Karri, Jay

Abstract Objective Genicular nerve radiofrequency (gRF) treatment is a widely used intervention for chronic pain from knee osteoarthritis (KOA). This systematic review and meta-analysis focuses on RCTs utilizing image guidance to address inconsistencies in previous reviews and provide higher-quality evidence. Design, Setting, and Methods This study included RCTs that compared gRF techniques (conventional, cooled, pulsed, bipolar) to non-gRF treatments, including sham procedures, intra-articular injections, ozone therapy, and oral medications. Primary and secondary outcomes were changes in pain and total WOMAC scores at 3, 6, and 12 months post-gRF treatments. Subgroup analyses explored differences by lesion size, use of prognostic blocks, industry sponsorship, and study location. Statistical heterogeneity was assessed via I 2 statistics. Results Eleven RCTs with 868 knee osteoarthritis patients (435 gRF, 433 non-gRF) were included. At 3 months, gRF significantly reduced pain (SMD -1.65, 95% CI: -3.20 to -0.10, I 2 = 98%, P = 0.040), but not at 6 months or 12 months. Secondary analyses showed no significant differences in total WOMAC scores between the gRF and control groups at 3, 6, and 12 months. Subgroup analysis showed that industry-sponsored studies reported significant 3-month pain reduction, whereas non-sponsored studies did not. This effect was independent of study location. Conclusions GRF provides short-term pain relief (up to 3 months) but neither functional improvement nor sustained pain reduction compared to non-gRF treatments. Our findings do not support the routine use of gRF for long-term chronic pain due to KOA.

Background Knee osteoarthritis (OA) is a leading cause of chronic pain and disability, with limited disease modifying therapies. While glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have established cardiometabolic benefits and have been associated with reductions in knee OA related pain, it is unclear whether they can reduce progression to total knee arthroplasty (TKA). Methods We conducted a retrospective cohort study using the TriNetX Global Research Network, identifying adults with knee OA diagnosed between January 1, 2010, and December 31, 2024. Patients were stratified by GLP-1 RA exposure class (any GLP-1 RA or new generation agents, semaglutide or tirzepatide) and treatment duration (1 or 3 years), and then compared with propensity score matched non-exposed cohorts balanced for age, sex, race, musculoskeletal diagnoses, obesity related conditions, body mass index, and proxies for healthcare access. The primary outcome was cumulative incidence of TKA at 1, 3, 5, and 8 years. Hazard ratios (HRs) were estimated by Cox proportional hazards models and absolute risk differences from Kaplan–Meier curves, expressed as exposed minus non-exposed. Results After propensity score matching, cohort sizes ranged from 13 351 (new generation GLP-1 RA, 3 year exposure) to 42 062 patients (any GLP-1 RA, 1 year exposure). GLP-1 RA use was associated with significantly lower cumulative TKA incidence across all exposure classes, durations, and follow-up intervals (all p<0.001). With 1 year exposure to any GLP-1 RA, the absolute risk difference at 8 years was −2.80 percentage points (HR 0.90, 95% CI 0.83 to 0.98). Risk reductions were greater with new generation agents and longer duration: 3 year exposure to semaglutide or tirzepatide gave an absolute risk difference of −4.71 percentage points at 8 years (HR 0.72, 95% CI 0.67 to 0.78). Conclusions In this large, multicenter, real world cohort study, GLP-1 RA use was associated with a significantly reduced long term risk of TKA in patients with knee OA, with effects that were greater with longer treatment duration and newer generation agents. These duration and agent dependent associations are consistent with potential disease modifying activity beyond weight loss alone, although prospective trials are needed to establish causality and define optimal treatment targets.

Importance Chronic pain is a leading cause of disability, and many affected patients rely on long-term opioid therapy despite its unfavorable adverse effect profile. Spinal cord stimulation is an established therapy for chronic pain that may secondarily reduce opioid consumption by providing sustained analgesia. Objective To quantify changes in opioid use following spinal cord stimulation implantation for the treatment of chronic pain through a systematic review and meta-analysis. Data sources We conducted a comprehensive search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus from each database’s inception to July 1, 2024. Study selection We included studies describing patients who underwent spinal cord stimulator implantation for the treatment of chronic pain. A total of 2,784 potential studies were identified and screened by multiple independent reviewers, yielding a final total of 43 studies included in the systematic review. Data extraction and synthesis Data extraction was completed by multiple independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis Of Observational Studies in Epidemiology guidelines. A random effects model with Hartung-Knapp-Sidik-Jonkman adjustment was used to estimate pooled estimates. Certainty assessment was performed following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Main outcome(s) and measure(s) The primary outcomes were change in continuous opioid use (ie, morphine milligram equivalent (MME)) and categorical opioid use (yes/no) from preimplantation to 12 months following spinal cord stimulator implantation. Results Meta-analysis of 12 month continuous MME use comprising 22 study comparisons (1,666 individuals) revealed a weighted mean difference of −18.06 MME (95% CI −24.41 to −11.70; 95% prediction interval −38.29 to 2.17; p<0.001). Meta-analysis of categorical opioid use at 12 months comprising 24 study comparisons (1,527 individuals) revealed an OR of 0.47 (95% CI 0.30 to 0.75; 95% prediction interval 0.10 to 2.11; p=0.003), signifying lower odds of opioid continuation. Conclusions and relevance Spinal cord stimulation is associated with reduced opioid dose consumption and increased odds of opioid cessation at 12 months postimplantation compared with baseline in patients with chronic pain; however, both of these conclusions are supported by evidence of very low GRADE certainty. PROSPERO registration number CRD42024574921.

