Does industry funding and study location impact findings from randomized controlled trials of spinal cord stimulation? A systematic review and meta-analysis.

BACKGROUND/IMPORTANCE: Concerns have been raised that effects observed in studies of spinal cord stimulation (SCS) funded by industry have not been replicated in non-industry-funded studies and that findings may differ based on geographical location where the study was conducted. OBJECTIVE: To investigate the impact of industry funding and geographical location on pain intensity, function, health-related quality of life and adverse events reported in randomized controlled trials (RCTs) of SCS. EVIDENCE REVIEW: Systematic review conducted using MEDLINE, CENTRAL, EMBASE and WikiStim databases until September 2022. Parallel-group RCTs evaluating SCS for patients with neuropathic pain were included. Results of studies were combined in random-effects meta-analysis using the generic-inverse variance method. Subgroup meta-analyses were conducted according to funding source and study location. Risk of bias was assessed using Cochrane RoB 2.0 tool. FINDINGS: Twenty-nine reports of 17 RCTs (1823 participants) were included. For the comparison of SCS with usual care, test for subgroup differences indicate no significant differences (p=0.48, moderate certainty evidence) in pain intensity score at 6 months for studies with no funding or funding not disclosed (pooled mean difference (MD) -1.96 (95% CI -3.23 to -0.69; 95% prediction interval (PI) not estimable, I2=0%, τ2=0)), industry funding (pooled MD -2.70 (95% CI -4.29 to -1.11; 95% PI -8.75 to 3.35, I2=97%, τ2=2.96) or non-industry funding (MD -3.09 (95% CI -4.47 to -1.72); 95% PI, I2 and τ2 not applicable). Studies with industry funding for the comparison of high-frequency SCS (HF-SCS) with low-frequency SCS (LF-SCS) showed statistically significant advantages for HF-SCS compared to LF-SCS while studies with no funding showed no differences between HF-SCS and LF-SCS (low certainty evidence). CONCLUSION: All outcomes of SCS versus usual care were not significantly different between studies funded by industry and those independent from industry. Pain intensity score and change in pain intensity from baseline for comparisons of HF-SCS to LF-SCS seem to be impacted by industry funding.

Cross-Country Differences in Pain Medication Before and After Spinal Cord Stimulation: A Pooled Analysis of Individual Patient Data From Two Prospective Studies in the United Kingdom and Belgium.

OBJECTIVES: Spinal cord stimulation (SCS) can reduce the need for opioids; however, the influence on the full spectrum of pain medication is less known. The aims of this study were to explore general prescription practices for patients scheduled for SCS, potential differences in prescriptions between Belgium and United Kingdom, and the influence of SCS on pain medication. MATERIALS AND METHODS: Individual patient data from the TRIAL-STIM study in the United Kingdom and DISCOVER in Belgium were pooled. Medication use was collected before SCS and three months after SCS from 180 chronic pain patients. The Medication Quantification Scale III (MQS) was used to calculate a total score for medication use, as well as subscores for several classes. Differences in prescription practices between United Kingdom and Belgium were evaluated with two-sided Wilcoxon tests. To evaluate differences in medication use after three months of SCS between United Kingdom and Belgium, Tweedie-generalized linear models were calculated. RESULTS: There was a statistically significant difference (-6.40 [95% CI from -3.40 to -9.10]) between the median total MQS score in United Kingdom and Belgium before SCS. Additionally, a significant difference was found for nonsteroidal anti-inflammatory drugs (NSAIDs) (-3.40 [95% CI -3.40 to -6.80]), neuropathic agents (-2.30 [95% CI -0.40 to -3.80]), and benzodiazepines (1.83e-05 [95% CI 2.64-05 to 7.45-05]) between United Kingdom and Belgium, before SCS. Tweedie-generalized models revealed a statistically significant interaction between country and time for MQS, neuropathic agents, and opioids. CONCLUSIONS: Our combined analysis revealed differences in prescription practice in patients scheduled for SCS implantation between Belgium and United Kingdom. NSAIDs and neuropathic mood agents are more frequently used in the United Kingdom, presumably due to easier access to repeat prescriptions and over the counter medications. After three months of SCS, a decrease in medication use is observed in both countries, with higher reductions in Belgium, presumably due to strict regulations concerning reimbursement criteria.

