Contact Heat in Magnetoencephalography: A Systematic Review.

BACKGROUND: Contact heat is commonly used in experimental research to evoke brain activity, most frequently acquired with electroencephalography (EEG). Although magnetoencephalography (MEG) improves spatial resolution, using some contact heat stimulators with MEG can present methodological challenges. This systematic review assesses studies that utilise contact heat in MEG, their findings and possible directions for further research. METHODS: Eight electronic databases were searched for relevant studies, in addition to the selected papers' reference lists, citations and ConnectedPapers maps. Best practice recommendations for systematic reviews were followed. Papers met inclusion criteria if they used MEG to record brain activity in conjunction with contact heat, regardless of stimulator equipment or paradigm. RESULTS: Of 646 search results, seven studies met the inclusion criteria. Studies demonstrated effective electromagnetic artefact removal from MEG data, the ability to elicit affective anticipation and differences in deep brain stimulation responders. We identify contact heat stimulus parameters that should be reported in publications to ensure comparisons between data outcomes are consistent. CONCLUSIONS: Contact heat is a viable alternative to laser or electrical stimulation in experimental research, and methods exist to successfully mitigate any electromagnetic noise generated by PATHWAY CHEPS equipment - though there is a dearth of literature exploring the post-stimulus time window.

Regulatory Framework for Implantable Neurostimulation Devices: Comparison of Systems in the US and European Union.

BACKGROUND: Implantable neurostimulation devices must be authorized before they are placed on the market. For this purpose, requirements, and processes for assessing their fulfillment, have been defined in different jurisdictions. OBJECTIVE: In this study, we aimed to address differences between the US and European Union (EU) regulatory systems and their relationship to innovation. MATERIALS AND METHODS: A literature review and analysis were conducted using legal texts and guidance documents. RESULTS: The US system has one central body, the Food and Drug Administration, whereas the EU system has several bodies with different responsibilities. The devices themselves are divided into risk classes, which are based on the vulnerability of the human body. This risk class determines the intensity of the review by the market authorization body. In addition to the requirements for development, manufacture, and distribution, the device itself must meet technical and clinical requirements. Compliance with technical requirements is indicated by nonclinical laboratory studies. Proof of efficacy is provided by means of clinical investigations. Procedures are defined for reviewing these elements. Once the market authorization process has been completed, the devices can be placed on the market. In the postmarketing phase, the devices must continue to be monitored, and measures must be initiated, if necessary. CONCLUSIONS: Both US and EU systems are intended to ensure that only safe and effective devices find their way to and remain on the market. The basic approaches of the two systems are comparable. In detail, however, there are differences in ways these goals are achieved.

Gradation of Clinical Holistic Response as New Composite Outcome to Evaluate Success in Spinal Cord Stimulation Studies for Pain.

INTRODUCTION: The most prominent outcome measurement in the field of neuromodulation is pain relief. Nevertheless, the number of studies that rely on composite outcomes has increased. The aims of this study are twofold: (1) to evaluate which measures are important to include in a composite outcome and (2) to develop this new composite outcome to evaluate the degree of being a clinical holistic responder with a corresponding minimal clinical important difference (MCID). MATERIALS AND METHODS: Data from patients with persistent spinal pain syndrome type 2 treated with High-Dose Spinal Cord Stimulation (HD-SCS) were used. Pain intensity for low back and leg pain, disability, health-related quality of life, medication use, and patient satisfaction were measured at baseline and after 12 months of HD-SCS. Exploratory and Confirmatory Factor Analyses were used to evaluate which measures should be included in the composite outcome. Anchor-based and distribution-based methods were applied to determine the MCID of the newly developed outcome measurement. RESULTS: A three-factor model was the most appropriate for this data set, in which leg pain intensity, EQ5D VAS, and disability had the largest loading on these factors. A clinical holistic outcome was created with a total score ranging from 0 (=better [no pain, no disability, and perfect health status]) to 300 (=worse [maximal pain, maximal disability, and worst health status]). The MCID value based on an absolute change score from baseline up to 12 months of HD-SCS was 87.97. When calculating with percentage changes, a MCID value of 48.4% was revealed. CONCLUSIONS: This new composite outcome evaluating the degree of deviation from being a holistic responder is a step toward a meaningful, overall outcome assessment for patients who are treated with SCS. Further studies to evaluate the psychometric properties and the generalizability toward other patient populations still need to be performed.

