CHAPTER 165 Evidence Base
Neurostimulation for Pain
This chapter, a critical examination of the evidentiary basis for the use of neurostimulation therapies to treat chronic noncancer pain, is unprecedented in the history of neurosurgical textbooks; it is bound to be controversial and to contradict other chapters in this section. Although many works of this sort tabulate previous reports about pain therapies, critical deconstruction of the nature and quality of those publications is unusual.1–3 This chapter is based on previous work by the authors and others who examined their work critically to establish whether and how we really know what we think we know about neurosurgical therapies—including those for chronic pain.4–11 Despite the apparently narrow focus of this work, our methods apply to the evaluation of other medical therapies and to any field amenable to empirical observation. The vocabulary of evidence-based medicine is in vogue and may reflect a serious trend.12 Nonetheless, most evidence-based reviews continue to replicate the biases and flaws of previous reports.13 In a similar vein, evidence-based econometric studies, which advocate private or national health system reimbursement coverage for particular neurostimulation therapies, serve economic ends and suffer from considerable input- and assumption-based biases.14–19 The problematic nature of econometric analyses has been examined in detail in the context of another category of medical devices, implantable cardioverter-defibrillators, which, arguably, are easier to evaluate than neurostimulation pain therapies because the efficacy end point (death) is unequivocal.20–25
Background
Patients with chronic pain, which may last indefinitely according to International Association for the Study of Pain definitions, now constitute about half of individuals who receive unemployment or disability benefits in industrialized countries.26,27 Many have work-related injuries, disorders of the lumbosacral spine, or pain that persists after multiple operations. It is now easier for many unemployed workers in the United States to obtain permanent, pain-related disability benefits than to find a new job.28,29 Reasons for this trend involve socioeconomic policies that intersect with and have nourished the growth of pain medicine as a specialty over the past three decades.
History
Mid-20th century experiments that led investigators to stimulate the ventral posterolateral and posteromedial sensory thalamic nuclei and periaqueductal-periventricular gray matter (VPL, VPM, and PAG-PVG) and to the gate theory, which led to stimulation of the dorsal columns of the spinal cord in patients with chronic intractable pain, are reviewed elsewhere.4,8,9,30–36 Reports of analgesic effects after MCS appeared in the 1980s,37 and reports of ONS to treat head pain disorders appeared in the 1990s.38,39 In the 1980s, the U.S. Food and Drug Administration (FDA) reviewed implantable neurostimulation devices and, on the basis of available publications and expert testimony, ruled that spinal cord and peripheral nerve stimulation devices could continue to be marketed in the United States without formal clinical trials of efficacy. Until recently, approvals of newer-generation devices were based on limited safety and usability trials and other provisions of the Code of Federal Regulations.40 In contrast, because DBS leads were substantial-risk investigational devices, new implants in the United States could proceed only in approved clinical trials, or by compassionate use. FDA approval of the Activa DBS system (Medtronic, Inc., Minneapolis, MN) for medically refractory tremor in 1997, Parkinson’s disease in 2002, and dystonia (humanitarian use) in 2003, respectively, made DBS devices available again for the treatment of pain, but as an unlabeled indication for an approved device. At present, MCS is unlabeled in the United States for any indication. A European multicenter trial of MCS for pain commenced in 2005 and was closed by the sponsor in 2007 because of slow enrollment and lack of a clear efficacy signal (Final report on clinical investigation with medical devices: A prospective, randomized, double blind, crossover, multicenter study to evaluate the safety and efficacy of motor cortex stimulation with the cortical stimulation lead model 2976 in patients with neuropathic pain [hereafter referred to as CONCEPT trial], Medtronic Europe, Tolochenaz, Switzerland, March 26, 2008). One multinational feasibility trial of ONS for chronic migraine using leads approved for SCS recently was completed (Clinical report, 3-month data: Occipital nerve stimulation for the treatment of chronic migraine headaches [hereafter referred to as ONSTIM trial], Medtronic, Inc., Minneapolis, MN, June 24, 2008), and other industry-sponsored trials are underway. A preview of our analysis of hundreds of publications, reviews, and (to date) unpublished multicenter clinical trials of neurostimulation modalities to treat chronic noncancer pain reveals that no study or industry-sponsored trial of any neurostimulation modality that employed adequate blinding, randomization, or a valid contemporaneous control group has shown clinically meaningful long-term analgesic efficacy. Other controlled, uncontrolled, blinded, or unblinded nonindustry neurostimulation studies, if carried beyond a few months, or at most, beyond 2 years, also revealed no statistically detectable analgesic effects.
