Cochrane Abstracts
Implanted spinal neuromodulation interventions for chronic pain in adults
Abstract
Background
Implanted spinal neuromodulation (SNMD) techniques are used in the treatment of refractory chronic pain. They involve the implantation of electrodes around the spinal cord (spinal cord stimulation (SCS)) or dorsal root ganglion (dorsal root ganglion stimulation (DRGS)), and a pulse generator unit under the skin. Electrical stimulation is then used with the aim of reducing pain intensity.
Objectives
To evaluate the efficacy, effectiveness, adverse events, and cost‐effectiveness of implanted spinal neuromodulation interventions for people with chronic pain.
Search methods
We searched CENTRAL, MEDLINE Ovid, Embase Ovid, Web of Science (ISI), Health Technology Assessments, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry from inception to September 2021 without language restrictions, searched the reference lists of included studies and contacted experts in the field.
Selection criteria
We included randomised controlled trials (RCTs) comparing SNMD interventions with placebo (sham) stimulation, no treatment or usual care; or comparing SNMD interventions + another treatment versus that treatment alone. We included participants ≥ 18 years old with non‐cancer and non‐ischaemic pain of longer than three months duration. Primary outcomes were pain intensity and adverse events. Secondary outcomes were disability, analgesic medication use, health‐related quality of life (HRQoL) and health economic outcomes.
Data collection and analysis
Two review authors independently screened database searches to determine inclusion, extracted data and evaluated risk of bias for prespecified results using the Risk of Bias 2.0 tool. Outcomes were evaluated at short‐ (≤ one month), medium‐ four to eight months) and long‐term (≥12 months). Where possible we conducted meta‐analyses. We used the GRADE system to assess the certainty of evidence.
Main results
We included 15 unique published studies that randomised 908 participants, and 20 unique ongoing studies. All studies evaluated SCS. We found no eligible published studies of DRGS and no studies comparing SCS with no treatment or usual care. We rated all results evaluated as being at high risk of bias overall. For all comparisons and outcomes where we found evidence, we graded the certainty of the evidence as low or very low, downgraded due to limitations of studies, imprecision and in some cases, inconsistency.
Results were only available at short‐term follow‐up for this comparison.
Pain intensity
Six studies (N = 164) demonstrated a small effect in favour of SCS at short‐term follow‐up (0 to 100 scale, higher scores = worse pain, mean difference (MD) ‐8.73, 95% confidence interval (CI) ‐15.67 to ‐1.78, very low certainty). The point estimate falls below our predetermined threshold for a clinically important effect (≥10 points). No studies reported the proportion of participants experiencing 30% or 50% pain relief for this comparison.
Adverse events (AEs)
The quality and inconsistency of adverse event reporting in these studies precluded formal analysis.
Pain intensity
Mean difference
Three studies (N = 303) demonstrated a potentially clinically important mean difference in favour of SCS of ‐37.41 at short term (95% CI ‐46.39 to ‐28.42, very low certainty), and medium‐term follow‐up (5 studies, 635 participants, MD ‐31.22 95% CI ‐47.34 to ‐15.10 low‐certainty), and no clear evidence for an effect of SCS at long‐term follow‐up (1 study, 44 participants, MD ‐7 (95% CI ‐24.76 to 10.76, very low‐certainty).
Proportion of participants reporting ≥50% pain relief
We found an effect in favour of SCS at short‐term (2 studies, N = 249, RR 15.90, 95% CI 6.70 to 37.74, I2 0% ; risk difference (RD) 0.65 (95% CI 0.57 to 0.74, very low certainty), medium term (5 studies, N = 597, RR 7.08, 95 %CI 3.40 to 14.71, I2 = 43%; RD 0.43, 95% CI 0.14 to 0.73, low‐certainty evidence), and long term (1 study, N = 87, RR 15.15, 95% CI 2.11 to 108.91 ; RD 0.35, 95% CI 0.2 to 0.49, very low certainty) follow‐up.
Adverse events (AEs)
Device related
No studies specifically reported device‐related adverse events at short‐term follow‐up. At medium‐term follow‐up, the incidence of lead failure/displacement (3 studies N = 330) ranged from 0.9 to 14% (RD 0.04, 95% CI ‐0.04 to 0.11, I2 64%, very low certainty). The incidence of infection (4 studies, N = 548) ranged from 3 to 7% (RD 0.04, 95%CI 0.01, 0.07, I2 0%, very low certainty). The incidence of reoperation/reimplantation (4 studies, N =5 48) ranged from 2% to 31% (RD 0.11, 95% CI 0.02 to 0.21, I2 86%, very low certainty). One study (N = 44) reported a 55% incidence of lead failure/displacement (RD 0.55, 95% CI 0.35, 0 to 75, very low certainty), and a 94% incidence of reoperation/reimplantation (RD 0.94, 95% CI 0.80 to 1.07, very low certainty) at five‐year follow‐up. No studies provided data on infection rates at long‐term follow‐up.