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.

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.

Spinal Cord Stimulation for Neuropathic Pain in England From 2010 to 2020: A Hospital Episode Statistics Analysis.

OBJECTIVES: Spinal cord stimulation (SCS) is a recognized intervention for the management of chronic neuropathic pain. The United Kingdom National Institute of Health and Care Excellence has recommended SCS as a management option for chronic neuropathic pain since 2008. The aim of this study is to undertake an assessment of SCS uptake across the National Health Service in England up to 2020. MATERIALS AND METHODS: Hospital Episode Statistics were obtained for patients with neuropathic pain potentially eligible for SCS and patients receiving an SCS-related procedure. Data were retrieved nationally and per region from the years 2010-2011 to 2019-2020. RESULTS: There were 50,288 adults in England attending secondary care with neuropathic pain in 2010-2011, increasing to 66,376 in 2019-2020. The number of patients with neuropathic pain with an SCS procedure increased on a year-to-year basis until 2018-2019. However, less than 1% of people with neuropathic pain received an SCS device with no evidence of an increase over time when considering the background increase in neuropathic pain prevalence. CONCLUSION: Only a small proportion of patients in England with neuropathic pain potentially eligible for SCS receives this intervention. The recommendation for routine use of SCS for management of neuropathic pain has not resulted in an uptake of SCS over the last decade.

Association Between Levels of Functional Disability and Health-Related Quality of Life With Spinal Cord Stimulation for Chronic Pain.

OBJECTIVES: Pain score, functional disability, and health-related quality of life (HRQoL) are core outcome domains for chronic pain clinical trials. Although greater levels of pain reduction have been shown to be linked to larger gains in HRQoL, little is known of the association between HRQoL and disability in the setting of chronic pain. The aims of this study were to 1) investigate the association between functional disability and HRQoL and 2) estimate the utility values associated with levels of functional disability in patients treated with evoked compound action potential (ECAP) spinal cord stimulation (SCS) for chronic pain. MATERIALS AND METHODS: Data on functional disability assessed using the Oswestry Disability Index (ODI) and HRQoL (EQ-5D-5L) were collected from 204 patients with an Evoke ECAP-SCS device and followed up to 12 months. SF-6D utility scores also were retrieved for 134 of these patients. Multivariable linear regression models adjusted for baseline utility values and patient demographics were used to compare differences in utility values across ODI categories. RESULTS: Significant improvements in functional disability and HRQoL were observed at three- and 12-month follow-up after SCS. Patients reporting "minimum disability," "moderate disability," "severe disability," and "crippled" had mean EQ-5D scores of 0.82, 0.73, 0.59, and 0.45, respectively. The mean change in EQ-5D score was 0.007 per unit change in total ODI score. The R2 statistic showed a moderate level association (49%-64% of variance in EQ-5D explained by ODI). CONCLUSION: ECAP-SCS results in significant improvements in functional disability and HRQoL. This study shows that improvement in function of people with chronic pain before and after ECAP-SCS is associated with improvement in HRQoL.

Holistic Treatment Response: An International Expert Panel Definition and Criteria for a New Paradigm in the Assessment of Clinical Outcomes of Spinal Cord Stimulation.

BACKGROUND: Treatment response to spinal cord stimulation (SCS) is focused on the magnitude of effects on pain intensity. However, chronic pain is a multidimensional condition that may affect individuals in different ways and as such it seems reductionist to evaluate treatment response based solely on a unidimensional measure such as pain intensity. AIM: The aim of this article is to add to a framework started by IMMPACT for assessing the wider health impact of treatment with SCS for people with chronic pain, a "holistic treatment response". DISCUSSION: Several aspects need consideration in the assessment of a holistic treatment response. SCS device data and how it relates to patient outcomes, is essential to improve the understanding of the different types of SCS, improve patient selection, long-term clinical outcomes, and reproducibility of findings. The outcomes to include in the evaluation of a holistic treatment response need to consider clinical relevance for patients and clinicians. Assessment of the holistic response combines two key concepts of patient assessment: (1) patients level of baseline (pre-treatment) unmet need across a range of health domains; (2) demonstration of patient-relevant improvements in these health domains with treatment. The minimal clinical important difference (MCID) is an established approach to reflect changes after a clinical intervention that are meaningful for the patient and can be used to identify treatment response to each individual domain. A holistic treatment response needs to account for MCIDs in all domains of importance for which the patient presents dysfunctional scores pre-treatment. The number of domains included in a holistic treatment response may vary and should be considered on an individual basis. Physiologic confirmation of therapy delivery and utilisation should be included as part of the evaluation of a holistic treatment response and is essential to advance the field of SCS and increase transparency and reproducibility of the findings.