Methods
The authors identified publications for analysis using the U.S. National Library of Medicine PubMed database and the following search strategies: “spinal cord stimulation AND pain,” “deep brain stimulation AND pain,” “deep brain stimulation AND cluster,” “motor cortex stimulation AND pain,” “occipital nerve stimulation AND pain,” or “occipital nerve stimulation AND cluster.” Search limits included “language = English” (or an English language abstract), and “human.” We identified additional historical references from the bibliographies of indexed publications and reviews and drew on our recent critical analyses of individual neurostimulation therapies.6,4,8,9 Publications that described clinical efficacy were selected for analysis of the features listed in Table 165-1.41,42 We focused on publications and accompanying editorials or correspondence that contained or analyzed clinical efficacy data and that appeared in print between March 31, 2004, the closure date for a previous analysis, and February 29, 2008. The aggregate results are summarized in Table 165-2.38,39,43–154 The current work excluded publications that described technical or procedural innovations or complications, imaging or anatomic observations, and physiologic or neurophysiologic phenomena apart from analgesic efficacy.
TABLE 165-1 Factors Used to Evaluate Reports of Neurostimulation for Chronic Pain*
| LEVELS OF EVIDENCE | CRITERIA |
|---|---|
* Adapted and modified from Canadian Task Force on the Periodic Health Examination. The periodic health examination: 2. 1987 update. Can Med Assoc J. 1988;138:618-626; and Weintraub M. How to evaluate reports of clinical trials. Pharm Therapeut. 1990;14:1463-1476.
Results
Success Criteria and Reported Efficacy Rates
A historically accepted success criterion in neurostimulation studies for pain is that greater than or equal to 50% of individual patients should report greater than or equal to 50% pain relief (PPR; or ≥50% reduction in the visual analog scale [VAS] of pain intensity) at follow-up—commonly after 6 to 24 months. Until the 1990s, most trials and studies had used minor variations of the 50 : 50 standard.6,47 By definition, and to prevent a few cases from skewing the results, average or aggregate pain ratings formerly were avoided in efficacy rate calculations. After historical series failed to achieve the 50 : 50 efficacy criterion, studies of SCS between the 1990s and the present were structured to determine whether statistically significant aggregate or average pain relief scores differed after treatment over relatively short periods (<2 years) compared with the patient’s baseline. According to our previous analyses and data summarized in Table 165-2, assessments commonly were performed by the implanters or their associates or did not reach the 50 : 50 efficacy threshold, or both. Studies of novel programming techniques or lead designs also found limited efficacy or lacked sufficient data to draw long-term conclusions. Most of the studies that we reviewed had open-label designs, and all compared the results with the patient’s pretreatment baseline. None reported greater than or equal to 50% long-term relief in greater than or equal to 50% of subjects unless efficacy was analyzed without regard for the duration of follow-up or unless subjects who were lost or disqualified from follow-up were excluded from the calculations.
Long-term, prospective, randomized, crossover comparisons of SCS and reoperation in subjects with persistent pain after previous back surgery, performed over about a 10-year interval, were not designed to measure the degree of pain relief afforded by SCS. Despite the preference of subjects for SCS compared with reoperation, the effect size of the analgesia afforded by SCS or of repeat low back surgery remained undefined.64,66 A problem with such study designs, in addition to the assignment of one cohort to repeat low back surgery, a treatment that had previously not relieved their pain, is that subjects with a demonstrable anatomic cause for their pain were as likely to be assigned to SCS as to another low back operation. Likewise, subjects with no demonstrable spinal abnormalities had a 50% likelihood of being assigned to undergo another spine operation despite the absence of surgically amenable pathology. Neither treatment served as an adequate control measure for the other, leaving the study uncontrolled, unblinded, and unlikely to answer fundamental questions about the efficacy of SCS.67 One randomized controlled trial, among nearly 600 articles on SCS for RSD or CRPS, found that SCS plus physical therapy (PT) significantly reduced pain after 6 months and 2 years compared with PT alone, but not after 5 years.53–5563 The early results did not achieve the traditional 50 : 50 success criterion, and the long-term results revealed no statistical difference between the SCS plus PT group and the PT alone group.
