrophy: does the sympathetic nervous system contribute to the generation of pain? Muscle Nerve. 1999;22(6):678-695.

4 Harke H, Gretenkort P, Ladleif HU, Rahman S. Spinal cord stimulation in sympathetically maintained complex regional pain syndrome type I with severe disability. A prospective clinical study. Eur J Pain. 2005;9(4):363-373.5 Forouzanfar T, Kemler MA, Weber WE, Kessels AG, van Kleef M. Spinal cord stimulation in complex regional pain syndrome: cervical and lumbar devices are comparably effective. Br J Anaesth. 2004;92(3):348-353.6 Stanton-Hicks M. Complex regional pain syndrome: manifestations and the role of neurostimulation in its management. J Pain Symptom Manage. 2006;31(4 suppl):S20-S24.7 Kemler MA, Barendse GAM, van Kleef M, et al. Spinal cord stimula-tion in patients with chronic reflex sympathetic dystrophy. N Engl J Med. 2000;343(9):618-624.8 Kemler MA, de Vet HC, Barendse GA, van den Wildenberg FA, van Kleef M. The effect of spinal cord stimulation in patients with chronic reflex sym-pathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann Neurol. 2004;55(1):13-18.9 Bennett DS, Aló KM, Oakley J, Feler CA. Spinal cord stimulation for com-plex regional pain syndrome [RSD]: a retrospective multicenter experience for 1995 to 1998 of 101 patients. Neuromodulation. 1999;2(3):201-210.10 Oakley JC, Weiner RL. Spinal cord stimulation for complex regional pain syndrome: A prospective study of 19 patients at two centers. Neuromodula-tion. 1999;2(1):47-50.11 Taylor RS, Van Buyten JP, Buchser E. Spinal cord stimulation for com-plex regional pain syndrome: a systematic review of the clinical and cost-effectiveness literature and assessment of prognostic factors. Eur J Pain. 2006;10(2):91-101.12 Cruccu G, Aziz TZ, Garcia-Larrea L, et al. EFNS guidelines on neurostimu-lation therapy for neuropathic pain. Eur J Neurol. 2007;14(9):952-70.13 Kemler MA, Barendse GA, van Kleef M, van den Wildenberg FA, Weber WE. Electrical spinal cord stimulation in reflex sympathetic dystrophy: ret-rospective analysis of 23 patients. J Neurosurg. 1999;90(1 suppl):79-83.14 Kemler MA, Furnée CA. Economic evaluation of spinal cord stimulation for chronic reflex sympathetic dystrophy. Neurology. 2002;59(8):1203-1209.

15 Kumar K, Wilson JR, Taylor RS, Gupta S. Complications of spinal cord stimulation, suggestions to improve outcome, and financial impact. J Neuro-surg Spine. 2006;5(3):191-203.16 Stanton-Hicks MD, Burton AW, Bruehl SP, Carr DB, Harden RN, Hassen-busch SJ, Lubenow TR, Oakley JC, Racz GB, Raj PP, Rauck RL, Rezai AR. An updated interdisciplinary clinical pathway for CRPS: report of an expert panel. Pain Pract. 2002;2(1):1-16.17 Baron R, Maier C. Reflex sympathetic dystrophy: Skin blood flow, sympa-thetic vasoconstrictor reflexes and pain before and after surgical sympathec-tomy. Pain. 1996;67(2-3):317-326.18 Kemler MA, de Vet HC, Barendse GA, van den Wildenberg FA, van Kleef M. Effect of spinal cord stimulation for chronic complex regional pain syndrome Type I : five-year follow-up of patients in a randomized controlled trial. J Neurosurg. 2008;108(2):292-298.19 Collins SL, Moore RA, McQuay HJ. The visual analogue pain intensity scale: what is moderate pain in millimetres? Pain. 1997 Aug;72(1-2):95-97.20 Eisenberg E, Geller R, Brill S. Pharmacotherapy options for complex regional pain syndrome. Expert Rev Neurother. 2007 May;7(5):521-31. 21 Rho RH, Brewer RP, Lamer TJ, Wilson PR. Complex regional pain syn-drome. Mayo Clin Proc. 2002 Feb;77(2):174-80.22 North RB, Kidd D, Shipley J, Taylor RS. Spinal cord stimulation versus reoperation for failed back surgery syndrome: a cost effectiveness and cost utility analysis based on a randomized, controlled trial. Neurosurgery. 2007;61(2):361-369.23 Taylor RJ, Taylor, RS. Spinal cord stimulation for failed back surgery syn-drome: a decision-analytic model and cost-effective analysis. Int J Technol Assess Health Care. 2005;21(3):351-358.24 Kumar K, Malik S, Demeria D. Treatment of chronic pain with spinal cord stimulation versus alternative therapies: cost effectiveness analysis. Neuro-surgery. 2002;51(1):106-116.25 Bell GK, Kidd D, North RB. Cost-effective analysis of spinal cord stimula-tion in treatment of failed back surgery syndrome. J Pain Symptom Manage. 1997;13(5):286-295.

Brief Summary: Product Technical Manuals and Programming Guides must be reviewed prior to use for detailed disclosure.

Indication for Use - Chronic, intractable pain of the trunk and/or limbs-including unilateral or bilateral pain. Contraindications: Diathermy. Warnings: Defibrillation, diathermy, electrocautery, MRI, RF ablation, & therapeutic ultrasound can result in unexpected changes in stimulation, serious patient injury or death. Rupture/piercing of neurostimulator can result in severe burns. Electrical pulses from the neurostimulator may result in an inappropriate response of the cardiac device. Precautions: The safety and effectiveness of this therapy has not been established for: pediatric use, pregnancy, unborn fetus, or delivery. Follow programming guidelines & precautions in product manuals. Avoid activities that stress the implanted neurostimulation system. EMI, postural changes, & other activities may cause shocking/jolting. Adverse Events: Undesirable change in stimulation; hematoma, epidural hemorrhage, paralysis, seroma, CSF leakage, infection, erosion, allergic response, hardware malfunction or migration, pain at implant site, loss of pain relief, chest wall stimulation, & surgical risks.

For full prescribing information, please call Medtronic at 1-800-328-0810 and/or consult Medtronic’s website at www.medtronic.com. USA Rx Only Rev 0209

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United States of AmericaMedtronic Neuromodulation 710 Medtronic Parkway Minneapolis, MN 55432-5604 USA Tel. 763-505-5000 Toll-free 1-800-328-0810

EuropeMedtronic International Trading Sàrl Route du Molliau 31 Case Postale CH-1131 Tolochenaz Switzerland Tel. +41-21-802-7000

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