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.

Health-Related Quality of Life Associated With Pain Health States in Spinal Cord Stimulation for Chronic Neuropathic Pain.

OBJECTIVES: A substantial proportion of patients have recently reported pain reduction levels of ≥80% following treatment with Evoked Compound Action Potential (ECAP) spinal cord stimulation (SCS). The additional health-related quality of life (HRQoL) utility gain that can be achieved in this patient group is unclear. The aim of this study is to quantify the HRQoL utility values seen in a remission health state (defined as ≥80% pain reduction) and contrast with more traditional health states of <50% and ≥50% pain relief. MATERIALS AND METHODS: Pain intensity assessed using a 100 mm visual analogue scale (VAS) and EQ-5D-5L questionnaires were collected from 204 patients treated with ECAP SCS for chronic back and leg pain and followed up to 12 months. Utility values were derived using EQ-5D-5L responses crosswalked to EQ-5D-3L. Linear regression models adjusted for baseline utility values and patient demographics were used to compare differences in utility values across health states. RESULTS: Patients in the remission health state (i.e., ≥80% pain reduction) consistently reported statistically significant greater utility values (+0.09 to +0.15, all p < 0.003) compared to patients reporting ≥50% pain relief at 3- and 12-month follow-up for overall, back, and leg VAS pain. The gain in utility values per percent unit of pain reduction was statistically significant at 3- and 12-month follow-up with a mean increase in HRQoL utility score between 0.003 and 0.005 observed for each percent of pain reduction. CONCLUSION: Our analyses show that patients in a remission health state report statistically and clinically significant better HRQoL than patients experiencing lesser pain relief.

To Trial or Not to Trial Before Spinal Cord Stimulation for Chronic Neuropathic Pain: The Patients' View From the TRIAL-STIM Randomized Controlled Trial.

Objectives Spinal cord stimulation (SCS) is an established treatment of chronic neuropathic pain. Although a temporary SCS screening trial is widely used to determine suitability for a permanent implant, its evidence base is limited. The recent TRIAL-STIM study (a randomized controlled trial at three centers in the United Kingdom) found no evidence that an SCS screening trial strategy provides superior patient outcomes as compared with a no trial approach. As part of the TRIAL-STIM study, we undertook a nested qualitative study to ascertain patients' preferences in relation to undergoing a screening trial or not. Materials and Methods We interviewed 31 patients sampled from all three centers and both study arms (screening trial/no trial) prior to SCS implantation, and 23 of these patients again following implantation (eight patients were lost to follow-up). Interviews were undertaken by telephone and audio-recorded, then transcripts were subject to thematic analysis. In addition, participants were asked to state their overall preference for a one-stage (no screening trial) versus two-stage (screening trial) implant procedure on a five-point Likert scale, before and after implantation. Results Emergent themes favoured the option for a one-stage SCS procedure. Themes identified include: saving time (off work, in hospital, attending appointments), avoiding the worry about having "loose wires" in the two-stage procedure, having only one period of recovery, and saving NHS resources. Participants' rated preferences show similar support for a one-stage procedure without a screening trial. Conclusions Our findings indicate an overwhelming preference among participants for a one-stage SCS procedure both before and after the implant, regardless of which procedure they had undergone. The qualitative study findings further support the TRIAL-STIM RCT results.

A Systematic Review of Economic Evaluations Reporting the Cost-Effectiveness of Spinal Cord Stimulation.