In all DBS clinical series reported until recently, fewer patients reported pain relief after 6 to 24 months of therapy than during the early postimplantation period, and no study achieved the 50 : 50 success level unless short-term results carried the same analytical weight as follow-up that lasted months to years.6,5,8 Two industry-sponsored open-label DBS trials for pain enrolled 246 patients from 1989 to 1995. The coated-wire DBS lead used in the first trial became obsolete and was withdrawn from the market (N = 196); a trial of the current model DBS lead was closed because of slow enrollment and unexpectedly low efficacy (N = 50).6 Nandi and associates83–85 originally reported that seven patients with internalized DBS systems (among eight patients with implanted electrodes) experienced 32% to 46% pain relief after 3 to 30 months. Subsequent reports from the same group described better results than the first cohorts. However, it eventually became impossible for reviewers to follow patients through the entire series of publications.86–88 In another recent publication, investigators, one of whom had decades of experience in the field, described the results of a small 10-year case series that divided patients retrospectively according to diagnosis, and in which more than half of patients experienced no clinically meaningful pain relief at any time after DBS lead implantation.90
Articles and reviews by investigators in Milan (8 of 14 reviewed in Table 165-2), nearly all covering the same overlapping patient cohort at different stages of follow-up, and all describing dramatic efficacy, have dominated the discussion of hypothalamic DBS to treat cluster headache and other intractable trigeminal autonomic cephalgias. The experience at other centers has been less dramatic, and a proposed U.S. trial to examine hypotheses generated during a physician-sponsored pilot study may eventually achieve funding-agency approval.106 However, a randomized, controlled, and blinded French multicenter trial recently failed to demonstrate a statistically significant difference in the prespecified primary efficacy variable (the weekly frequency cluster headache attacks) between the stimulation “on” and “off” periods.107
The industry-sponsored European multinational study of MCS to treat facial (trigeminal) deafferentation pain and central poststroke pain enrolled and implanted only 24 subjects in 2 years, out of a planned cohort of 104 enrollments calculated to yield 82 evaluable subjects for the primary efficacy end point, before being closed by the sponsor because of slow enrollment. Although one can draw only limited conclusions because the prospectively planned N number was not achieved, 7 of 24 subjects (29%) withdrew or were discontinued from the study after lead implantation, but before randomization (to sham or active MCS) because of lack of efficacy during either the trial stimulation or early postinternalization study phases. Among the 11 randomized subjects who completed blinded one-way crossover MCS (on to off, or off to on; 4 weeks duration, each) and who completed all scheduled follow-up visits, none expressed a preference for the MCS “on” condition regardless of the on-off sequence to which they were randomized. No other large-scale blinded and controlled trial of MCS has been undertaken to date. Results of the MCS trial, albeit incomplete, fail to validate the more positive findings of the other controlled or uncontrolled single-center studies that we reviewed in Table 165-2.
Success rates in two early case series of ONS for head pain disorders were 64.5% and 100% during a mean follow-up of 18 months.38,39 In one report of 25 patients, 9 (36%) still had moderately or severely disabling headaches after 9 to 36 months.39 However, results of the randomized, controlled, industry-sponsored ONS clinical feasibility trial, which met prospectively defined enrollment, follow-up, and analysis goals (N = 110 enrolled subjects), showed no clear efficacy signal.150 The difference in the primary efficacy end point “number of headache days per month” was not statistically significant among the adjustable stimulation group (active therapy) and three different control groups: a group with preset stimulation (1 minute of stimulation per day, automatically programmed), a group with medical management (no device implant), or an ancillary group of eight subjects who were implanted and received adjustable stimulation, but who had failed to respond to an occipital nerve block during the preimplantation screening phase. The positive results reported from other case series and studies analyzed in Table 165-2 do not comport with the findings of this monitored and audited industry-sponsored trial.
The Neurostimulation Literature
Nature of the Reports
Evidence-related features of the recent neurostimulation clinical literature are listed in detail in Table 165-2 and organized according to published criteria for the evaluation of medical evidence.41,42 The prospective studies of SCS in RSD and of SCS compared with reoperation for low back pain each employed control groups and randomization. However, as noted previously, patients and evaluators were not blinded.53–55,63–67 Industry-sponsored studies of MCS and ONS were controlled, randomized, and blinded and revealed no clear signals of efficacy. This leaves unexplained the one prospective and partially blinded single-institution study of MCS that reported positive results.145 The remainder of neurostimulation publications consisted of retrospective case series, case reports, or meeting abstracts (see Table 165-2).