Effectiveness and Safety of Intrathecal Drug Delivery Systems for the Management of Cancer Pain: A Systematic Review and Meta-Analysis.

OBJECTIVES: Intrathecal drug delivery systems (IDDS) and spinal cord stimulation (SCS) have been proposed and assessed for the management of cancer pain; however, such treatments remain underused. We conducted a systematic review to evaluate the effectiveness and safety of IDDS and SCS for cancer pain. MATERIALS AND METHODS: Electronic databases MEDLINE, CENTRAL, EMBASE, and WikiStim were searched from 1988 to March 2021. Randomized controlled trials and observational studies of adults with pain related to cancer or its treatment who received an implantable IDDS or SCS were eligible for inclusion. The primary outcome of the review was change in pain intensity from baseline to the last available follow-up, measured using a visual analog scale or numerical rating scale. The protocol for this review is registered on PROSPERO (CRD42021240717). RESULTS: A total of 22 studies (24 reports) included a total of 3043 participants who received either IDDS or SCS for cancer pain. Eight studies reporting data for 405 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction at the latest posttreatment follow-up time compared with baseline (mean difference [MD], -3.31; 95% CI, -4.18 to -2.45; p < 0.001). Six studies reporting data for 325 participants with an IDDS could be included in the meta-analysis of pain intensity that showed a statistically significant reduction up to one month after treatment compared with baseline (MD, -3.53; 95% CI, -4.06 to -3.00; p < 0.001). A meta-analysis including studies of participants with either an IDDS or an SCS device showed similar results. Improvements in other outcomes following implantation of IDDS also were observed. Postdural puncture headache was the most reported complication, whereas urinary retention, nausea, and vomiting were commonly reported side effects. CONCLUSION: Our findings suggest that IDDS is effective in reducing pain intensity for patients with cancer pain when compared with pretreatment.

Systematic Review to Identify Predictors of Treatment Response to Neuromodulation in Patients With Neuropathic Pain-Protocol.

OBJECTIVES: Patients who suffer from long-term, neuropathic pain that proves refractory to conventional medical management are high consumers of health care resources and experience poorer physical and mental health than people with other forms of pain. Pharmacologic treatments have adverse effects; nonpharmacologic interventions have limitations. Spinal cord stimulation (SCS) is an effective treatment for neuropathic pain, although 30% to 40% of patients fail to achieve acceptable levels of pain relief. There are currently no objective methods to predict the success of SCS to treat neuropathic pain, and therefore, it is important to understand which patient factors may be predictive of a lack of response to SCS, to inform future patient treatment options. This study proposes a protocol for a systematic review and meta-analysis of published studies to examine these predictive factors. MATERIALS AND METHODS: Several bibliographic databases will be searched to identify relevant studies published since 2012 that provide data on patient characteristics (eg, age, gender, pain severity) as predictors of SCS outcomes of pain, function, and health-related quality of life. Two independent reviewers will screen citations; data will be extracted after full-text screening. Risk of bias will be assessed using the Quality In Prognosis Studies tool. RESULTS: A formal quantitative synthesis is planned in which data from studies with the same predictive factors are available; this will be considered for pooling into separate meta-analyses. In cases of high heterogeneity or inconsistency in the data, subgroup analysis will be conducted. CONCLUSIONS: This study seeks to provide a contemporary review of patient predictors of success of neuromodulation for neuropathic pain. We anticipate that findings may guide the use of neuromodulation in patient subgroups and the design and reporting of future clinical studies in this field.

A Clinical Evaluation of the Accuracy of an Intrathecal Drug Delivery Device.