OBJECTIVES: Spinal cord stimulation (SCS) is a recognized treatment for chronic pain. This systematic review aims to assess economic evaluations of SCS for the management of all chronic pain conditions, summarize key findings, and assess the quality of studies to inform healthcare resource allocation decisions and future research. METHODS: Economic evaluations were identified by searching general medical and economic databases complemented with screening of reference lists of identified studies. No restrictions on language or treatment comparators were applied. Relevant data were extracted. The quality of included studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Fourteen studies met the inclusion criteria and were judged to be of acceptable quality. Economic evaluations assessed SCS for the management of refractory angina pectoris, failed back surgery syndrome (FBSS), complex regional pain syndrome (CRPS), diabetic peripheral neuropathy (DPN), and peripheral arterial disease. Model-based studies typically applied a 2-stage model, i.e. decision tree followed by Markov model. Time horizon varied from 1 year to lifetime. Cost-effectiveness ranged widely from dominant (SCS cost-saving and more effective) to incremental cost-effectiveness ratio of >£100,000 per quality-adjusted life-year. Cost-effectiveness appeared to depend on the time horizon, choice of comparator, and indication. Ten of the studies indicated SCS as cost-saving or cost-effective compared with the alternative strategies. CONCLUSION: The results consistently suggest that SCS is cost-effective when considering a long-term time horizon, particularly for the management of FBSS and CRPS. Further studies are needed to assess the cost-effectiveness of SCS for ischemic pain and DPN.

Antibiotic therapy for pelvic inflammatory disease.

