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In Part I of this series, we provide guidance for preparing a systematic review protocol. In this article, we highlight important steps and supplement with exemplars on conducting and reporting the results of a systematic review. We suggest how authors can manage protocol violations, multiplicity of outcomes and analyses, and heterogeneity. The quality (certainty) of the evidence and strength of recommendations should follow the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. It is our goal that Part II of this series provides valid guidance to authors and peer reviewers who conduct systematic reviews to adhere to important constructs of transparency, structure, reproducibility, and accountability. This will likely result in more rigorous systematic reviews being submitted for publication to the journals like Regional Anesthesia & Pain Medicine and Anesthesia & Analgesia.

In Part I of this series, we provide guidance for preparing a systematic review protocol. In this article, we highlight important steps and supplement with exemplars on conducting and reporting the results of a systematic review. We suggest how authors can manage protocol violations, multiplicity of outcomes and analyses, and heterogeneity. The quality (certainty) of the evidence and strength of recommendations should follow the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. It is our goal that Part II of this series provides valid guidance to authors and peer reviewers who conduct systematic reviews to adhere to important constructs of transparency, structure, reproducibility, and accountability. This will likely result in more rigorous systematic reviews being submitted for publication to the journals like Regional Anesthesia & Pain Medicine and Anesthesia & Analgesia .

Comprehensive resources exist on how to plan a systematic review and meta-analysis. The objective of this article is to provide guidance to authors preparing their systematic review protocol in the fields of regional anesthesia and pain medicine. The focus is on systematic reviews of health care interventions, with or without an aggregate data meta-analysis. We describe and discuss elements of the systematic review methodology that review authors should prespecify, plan, and document in their protocol before commencing the review. Importantly, authors should explain their rationale for planning their systematic review and describe the PICO framework—participants (P), interventions (I), comparators (C), outcomes (O)—and related elements central to constructing their clinical question, framing an informative review title, determining the scope of the review, designing the search strategy, specifying the eligibility criteria, and identifying potential sources of heterogeneity. We highlight the importance of authors defining and prioritizing the primary outcome, defining eligibility criteria for selecting studies, and documenting sources of information and search strategies. The review protocol should also document methods used to evaluate risk of bias, quality (certainty) of the evidence, and heterogeneity of results. Furthermore, the authors should describe their plans for managing key data elements, the statistical construct used to estimate the intervention effect, methods of evidence synthesis and meta-analysis, and conditions when meta-analysis may not be possible, including the provision of practical solutions. Authors should provide enough detail in their protocol so that the readers could conduct the study themselves.

Abstract Background Chronic intractable pain from peripheral neuropathy is a debilitating condition that might not respond to conventional medical management and pharmacotherapy. The primary objective of this systematic review was to assess change (or reduction) in pain intensity in patients with length-dependent peripheral neuropathy after spinal cord stimulation (SCS) therapy. Methods This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The primary outcome was change (or reduction) in pain intensity after 12 months of SCS therapy compared with baseline in participants with length-dependent peripheral neuropathy. Secondary outcomes included change in pain intensity after 6 months and change in opioid consumption after 12 months. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines were used to appraise the quality of evidence. Results Nineteen studies consisting of 376 participants who underwent SCS implantation met the inclusion criteria. Qualitative synthesis revealed that all eligible studies reported a significant improvement in pain intensity after 12 months of SCS therapy as compared with baseline. Mean differences with 95% confidence intervals were calculated for 4 studies, all of which achieved the minimal clinically important difference for change in pain intensity at 12 months. The GRADE quality of evidence for this outcome was appraised as very low quality. Conclusion This systematic review highlights that SCS could lead to significant improvement in pain intensity for length-dependent peripheral neuropathy, although future well-powered randomized controlled trials are warranted to increase the certainty of evidence in this finding. Study registration PROSPERO (https://www.crd.york.ac.uk/PROSPERO/) ID: CRD42022377572.