Diagnoses and Patient Selection
Diagnoses, demographic data, the number of eligible patients who were evaluated or excluded, the pretreatment duration of pain, and previous pain therapies were reported unevenly or not at all in several publications (see Table 165-2). The assignment of diagnoses or pain categories, including nociceptive, deafferentation, central, mixed pain, and headache disorders, was inconsistent among centers, and sometimes among multiple reports from the same institution. Patients treated successfully with ONS for occipital neuralgia in one series were followed by a second series that had the newly minted diagnosis of chronic or transformed migraine headache using criteria that continued to evolve after commencement of the ONS trials.38,149,155
Reports and reviews continued to describe selection criteria believed to maximize the likelihood of success for neurostimulation therapies, including pain in contiguous regions that can be covered by stimulation-induced paresthesias, favorable responses to transcutaneous electrical nerve stimulation (TENS), diagnoses previously reported to respond favorably, and rejection of patients with presumably unfavorable psychological or personality profiles, drug addiction, or pending litigation. In other reports, the results of psychological or pharmacologic screening either were not reported or had little influence on whether patients were accepted for therapy (see Table 165-2). The recently completed ONS feasibility trial revealed no predictive value for occipital nerve blocks. Psychological selection criteria for other neurostimulation therapies also had little predictive value.5,156,157
Stimulation Targets, Test Simulation, and Ancillary Treatments
The neural target for SCS was the dorsal columns of the spinal cord at cervical or thoracic levels to treat upper or lower extremity pain, respectively, and using percutaneous or surgically implanted epidural leads. DBS targets for classic indications included the VPL-VPM thalamic nuclei or the PAG-PVG region, or both, depending on the surgeon’s judgment, the patient’s symptoms, or the results of preoperative screening tests. Hypothalamic target coordinates for DBS to treat cluster headache are very close to the classic PVG target.158 MCS lead implantation techniques evolved during the past 20 years to include neuroimaging guidance, electrophysiologic localization, single-stage surgery, and epidural, instead of subdural, lead placement.5,9 ONS involved percutaneous fluoroscopically guided insertion of SCS leads into the subcutaneous tissue at the C1 level. A transverse trajectory placed the electrical contact surfaces across the course of the greater and lesser occipital nerves. Technical reports and small case series described procedures for ONS lead placement under direct vision; however, those techniques have not yet been studied in formal clinical trials. For all neurostimulation therapies, the use or duration of a trial period before system internalization, the methods used to select active electrode contacts, the stimulation parameters that were employed, and the daily schedule of treatment sessions varied among centers and among individual patients. Many publications contained no information about how analgesic medications, psychoactive drugs, or other concomitant therapies were managed, and all information regarding decreased pain medication intake relied on patient self-reports that were not verified by pill counts, drug testing of body fluids, or other quantitative methods (see Table 165-2).
Follow-up, Outcome Measures, Data Collection, Reporting, and Analysis
Other than the industry-sponsored trials, relatively few studies employed independent evaluators (see Table 165-2). In most studies, the implanters or their associates, who were aware of the patients’ history and previous assessments and who were responsible for their ongoing care, performed follow-up evaluations. Again, with the exception of industry studies, the duration of follow-up often was unclear, not reported, or varied from months to years in the same series. And multiple reports of the same patient cohort frequently did not track individual cases through the series of publications. Because follow-up periods were not uniform, because subjects frequently did not comply with long-term follow-up, and because life table analyses were not performed, different durations of therapy carried equal weight in efficacy calculations. The studies that had well-defined follow-up periods are listed in Table 165-2 as “uniform timing reported” and included all of the recent and historical industry-sponsored trials.
Reviews, Meta-analyses, and Practice Guidelines
Few reviews, editorials, or journal correspondence critically analyzed efficacy claims. As a rule, review articles recapped previous claims without analyzing the validity of the underlying methods and data, or the plausibility of the claims themselves. This held true for articles, chapters, meta-analyses, and quasi-official publications of evidence-based practice guidelines for neurostimulation therapies.13,159–166 Most reviewers accepted the hypothesis that neurostimulation provided pain relief as described in the original reports, and some put forth mechanisms to explain stimulation-produced analgesia in the absence of evidence that analgesia actually occurs.167