BACKGROUND: Pelvic inflammatory disease (PID) affects 4% to 12% of women of reproductive age. The main intervention for acute PID is broad-spectrum antibiotics administered intravenously, intramuscularly or orally. We assessed the optimal treatment regimen for PID.  OBJECTIVES: To assess the effectiveness and safety of antibiotic regimens to treat PID. SEARCH METHODS: In January 2020, we searched the Cochrane Sexually Transmitted Infections Review Group's Specialized Register, which included randomized controlled trials (RCTs) from 1944 to 2020, located through hand and electronic searching; CENTRAL; MEDLINE; Embase; four other databases; and abstracts in selected publications. SELECTION CRITERIA: We included RCTs comparing antibiotics with placebo or other antibiotics for the treatment of PID in women of reproductive age, either as inpatient or outpatient treatment. We limited our review to a comparison of drugs in current use that are recommended by the 2015 US Centers for Disease Control and Prevention guidelines for treatment of PID. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the quality of evidence. MAIN RESULTS: We included 39 RCTs (6894 women) in this review, adding two new RCTs at this update. The quality of the evidence ranged from very low to high, the main limitations being serious risk of bias (due to poor reporting of study methods and lack of blinding), serious inconsistency, and serious imprecision. None of the studies reported quinolones and cephalosporins, or the outcomes laparoscopic evidence of resolution of PID based on physician opinion or fertility outcomes. Length of stay results were insufficiently reported for analysis. Regimens containing azithromycin versus regimens containing doxycycline We are uncertain whether there was a clinically relevant difference between azithromycin and doxycycline in rates of cure for mild-moderate PID (RR 1.18, 95% CI 0.89 to 1.55; 2 RCTs, 243 women; I2 = 72%; very low-quality evidence). The analyses may result in little or no difference between azithromycin and doxycycline in rates of severe PID (RR 1.00, 95% CI 0.96 to 1.05; 1 RCT, 309 women; low-quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.71, 95% CI 0.38 to 1.34; 3 RCTs, 552 women; I2 = 0%; low-quality evidence). In a sensitivity analysis limited to a single study at low risk of bias, azithromycin probably improves the rates of cure in mild-moderate PID (RR 1.35, 95% CI 1.10 to 1.67; 133 women; moderate-quality evidence), compared to doxycycline.  Regimens containing quinolone versus regimens containing cephalosporin The analysis shows there may be little or no clinically relevant difference between quinolones and cephalosporins in rates of cure for mild-moderate PID (RR 1.05, 95% CI 0.98 to 1.14; 4 RCTs, 772 women; I2 = 15%; low-quality evidence), or severe PID (RR 1.06, 95% CI 0.91 to 1.23; 2 RCTs, 313 women; I2 = 7%; low-quality evidence). We are uncertain whether there was a difference between quinolones and cephalosporins in adverse effects leading to discontinuation of treatment (RR 2.24, 95% CI 0.52 to 9.72; 6 RCTs, 1085 women; I2 =  0%; very low-quality evidence). Regimens with nitroimidazole versus regimens without nitroimidazole There was probably little or no difference between regimens with or without nitroimidazoles (metronidazole) in rates of cure for mild-moderate PID (RR 1.02, 95% CI 0.95 to 1.09; 6 RCTs, 2660 women; I2 = 50%; moderate-quality evidence), or severe PID (RR 0.96, 95% CI 0.92 to 1.01; 11 RCTs, 1383 women; I2 = 0%; moderate-quality evidence). The evidence suggests that there was little to no difference in in adverse effects leading to discontinuation of treatment (RR 1.05, 95% CI 0.69 to 1.61; 17 studies, 4021 women; I2 = 0%; low-quality evidence). . In a sensitivity analysis limited to studies at low risk of bias, there was little or no difference for rates of cure in mild-moderate PID (RR 1.05, 95% CI 1.00 to 1.12; 3 RCTs, 1434 women; I2 = 0%; high-quality evidence). Regimens containing clindamycin plus aminoglycoside versus quinolone We are uncertain whether quinolone have little to no effect in  rates of cure for mild-moderate PID compared to clindamycin plus aminoglycoside (RR 0.88, 95% CI 0.69 to 1.13; 1 RCT, 25 women; very low-quality evidence). The analysis may result in little or no difference between quinolone vs. clindamycin plus aminoglycoside in severe PID (RR 1.02, 95% CI 0.87 to 1.19; 2 studies, 151 women; I2 =  0%; low-quality evidence). We are uncertain whether quinolone reduces adverse effects leading to discontinuation of treatment (RR 0.21, 95% CI 0.02 to 1.72; 3 RCTs, 163 women; I2 =  0%; very low-quality evidence). Regimens containing clindamycin plus aminoglycoside versus regimens containing cephalosporin We are uncertain whether clindamycin plus aminoglycoside improves the rates of cure for mild-moderate PID compared to cephalosporin (RR 1.02, 95% CI 0.95 to 1.09; 2 RCTs, 150 women; I2 =  0%; low-quality evidence). There was probably little or no difference in rates of cure in severe PID with clindamycin plus aminoglycoside compared to cephalosporin (RR 1.00, 95% CI 0.95 to 1.06; 10 RCTs, 959 women; I2= 21%; moderate-quality evidence). We are uncertain whether clindamycin plus aminoglycoside reduces adverse effects leading to discontinuation of treatment compared to cephalosporin (RR 0.78, 95% CI 0.18 to 3.42; 10 RCTs, 1172 women; I2 =  0%; very low-quality evidence). AUTHORS' CONCLUSIONS: We are uncertain whether one treatment was safer or more effective than any other for the cure of mild-moderate or severe PID Based on a single study at a low risk of bias, a macrolide (azithromycin) probably improves the rates of cure of mild-moderate PID, compared to tetracycline (doxycycline).

The Unmet Need for Intrathecal Drug Delivery Pumps for the Treatment of Cancer Pain in England: An Assessment of the Hospital Episode Statistics Database.

OBJECTIVES: Intrathecal drug delivery (ITDD) devices have been shown to be a clinically effective and cost-effective option for the management of cancer pain and recommended for use in England. The aim of this study is to assess the impact of the 2015 NHS England Clinical Commissioning Policy on the uptake of ITDD pumps for the management of cancer pain or if there is an ongoing unmet need for this intervention in England. MATERIALS AND METHODS: Hospital Episode Statistics (HES) were obtained for all patients undergoing ITDD for the management of cancer pain between 2014 and January 2020. In addition, HES were utilized to estimate the number of patients with cancer potentially eligible for ITDD pump during the same period. RESULTS: The number of patients with cancer and those potentially suitable to receive an ITDD for the management of cancer pain have increased year on year since 2014. This increase has not been matched by an uptake in the provision of ITDD. Conservative estimates suggest that at least 8000 people with cancer pain would be eligible for ITDD; 458 patients received an intervention for pain management between April 2018 and March 2019 and only 30 ITDD pumps were implanted in that same period. CONCLUSIONS: We observed a substantial gap between the need and provision of ITDD for patients with refractory cancer pain in England despite the recommendation for the use of ITDD for this patient population. In addition, we present suggestions for improvement of access to and provision of ITDD in England.