We found reports of some serious adverse events as a result of the intervention. These included autonomic neuropathy, prolonged hospitalisation, prolonged monoparesis, pulmonary oedema, wound infection, device extrusion and one death resulting from subdural haematoma.
Other
No studies reported the incidence of other adverse events at short‐term follow‐up. We found no clear evidence of a difference in otherAEs at medium‐term (2 studies, N = 278, RD ‐0.05, 95% CI ‐0.16 to 0.06, I2 0%) or long term (1 study, N = 100, RD ‐0.17, 95% CI ‐0.37 to 0.02) follow‐up.
Very limited evidence suggested that SCS increases healthcare costs. It was not clear whether SCS was cost‐effective.
Authors' conclusions
We found very low‐certainty evidence that SCS may not provide clinically important benefits on pain intensity compared to placebo stimulation. We found low‐ to very low‐certainty evidence that SNMD interventions may provide clinically important benefits for pain intensity when added to conventional medical management or physical therapy. SCS is associated with complications including infection, electrode lead failure/migration and a need for reoperation/re‐implantation. The level of certainty regarding the size of those risks is very low. SNMD may lead to serious adverse events, including death. We found no evidence to support or refute the use of DRGS for chronic pain.
Author(s)
Neil E O'Connell, Michael C Ferraro, William Gibson, Andrew SC Rice, Lene Vase, Doug Coyle, Christopher Eccleston
Abstract
Plain language summary
What are the benefits and risks of electrical spinal cord and dorsal root ganglion stimulation for the treatment of chronic pain in adults?
Why this question is important
Persistent (chronic) pain is a common problem that affects people from all walks of life. It can be the result of a wide range of different medical conditions and is sometimes unexplained, but it often causes substantial suffering, distress and disability and can have major impacts on a person's quality of life.
Implanted spinal neuromodulation (SNMD) interventions involve surgically implanting wires (electrodes) into the space around nerves or the spinal cord that are connected to a "pulse generator" device which is usually implanted under the patient's skin. This delivers electrical stimulation to the nerves or spinal cord. It is thought that this stimulation interferes with danger messages being sent to the spinal cord and brain with the goal of reducing the perception of pain. Once implanted with a SNMD device people live with the device implanted, potentially on a permanent basis. We reviewed the evidence to find out whether these interventions were effective at reducing pain, disability and medication use, at improving quality of life and to find out the risk and type of complications they might cause. There are two broad types of SNMD: spinal cord stimulation (SCS), where electrodes are placed near the spinal cord and dorsal root ganglion stimulation (DRGS) where electrodes are placed near the nerve root, where the nerve branches off from the spinal cord.
How we identified and assessed the evidence
First, we searched for all relevant studies in the medical literature. We then compared the results, and summarised the evidence from all the studies. Finally, we assessed the certainty of the evidence. We considered factors such as the way studies were conducted, study sizes, and consistency of findings across studies. Based on our assessments, we rated the evidence as being of very low, low, moderate or high certainty.
What we found
We found 15 published studies that included 908 people with persistent pain due to a variety of causes including nerve disease, chronic low back pain, chronic neck pain and complex regional pain syndrome. All of these studies evaluated SCS; no studies evaluated DRGS.
Eight studies (that included 205 people) compared SCS with a sham (placebo) stimulation, where the electrodes were implanted, but no stimulation was delivered. Six studies that included 684 people compared SCS added with either medical management or physical therapy with medical management or physical therapy on its own. We rated the evidence as being of low, or very low certainty. Limitations in how the studies were conducted and reported, the amount of evidence we found and inconsistency between studies in some instances means that our confidence in the results is limited.
The evidence suggests the following.
Compared to receiving medical management or physical therapy alone, people treated with the addition of SCS may experience less pain and higher quality of life after one month or six months of stimulation. There is limited evidence to draw conclusions in the long term of one year or more. It is unclear whether SCS reduces disability or medication use.
Compared to a sham (placebo) stimulation, SCS may result in small reductions in pain intensity in the short term that may not be clinically important, but this is currently unclear. There is no evidence at medium or long‐term follow‐up points.