Background The analgesic effectiveness of contemporary motor-sparing nerve blocks used in combination for analgesia in total knee arthroplasty is unclear. This network meta-analysis was conducted to evaluate the analgesic effectiveness of adding single-injection or continuous adductor canal block (ACB) with or without infiltration of the interspace between the popliteal artery and the capsule of the posterior knee (iPACK) to intraoperative local infiltration analgesia (LIA), compared to LIA alone, after total knee arthroplasty. Methods Randomized trials examining the addition of single-injection or continuous ACB with or without single-injection block at the iPACK to LIA for total knee arthroplasty were considered. The two primary outcomes were area-under-the-curve pain scores over 24 to 48 h and postoperative function at greater than 24 h. Secondary outcomes included rest pain scores at 0, 6, 12, and 24 h; opioid consumption (from 0 to 24 h and from 25 to 48 h); and incidence of nausea/vomiting. Network meta-analysis was conducted using a frequentist approach. Results A total of 27 studies (2,317 patients) investigating the addition of (1) single-injection ACB, (2) continuous ACB, (3) single-injection ACB and single-injection block at the iPACK, and (4) continuous ACB and single-injection block at the iPACK to LIA, as compared to LIA alone, were included. For area-under-the-curve 24- to 48-h pain, the addition of continuous ACB with single-injection block at the iPACK displayed the highest P -score probability (89%) of being most effective for pain control. The addition of continuous ACB without single-injection block at the iPACK displayed the highest P -score probability (87%) of being most effective for postoperative function. Conclusions The results suggest that continuous ACB, but not single-injection ACB and/or single-injection block at the iPACK, provides statistically superior analgesia when added to LIA for total knee arthroplasty compared to LIA alone. However, the magnitude of these additional analgesic benefits is clinically questionable. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Enhanced recovery after surgery (ERAS) protocols are standardized and designed to provide superior analgesia, reduce opioid consumption, improve patient recovery, and reduce hospital length of stay. Yet, moderate-to-severe postsurgical pain continues to afflict over 40% of patients and remains a major priority for anesthesia research. Methadone administration in the perioperative setting may reduce postoperative pain scores and have opioid-sparing effects, which may be beneficial for enhanced recovery. Methadone possesses a multimodal profile consisting of µ-opioid agonism, N -methyl-d-aspartate (NMDA) receptor antagonism, and reuptake inhibition of serotonin and norepinephrine. Furthermore, it may attenuate the development of chronic postsurgical pain. However, caution is advised with perioperative use of methadone in specific high-risk patient populations and surgical settings. Methadone’s wide pharmacokinetic variability, opioid-related adverse effects, and potential negative impact on cost-effectiveness may also limit its use in the perioperative setting. In this PRO-CON commentary article, the authors debate whether methadone should be incorporated in ERAS protocols to provide superior analgesia with no increased risks.

Background Spinal cord stimulation (SCS) has emerged as an important treatment for chronic pain disorders. While there is evidence supporting improvement in pain intensity with SCS therapy, efforts to synthesize the evidence on physical functioning are lacking. Objective The primary objective of this meta-analysis was to assess long-term physical function following 12 months of SCS for chronic back pain. Evidence review PubMed, EMBASE, Scopus, and CENTRAL databases were searched for original peer-reviewed publications investigating physical function following SCS. The primary outcome was physical function at 12 months following SCS therapy for chronic back pain compared with baseline. A random effects model with an inverse variable method was used. The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) framework was used to determine the certainty of evidence. Findings A total of 518 studies were screened, of which 36 were included. Twenty-two studies were pooled in the meta-analysis. There was a significant reduction in Oswestry Disability Index (ODI) scores at all time frames up to 24 months following implantation. Pooled results revealed significant improvement in ODI scores at 12 months with a mean difference of −17.00% (95% CI −23.07 to −10.94, p<0.001). There was a very low certainty of evidence in this finding as per the GRADE framework. There was no significant difference in subgroup analyses based on study design (randomised controlled trials (RCTs) vs non-RCTs), study funding, or stimulation type. Conclusion This meta-analysis highlights significant improvements in physical function after SCS therapy. However, this finding was limited by a very low GRADE certainty of evidence and high heterogeneity.

Current pharmacologic treatments may provide limited analgesia in fibromyalgia and other chronic pain disorders. Low-dose naltrexone (LDN) has emerged as a potential analgesic option that has been minimally explored. This study aims to describe current real-world prescribing practices of LDN, to investigate if patients have a perceived benefit of LDN in treating pain symptoms and to identify predictors associated with a perceived benefit or discontinuation of LDN. We evaluated all outpatient prescriptions for LDN prescribed for any pain indication in the Mayo Clinic Enterprise from 1 January 2009 to 10 September 2022. A total of 115 patients were included in the final analysis. The patients were 86% female, had a mean age of 48 ± 16 years, and 61% of prescriptions were for fibromyalgia-related pain. The final daily dose of oral LDN ranged from 0.8 to 9.0 mg, while the most common dose was 4.5 mg once daily. Of patients who reported follow-up data, 65% reported benefit in their pain symptoms while taking LDN. Adverse effects were reported in 11 (11%) patients and 36% discontinued taking LDN by the most recent follow-up. Concomitant analgesic medications were used by 60% of patients and were not associated with perceived benefit nor discontinuation of LDN, including concomitant opioids. LDN is a relatively safe pharmacologic option that may benefit patients with chronic pain conditions and warrants further investigation in a prospective, controlled, and well-powered randomized clinical trial.

This case series aims to highlight the efficacy of peripheral nerve stimulation (PNS) in the treatment of phantom limb pain, as well as provide an alternative method for the treatment of this pain syndrome. In this report, we describe three amputee patients with severe phantom limb pain who obtained substantial analgesia and improvement in physical functionality after implantation of a temporary PNS device. Future studies should assess predictors of successful response or poor response to PNS therapy, such as mental health, environmental stressors, coping skills, and procedural factors. These factors may facilitate an individualized approach for each patient to ensure appropriate candidacy for PNS and better prognosis. Considering that patients in our cohort did not achieve long-lasting benefit after removal of temporary PNS, future research should assess if patients with phantom limb pain would benefit from permanent PNS, rather than temporary PNS.