Randomized Placebo-/Sham-Controlled Trials of Spinal Cord Stimulation: A Systematic Review and Methodological Appraisal.

OBJECTIVES: The recent availability of paraesthesia/sensation free spinal cord stimulation (SCS) modalities allow the design of clinical trials of SCS using placebo/sham controls and blinding of patients, clinicians, and researchers. The aims of this study were to: 1) systematically review the current evidence base of randomized controlled trials (RCTs) of SCS placebo/sham trials and 2) to undertake a methodological critique of their methods. Based on this critique, we developed a checklist for the design and reporting of future RCTs of SCS. MATERIALS AND METHODS: Electronic data bases were searched from inception until January 2019 for RCTs of SCS using a placebo/sham control. RCTs with only an active comparator arm were excluded. The results are presented as a narrative synthesis. RESULTS: Searches identified 12 eligible RCTs. SCS modalities included paraesthesia stimulation, subthreshold, burst, and high-frequency SCS and were mainly conducted in patients with failed back surgery syndrome, complex regional pain syndrome, and refractory angina. The quality and transparency of reporting of the methods of placebo stimulation, blinding of patients, clinicians, and researchers varied markedly across studies. CONCLUSIONS: To date the methods of placebo/sham control and blinding in RCTs have been poorly reported, leading to concerns about the validity and replicability of the findings. Important aspects that need to be clearly reported in the design of placebo-/sham-controlled RCTs of SCS include the transparent reporting of stimulation programming parameters, patient position during perception threshold measurement, management of the patient handheld programmer, frequency of recharging, and assessment of the fidelity of blinding.

Antibiotic therapy for pelvic inflammatory disease: an abridged version of a Cochrane systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To assess the effectiveness and safety of antibiotic regimens used to treat pelvic inflammatory disease (PID). DESIGN: This is a systematic review and meta-analysis of randomised controlled trials (RCTs). Risk of bias was assessed using the criteria outlined in the Cochrane guidelines. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation. DATA SOURCES: Eight electronic databases were searched from date of inception up to July 2016. Database searches were complemented by screening of reference lists of relevant studies, trial registers, conference proceeding abstracts and grey literature. ELIGIBILITY CRITERIA: RCTs comparing the use of antibiotics with placebo or other antibiotics for the treatment of PID in women of reproductive age, either as inpatient or outpatient treatment. RESULTS: We included 37 RCTs (6348 women). The quality of evidence ranged from very low to high, the main limitations being serious risk of bias (due to poor reporting of study methods and lack of blinding), serious inconsistency and serious imprecision. There was no clear evidence of a difference in the rates of cure for mild-moderate or for severe PID for the comparisons of azithromycin versus doxycycline, quinolone versus cephalosporin, nitroimidazole versus no use of nitroimidazole, clindamycin plus aminoglycoside versus quinolone, or clindamycin plus aminoglycoside versus cephalosporin. No clear evidence of a difference between regimens in antibiotic-related adverse events leading to discontinuation of therapy was observed. CONCLUSIONS: We found no conclusive evidence that one regimen of antibiotics was safer or more effective than any other for the treatment of PID, and there was no clear evidence for the use of nitroimidazoles (metronidazole) compared with the use of other drugs with activity against anaerobes. More evidence is needed to assess treatments for women with PID, particularly comparing regimens with or without the addition of nitroimidazoles and the efficacy of azithromycin compared with doxycycline.

Biologic Drugs as Analgesics for the Management of Low Back Pain and Sciatica.