SCS can result in complications. These include movement or malfunction of the electrode wires, wound infections and the need for further surgical procedures to fix issues with the implanted devices. We also found instances of serious complications that included one death, nerve damage, lasting muscle weakness, lung injury, serious infection, prolonged hospital stay and the extrusion of a stimulation device through the skin.
Very limited evidence around the costs and economics of SCS suggested that SCS increases the costs of healthcare. It was not clear whether SCS was cost‐effective.
What this means
SCS may reduce pain intensity in people with chronic pain. It is currently not clear how much of this effect is due to the SCS itself and how much is due to so‐called "placebo" effects, which are the result of the experience of undergoing the procedure and the person's expectations that it will help them. Receiving SCS does present a risk of relatively common complications and less common serious complications. We are currently unsure of the precise degree of this risk.
How up‐to‐date is this review?
The evidence in this review is current to September 2021.
Author(s)
Neil E O'Connell, Michael C Ferraro, William Gibson, Andrew SC Rice, Lene Vase, Doug Coyle, Christopher Eccleston
Reviewer's Conclusions
Authors' conclusions
Implications for practice
For people with chronic pain
There is low‐ to very low‐certainty evidence that implanted spinal cord stimulation (SCS) devices provide clinically important benefits for pain intensity and benefits on health‐related quality of life (HRQoL) when added to conventional medical management or physical therapy. However, we also found very low‐certainty evidence that SCS may not provide clinically important benefits on pain intensity or HRQoL when compared with placebo (sham) stimulation. These findings raise questions about how much of the observed benefits of SCS may result from the stimulation itself and how much may be the result of the contextual effects of receiving this complex, expensive and invasive intervention. SCS can result in relatively common complications such as infection, electrode lead failure or migration and a need for further surgical procedures. We found instances of serious adverse events (SAEs)resulting from unintended neurological injury including one death, but were not able to accurately estimate the risk of these. We found no clear evidence of benefit from SCS for disability or medication use. The low to very low certainty of our findings means that our confidence in them is limited. We found no evidence at all to support or refute the use of dorsal root ganglion stimulation (DRGS) for chronic pain.
For clinicians
We found very low‐certainty evidence that SCS may not provide clinically important benefits on pain intensity when compared to a sham (placebo) stimulation and low‐ to very low‐certainty evidence that SCS when added to medical care or physical therapy may provide clinically important benefits for pain intensity and health‐related quality of life (HRQoL) for people with persistent pain, but no clear evidence for a beneficial effect for disability or medication use. SCS can result in complications such as infection, electrode lead failure or migration and a need for further surgical procedures. We found instances of SAEs resulting from unintended neurological injury including one death, but were not able to accurately estimate the risk of these. The low to very low certainty of our findings means that our confidence in them is limited. We found no evidence to support or refute the use of DRGS for chronic pain.
For policymakers and funders of the intervention
We found very low‐certainty evidence that SCS may not provide clinically important benefits on pain intensity when compared to a sham (placebo) stimulation and low‐ to very low‐certainty evidence that SCS when added to medical care or physical therapy may provide clinically important benefits for pain intensity and HRQoL for people with persistent pain, but no clear evidence for a beneficial effect for disability or medication use. SCS can result in complications such as infection, electrode lead failure or migration and a need for further surgical procedures. We found instances of SAEs resulting from unintended neurological injury including one death, but were not able to accurately estimate the risk of these. The low to very low certainty of our findings means that our confidence in them is limited. We found limited economic evidence, but the included evidence suggests that SCS is associated with substantial additional healthcare costs, which are dominated by the costs of the device/apparatus and the implantation processes and the costs of managing complications. The only cost‐effectiveness analysis that we included suggested that the cost‐effectiveness of SCS was uncertain at willingness to pay thresholds of both 20,000 to 80,000 Euros perQuality Adjusted Life Years (QALY). We found no evidence at all to support or refute the use of DRGS for chronic pain. While some guidelines make recommendations for spinal neuromodulation (SNMD) interventions for selected participants with chronic pain, they do not specifically consider the uncertainty around clinical benefit compared to placebo stimulation based on current evidence (MoH‐LTC 2005; NICE 2008; NICE 2019).