INTRODUCTION: Implantable intrathecal drug delivery (ITDD) devices are used to treat severe pain and spasticity refractory to conventional medical management. Although off-label medications and drug admixtures are commonly used in clinical practice and recommended by international guidelines, manufacturers state that this practice can result in device failure. The impact of off-label drugs and drug combinations on pump accuracy has hitherto never been assessed. MATERIALS AND METHODS: A multinational, three-center, retrospective review of patient records was undertaken. The inclusion criterion was the presence of an ITDD device implantation in adult patients, with the pump in situ for the expected battery lifespan. Residual drug volumes at each refill, drug mixtures and concentrations, and rate and flow pattern of the pump (simple or flex) were recorded. A normalized flow rate ratio was calculated (actual to theoretical flow rate). The impact of nonapproved drugs, battery life, pump size, and flow program on drug delivery accuracy was assessed. RESULTS: Data from 1402 pump refills were collected (73 patients). The overall mean accuracy ratio was 0.995 (95% CI = 0.986-1.004). The ratio for approved drug status was 0.990 vs 0.997 in nonapproved, with a difference of -0.007 (-0.032 to 0.017). At the tenth centile for remaining battery life (14 months), the ratio was 0.983 vs 1.009 for the 90th centile (69 months), with a difference of -0.026 (-0.038 to -0.014). The ratio for flex administration was 0.982 vs 1.006 for simple, with a difference of -0.024 (-0.040 to -0.008). For pump size of 40 mL, the ratio was 0.975 vs 1.010 for 20 mL, with a difference of -0.035 (-0.063 to -0.008). The 95% prediction interval for individual refill ratios was ±0.15. CONCLUSION: In a clinical setting, the ITDD pumps retained high levels of accuracy and acceptable precision across their lifespan despite using unapproved drugs or admixtures and under various flow modes and rates.

Ziconotide for the Management of Cancer Pain: A Budget Impact Analysis.

OBJECTIVES: Recent recommendations on starting dose, smaller dose increments, and longer intervals between dose increase have the potential to increase the safety of ziconotide administration in addition to improving its value for money. Ziconotide is not routinely commissioned in England, with one of the concerns being whether it represents the best use of resources. The aim of this project is to conduct a budget impact analysis to estimate the costs or savings associated with the changes in ziconotide dosage in addition to its use in combination with morphine for the management of cancer pain. MATERIALS AND METHODS: An open, Markov-like cohort decision analytic model was developed to estimate the budget impact of ziconotide in combination with morphine (ziconotide combination therapy) vs morphine monotherapy through intrathecal drug delivery (ITDD) for the management of cancer pain. The perspective adopted was that of the UK National Health Service, with a five-year time horizon. Sensitivity analyses were conducted to evaluate different scenarios. RESULTS: Ziconotide combination therapy was more expensive than treatment with morphine monotherapy. The total costs of ziconotide combination therapy and morphine monotherapy for the first year were £395,748 and £136,628 respectively. The estimated five-year cumulative budget impact of treatment with ziconotide combination therapy for the five-year time horizon was £2,487,539, whereas that of morphine monotherapy was £913,804. The additional costs in any of the first five years are below the resource impact significance level of £1 million for medical technologies in England. CONCLUSIONS: The results of this budget impact analysis suggest that although a combination of intrathecal ziconotide in combination with morphine is associated with higher costs to the health care system in England, the incremental costs are not significant. Routine commissioning of ziconotide alone or in combination with morphine would provide an alternative for a population with limited ITDD treatment options.

Systematic Review and Network Meta-analysis of Neurostimulation for Painful Diabetic Neuropathy.

BACKGROUND: Different waveforms of spinal cord stimulation (SCS) have now been evaluated for the management of painful diabetic neuropathy (PDN). However, no direct or indirect comparison between SCS waveforms has been performed to date. PURPOSE: To conduct a systematic review and network meta-analysis to evaluate the effectiveness of SCS for PDN. DATA SOURCES: MEDLINE, CENTRAL, Embase, and WikiStim were searched from inception until December 2021. STUDY SELECTION: Randomized controlled trials (RCTs) of SCS for PDN were included. DATA EXTRACTION: Pain intensity, proportion of patients achieving at least a 50% reduction in pain intensity, and health-related quality of life (HRQoL) data were extracted. DATA SYNTHESIS: Significant reductions in pain intensity were observed for low-frequency SCS (LF-SCS) (mean difference [MD] -3.13 [95% CI -4.19 to -2.08], moderate certainty) and high-frequency SCS (HF-SCS) (MD -5.20 [95% CI -5.77 to -4.63], moderate certainty) compared with conventional medical management (CMM) alone. There was a significantly greater reduction in pain intensity on HF-SCS compared with LF-SCS (MD -2.07 [95% CI -3.26 to -0.87], moderate certainty). Significant differences were observed for LF-SCS and HF-SCS compared with CMM for the outcomes proportion of patients with at least 50% pain reduction and HRQoL (very low to moderate certainty). No significant differences were observed between LF-SCS and HF-SCS (very low to moderate certainty). LIMITATIONS: Limited number of RCTs and no head-to-head RCTs conducted. CONCLUSIONS: Our findings confirm the pain relief and HRQoL benefits of the addition of SCS to CMM for patients with PDN. However, in the absence of head-to-head RCT evidence, the relative benefits of HF-SCS compared with LF-SCS for patients with PDN remain uncertain.