Background: The use of spinal cord stimulation (SCS) for managing severe refractory chronic pain has expanded considerably due to positive statistical evidence regarding its use; however, the statistical robustness of the underlying randomized controlled trials (RCTs) requires further scrutiny. One such tool that can be used for this purpose is the fragility index, which quantifies how many individual outcome events must be altered for an outcome to lose statistical significance. Thus the index can be used quantitatively to assess the stability and robustness of an RCT’s conclusions, with higher values indicating increased trial stability. This study assesses the fragility of pain outcomes across RCTs investigating SCS for chronic pain to better understand the quality and robustness of evidence. Methods: A systematic search was conducted for RCTs assessing SCS for any chronic pain indication. The primary outcome was an evaluation of the trial-specific fragility index for the prespecified pain primary outcomes of RCTs. Secondary outcomes included an evaluation of fragility for (1) specified indications for SCS therapy, (2) reported pain outcomes appearing in three or more RCTs, (3) the presence/absence of a conflict of interest, and (4) comparisons of SCS to conservative management or different SCS waveform modalities. Results: A total of 30 RCTs were included. The median (interquartile range [IQR]) fragility index across the primary outcome of all trials was 5.45 (3.00 to 11.45). There was no statistical difference between the (1) types of outcomes (dichotomous vs. continuous; P = 0.710), (2) primary versus secondary pain outcomes ( P = 0.771), or (3) presence versus absence of trial conflict of interest ( P = 0.753). Indications with a median (IQR) fragility score greater than three included persistent spinal pain syndrome type 2 with a score of 8.00 (2.80 to 12.60), painful diabetic neuropathy with a score of 6.00 (3.00 to 11.80), complex regional pain syndrome with a score of 7.20 (4.62 to 81.50), mixed etiologies with a score of 9.00 (3.00 to 38.00), and other etiologies with a score of 3.00 (1.00 to 8.55). Conclusions: This study suggests that the majority of RCTs investigating primary pain outcomes after SCS therapy are robust with relatively high fragility scores. Reporting the fragility of outcomes in trials can provide a more comprehensive assessment of trial robustness and can further aid clinicians in interpreting trial results and making informed treatment decisions.

Background Peripheral nerve stimulation (PNS) is an emerging neuromodulation therapy for chronic pain, yet its use in clinical practice varies significantly. Although temporary PNS is widely incorporated, either as a screening trial or a treatment itself, the evidence supporting the use of temporary PNS prior to permanent implantation is limited. We aimed to compare pain relief, opioid consumption, and adverse events between an approach implementing temporary PNS before permanent implantation (temporary-to-permanent (TTP)) vs proceeding directly to permanent PNS implantation (direct-to-permanent (DTP)). Methods A multicenter retrospective study was undertaken at seven major academic institutions from January 1, 2014, to January 1, 2024. Adult patients who underwent permanent PNS implantation for the treatment of chronic pain conditions were included and were divided into TTP or DTP cohorts based on their clinical approach. The dual primary outcomes were pain relief and opioid consumption (in oral morphine equivalents) at 6 months compared with baseline before any PNS therapy. Multivariable Tobit regression analysis was performed to identify predictors of pain relief at 6 months using a stepwise approach. Results A total of 130 patients were analyzed (54 in TTP approach, 76 in DTP approach). Patient-reported percentage pain relief was 56.7%±27.9% at 6 months compared with baseline (before PNS implantation) in the TTP cohort, and 45.1%±33.6% in the DTP cohort. The estimated mean percentage pain relief at 6 months was similar in the TTP and DTP cohorts (between-group difference 15.24%; 95% CI −0.32 to 30.80, p=0.052), with consistent findings after sensitivity analysis with multiple imputation. Opioid consumption declined similarly in the TTP (−3.1±9.9 mg) and DTP (−2.1±8.1 mg) cohorts at 6 months with no statistical difference between cohorts (mean between-group difference: −1.00, 95% CI −4.57 to 2.57, p=0.580), and with consistent findings after sensitivity analysis. Device explantation rates and adverse event profiles were comparable between cohorts. Conclusion Although temporary PNS is widely performed prior to permanent PNS implantation, there was no evidence that the TTP approach is associated with superior analgesic outcomes compared with the DTP approach. Further, patients in both approaches achieved clinically meaningful pain relief at 6 months compared with baseline status prior to PNS therapy.