Implications for research
General
We have identified that a key area of uncertainty is whether SCS provides clinically important benefits versus placebo. To reduce uncertainty around this question there is a need for larger studies. It can be argued that further small, short‐term cross‐over studies, of the type that dominate the ongoing studies we have identified for this comparison are unlikely to meaningfully improve certainty. Instead, larger parallel trials, that compare SNMD approaches with placebo for a more clinically relevant time period and that fully report both important efficacy outcomes and adverse effects are needed. In our search for ongoing studies we identified one trial with this type of design in people with chronic low back pain (MODULATE‐ LBP, N = 96) but arguably further such trials are needed, and in a broader range of conditions. While further open‐label studies of SNMD might improve the precision of our estimates of effectiveness they will not reduce the uncertainty around the important question of the mechanisms of observed effects.
The field has generated and might continue to develop and promote novel forms of stimulation with claims of superior efficacy. There is currently uncertainty surrounding the efficacy of all existing forms of SNMD. There is a need to establish clear evidence of efficacy for all forms of SCS over placebo. Until there is compelling evidence for the efficacy of existing forms of SNMD any novel stimulation approach should also be validated by comparison with placebo. Future trials should include a formal analysis of healthcare and non‐healthcare costs with long‐term time horizons and conduct formal cost‐effectiveness analysis. Future studies should also be clear as to whether or not participants are recruited on the basis of pain of suspected neuropathic nature and clearly report the approaches used to establish that. If efficacy (versus placebo) is established with certainty then it would be valuable to study how SNMD interventions impact on supported self‐management of persistent pain.
The evidence base is dominated by industry‐sponsored studies and there is a high rate of authors' declarations of industry relationships. Publicly‐funded trials, independent of industry involvement would improve confidence in this evidence base. There is an urgent need to improve the audit trail and transparency for trials in this field with pre‐registration and regular updating of trial status in the registries, routine availability of study protocols and statistical analysis plans, and posting results in the trials registries. Given the apparent trade‐off between clinical benefits and potentiallySAEs there would be value in further formal evaluation of patient preferences. These should be conducted independently of industry involvement.
Design
Placebo‐controlled trials in this, as in all surgical fields, are challenging but can be feasible (Wartolowska 2016). There are specific challenges for SNMD trials that require careful attention, relating to threats to participant blinding associated with the handheld programming units, battery recharging requirements and the presence of paraesthesias (the latter particularly with conventional stimulation). In a recent consensus exercise which aimed to identify important elements for successful sham controls for physical interventions, Braithwaite 2020 found that essential strategies centred around maintaining the credibility of the sham by adhering to expectations and beliefs of participants using clinical interactions, professional behaviours, trial information and environmental setup, whereas exact replication of the intervention itself did not feature as strongly. This suggests that careful consideration needs to be given to the broader clinical interaction in sham‐controlled trials of SCS to maximise the credibility of the sham condition. For all sham‐controlled studies a formal assessment of the success of blinding and/or the credibility of sham controls should be considered essential.
The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), the Institute of Neuromodulation (ION), and the International Neuromodulation Society (INS) have recently published recommendations (Katz 2021) on the design, conduct, analysis, and interpretation of RCTs of SCS for chronic pain and many of their recommendations are closely aligned with ours. Specifically, they recommend trials disclose all funding sources and potential conflicts; incorporate mechanistic objectives when possible; avoid non‐inferiority designs without internal demonstration of assay sensitivity; achieve and document double‐blinding whenever possible; document investigator and site experience; keep all information provided to patients balanced with respect to the expectation of benefit; disclose all information provided to patients, include verbal scripts; use placebo/sham controls when possible; account for ancillary pharmacologic and nonpharmacologic treatments in a clear manner; provide a complete description of intended and actual programming interactions; make a prospective ascertainment of SCS‐specific safety outcomes; train patients and researchers on appropriate expectations, outcome assessments, and other key aspects of study performance; and provide transparent and complete reporting of results according to applicable reporting guidelines. Future trial reports should fully comply with CONSORT (Schulz 2010).
Outcome assessment
Future trials must include measurement of outcomes known to be important to people with chronic pain. Katz 2021 recommend the following core domains: pain intensity, physical function, emotional functioning, global improvement or satisfaction, concomitant and rescue medications, patient disposition to treatment, sleep and fatigue, health‐related quality of life, costs and cost‐effectiveness. There is a need for improvement in the methodology and reporting of adverse events. Careful, long‐term active surveillance for known complications of SCS is essential and should include all cases of neurological injury and any resultant SAEs. The nature and incidence of all AEs should be reported in full. In addition to clinical trials, there would be value in the establishment of national and international clinical registries to allow more comprehensive surveillance of safety outcomes for these interventions.