OBJECTIVE: To discuss the current knowledge on the impact of commonly used biologic agents (i.e., anti-tumor necrosis factor-alpha [anti-TNF-α] and anti-nerve growth factor [anti-NGF]) in the management of low back pain with or without sciatica. METHODS: A narrative literature review of studies investigating the use of biologic agents for the management of low back pain and sciatica was conducted. We searched MEDLINE and EMBASE for English language publications. A hand-search of reference lists of relevant studies was also performed. RESULTS: Although some observational studies showed that inhibition of TNF-α reduced pain and improved function, randomized controlled trials and a meta-analysis failed to demonstrate the superiority of anti-TNF-α over placebo in this regard. Anti-TNF-α, however, reduced the risk of having invasive procedures such as discectomy and radicular block in cases of sciatica. Conversely, controlled studies showed moderate pain reduction and mild functional improvement with anti-NGF administration, but the side effect profile of anti-NGF was unfavorable compared with placebo. CONCLUSIONS: Overall, anticytokine treatments have limited efficacy in patients with chronic low back pain with or without sciatica. However, larger and better-designed studies may need to be performed in specific patient subpopulations. Low back pain is particularly disabling in younger patients. This group therefore represents a potential target population for investigating the effectiveness of anticytokine therapies, especially where other pharmacological and nonpharmacological management strategies have failed.

Trial Versus No Trial of Spinal Cord Stimulation for Chronic Neuropathic Pain: Cost Analysis in United Kingdom National Health Service.

OBJECTIVES: The aim of the current project was to evaluate the spinal cord stimulation (SCS) screening trial success rate threshold to obtain the same cost impact across two identical sets of patients following either a prolonged screening trial prior to implantation strategy or a full implant without a screening trial. MATERIALS AND METHODS: A cost impact analysis was carried out from a health care perspective and considered trial to implant rates reported in the literature. Items of resource use were costed using national averages obtained from the National Health Service (NHS) reference cost data base. Cost components were added up to derive total patient level costs for the NHS. Only the costs associated with the screening trial procedures and devices were considered. RESULTS: The most conservative of our estimates suggest that a failure rate of less than 15% is cost saving to the NHS. A failure rate as high as 45% can also be cost saving if the less expensive nonrechargeable SCS devices are used. All the thresholds observed represent a considerably higher screening failure rate than that reported in the latest randomized controlled trials (RCTs) of SCS. A trial to implant ratio of 91.6% could represent savings between £16,715 (upper bound 95% CI of rechargeable implantable pulse generator [IPG] cost) and £246,661 (lower bound 95% CI of nonrechargeable IPG cost) per each 100 patients by adopting an implantation only strategy. CONCLUSIONS: Considerable savings could be obtained by adopting an implantation strategy without a screening trial. It is plausible that accounting for other factors, such as complications that can occur with a screening trial, additional savings could be achieved by choosing a straight to implant treatment strategy. Nevertheless, additional evidence is warranted to support this claim.

Intrathecal Drug Delivery Systems for the Management of Chronic Noncancer Pain: A Systematic Review of Economic Evaluations.

BACKGROUND: Intrathecal drug delivery (ITDD) systems are one of a limited number of management options for chronic noncancer pain, cancer pain, and spasticity. Concerns over their effectiveness and high initial costs led National Health Service (NHS) England to decommission ITDD for patients with chronic noncancer pain. However, the extent to which this decision is in line with existing economic evidence is unclear. The aim of this systematic review was to identify and review the existing evidence on the cost effectiveness of ITDD for chronic noncancer pain. METHODS: Full and partial economic evaluations on ITDD were identified through systematic searches in MEDLINE, Embase, Web of Science, and the NHS for Reviews and Dissemination databases. Database searches were complemented by hand searching of reference lists of relevant studies and searches of grey literature. Study selection was carried out by 2 assessors, independently. Study quality assessment was performed to inform critical appraisal of health economics studies. Data were extracted using a data extraction form developed for the purposes of this study. RESULTS: Four thousand four hundred and sixty-four unique studies were identified, of which 7 met the inclusion criteria. With the exception of 1 study, the studies found ITDD to be either cost saving or cost effective compared to conventional medical management. ITDD became cost ineffective in 1 further study following price year adjustment to 2016. CONCLUSIONS: Study findings showed ITDD to be not cost effective only in extremely conservative scenarios. There is limited evidence on the effectiveness of ITDD in noncancer pain; however, the available economic evidence controverts arguments to refute the treatment on economic grounds.