Cauda equina syndrome after unilateral medial branch blocks of the lower lumbar zygapophyseal joints.

Medial branch blockade of the lumbar facet joints is widely performed and generally accepted as a safe intervention. We present a case of neurological damage following a medial branch blockade with local anesthetic and steroid. A patient suffering from chronic low back pain radiating to the buttocks and thighs underwent nine medial branch blockades over a few years. Three months after successful back surgery to remove a herniated L2-3 disk, the pain recurred, and left L3-4 , L4-5, and L5 -S1  medial branch blocks were performed under fluoroscopy. Immediately following the procedure, the patient developed paraparesis in both legs, loss of pinprick but preserved fine touch sensation, proprioception, and sphincter sensory and motor function. MRI showed ischemic lesions of the cauda equina. Direct needle trauma was discounted as a cause, due to the bilateral neurological deficit, plus the lack of pain during the procedure. Particulate steroid preparations can form aggregates, which may embolize and block small terminal arteries, causing neurological damage. Although the patient received nine sets of injections uneventfully during the previous 36 months, this procedure took place 3 months following spinal surgery. This rare, but catastrophic case of cauda equina syndrome occurred following L3-4 , L4-5 , and L5 -S1  medial branch blockades 3 months after spinal surgery, which is believed to be caused by accidental intra-arterial injection of particulate methylprednisolone, with consequent aggregates causing blockage and ensuing ischemia. Therefore we suggest particulate steroid preparations should not be used in axial spinal injection.

A prospective long-term follow-up of dorsal root ganglion stimulation for the management of chronic intractable pain.

ABSTRACT: Initial clinical studies have shown that the stimulation of the dorsal root ganglion (DRG) can significantly reduce chronic intractable pain. However, clinical data on long-term results and complications of these systems are limited. The aim of this prospective study is to report on a single center long-term follow-up of DRG stimulation for intractable chronic pain. Participants were implanted with DRG stimulation devices between 2013 and 2015 with an observation period of 24 months. Patients were contacted again in 2020 for a final follow-up (ie, between 5 and 7 years postimplantation). Forty-two participants were recruited, of whom 32 received the fully implantable pulse generator (IPG). At the final follow-up, 50% (16/32) of participants were still using DRG stimulation. Two participants still had the original IPG and 14 had received a replacement IPG. Pain scores were significantly reduced at 24 months, mean difference 1.7 (95% confidence interval: 0.2-3.3, P = 0.03), and at the last follow-up, mean difference 2.1 (95% confidence interval: 0.3-4, P = 0.03). Significant improvements were observed for health-related quality of life. The findings were generally robust to imputation methods of missing data. Implantable pulse generators of 8 patients were explanted because of dissatisfaction with pain relief. In conclusion, DRG stimulation can provide effective pain relief and improved quality of life in patients suffering with neuropathic pain, although this study had a revision rate of 42% within the first 24 months, and 56% of IPGs that were replaced because of battery depletion had a shorter than expected battery life.

Reporting Guidelines for Clinical Trial Protocols and Reports of Implantable Neurostimulation Devices: Protocol for the SPIRIT-iNeurostim and CONSORT-iNeurostim Extensions.

OBJECTIVES: SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) statements have been shown to improve the quality of reporting of trial protocols and randomized controlled trials. Extensions to the SPIRIT and CONSORT statements specific to certain interventions have the potential to address methodological considerations that would otherwise be overlooked. The aim of this protocol is to describe the methods to develop reporting guidelines for clinical trial protocols and reports of implantable neurostimulation devices. MATERIALS AND METHODS: The SPIRIT-iNeurostim and CONSORT-iNeurostim extensions will be developed through a staged consensus process involving literature review and expert consultation. The initial list of candidate items will be informed by findings from previous systematic reviews and published protocols and clinical trials of implantable neurostimulation devices. The candidate items will be included in a two-round Delphi survey. In the first round, participants will be invited to vote on the importance of each item and to suggest additional relevant items. In the second round, participants will be invited to re-score the items considering feedback received and the suggested additional items. A consensus meeting will then take place to discuss the results of the Delphi survey and reach consensus on the items to include in the extensions. DISCUSSION: Development of the SPIRIT-iNeurostim and CONSORT-iNeurostim extensions has the potential to lead to improvements and increase in transparency of the reporting of clinical trial protocols and reports of implantable neurostimulation devices.

Tumour lysis syndrome in a patient with intravascular spread from a recurrent epithelial ovarian cancer.

Tumour lysis syndrome is a potentially life-threatening oncological emergency most commonly encountered in patients with rapidly proliferating, treatment-responsive haematological malignancies. It is rarely observed in solid tumours and, to our knowledge, this is the first time that it has been reported in a cancer with an intravascular tumour extension. In this report, we describe a case of a woman who presented with recurrent ovarian cancer and was found to have tumour invading into her vasculature. The patient subsequently developed tumour lysis syndrome after receiving chemotherapy. The case highlights the importance of considering tumour lysis syndrome prophylaxis when treating patients with intravascular involvement from a solid malignancy even if, as in this case, it is a recurrent tumour. Included is a brief review of the literature. We propose that 'intravascular tumour invasion is recognised as an important risk factor for the development of tumour lysis syndrome.

The importance of complete screening for amyloid fibril type and systemic disease in patients with amyloidosis in the respiratory tract.

BACKGROUND: Patients with symptomatic thoracic involvement by amyloidosis are virtually all of AL-type, and have historically been divided into systemic and localised disease, a subdivision that helps predict outcome and aids management. Assessment and classification of amyloid has evolved in recent years to include a variety of tests, including radiolabelling of the serum amyloid P component (SAP scan) to assess anatomical distribution and immunohistochemical studies to assess fibril subtypes. Furthermore, CT scanning is now a frequent investigation for the diagnosis of thoracic disease. We wished to determine the value of these investigations on the management of such patients with amyloidosis. METHODS: Clinicopathological data, including immunohistochemical analysis, CT scans and SAP scan results, were retrospectively reviewed from patients presenting with amyloidosis in the respiratory tract. These were then analysed to determine their impact on classification and prognosis. RESULTS: Seventeen patients over ten years were identified, one case being related to metastatic medullary carcinoma of the thyroid. Of the remaining 16 cases, one was shown to have hereditary amyloid of transthyretin-type (TTR) on immunohistochemistry, altering management. The remaining 15 cases were AL-type, with 6 cases being classified as localised and 9 cases as systemic, after evaluation for serum and/or urine monoclonal products, cardiac involvement via echocardiography, plasma cell abnormalities on bone marrow examination, CT scan and SAP scan. 3/3 patients with localised AL-type disease had a negative SAP scan, whilst 3/5 patients with systemic AL-type disease had a positive scan. SAP scan of the patient with TTR-type disease provided information on extent of disease and supported the diagnosis by the pattern of distribution. Using CT scans to discriminate between localised and systemic disease showed a significant association with mortality at 2 years (p = 0.03). CONCLUSION: Although the majority of symptomatic patients with pulmonary amyloidosis have AL-type disease, immunohistochemical confirmation is necessary in order not to miss rarer subtypes with completely different treatment regimes. Furthermore, a comprehensive evaluation, including SAP scan and CT scan of the thorax, in conjunction with echocardiography, bone marrow, serum and urine studies, needs to be undertaken in order to achieve maximum accuracy with regard to localised and systemic disease.