Pulsed Radiofrequency Neuromodulation of the Greater Occipital Nerve for the Treatment of Headache Disorders in Adults: A Systematic Review.

Background: Pulsed radiofrequency neuromodulation (PRFN) of greater occipital nerve (GON) is considered in patients with headaches failing to achieve sustained analgesic benefit from nerve blocks with local anesthetic and steroids. However, the evidence supporting this practice is unclear. Aims: This narrative systematic review aims to explore the effectiveness and safety of GON PRFN on headaches. Methods: Databases were searched for studies, published up to February 1, 2024, investigating PRFN of GON for adults with headaches. Abstracts and posters were excluded. Primary outcome was change in headache intensity. Secondary outcomes included effect on monthly headache frequency (MHF), mental and physical health, mood, sleep, analgesic consumption, and side-effects. Two reviewers screened and extracted data. Results: Twenty-two papers (2 randomized controlled trials (RCT), 11 cohort, and 9 case reports/series) including 608 patients were identified. Considerable heterogeneity in terms of study design, headache diagnosis, PRF target and settings, and image-guidance was noted. PRFN settings varied (38-42°C, 40-60 V, and 150-400 Ohms). Studies demonstrated PRFN to provide significant analgesia and reduction of MHF in chronic migraine (CM) from 3 to 6 months; and significant pain relief for ON from six to ten months. Mild adverse effects were reported in 3.1% of cohort. A minority of studies reported on secondary outcomes. The quality of the evidence was low. Conclusions: Low-quality evidence indicates an analgesic benefit from PRFN of GON for ON and CM, but its role for other headache types needs more investigation. Optimal PRFN target and settings remain unclear. High-quality RCTs are required to further explore the role of this intervention. PROSPERO ID CRD42022363234.

Contexte: La neuromodulation par radiofréquence pulsée (NRFP) du nerf grand occipital (NGO) est envisagée chez les patients souffrant de céphalées qui ne parviennent pas à obtenir un bénéfice analgésique durable à partir des blocages nerveux à l'aide d'un anesthésique local et de stéroïdes. Cependant, les données probantes à l'appui de cette pratique ne sont pas claires.Objectifs: Cette revue systématique narrative vise à explorer l'efficacité et la sécurité de la NRFP du NGO sur les maux de téte.Méthodes: Des bases de données ont été consultées pour trouver des études, publiées jusqu'au 1er février 2024, portant sur la NRFP du NGO chez des adultes souffrant de céphalées. Les résumés et les affiches ont été exclus. Le critére principal était le changement dans l'intensité des maux de téte. Les critéres secondaires comprenaient l'effet sur la fréquence mensuelle des céphalées, la santé mentale et physique, l'humeur, le sommeil, la consommation d'analgésiques et les effets secondaires. Deux examinateurs ont évalué et extrait les données.Résultats: Vingt-deux articles (2 essais contrôlés randomisés, 11 cohortes et 9 rapports de cas/séries) portant sur 608 patients ont été recensés. Une hétérogénéité considérable a été observée en termes de devis de l'étude, de diagnostic des céphalées, de la cible et des paramétres de la FRP et de l'orientation de l'image. Les réglages de la NRFP variaient (38-42°C, 40-60 V, et 150-400 Ohms). Les études ont démontré que la NRFP procurait une analgésie significative et réduisait la fréquence des céphalées dans la migraine chronique de trois à six mois, et un soulagement significatif de la douleur pour la névralgie occipitale pendant six à dix mois. Des effets indésirables légers ont été signalés dans 3,1 % des participants de la cohorte. Une minorité déétudes ont fait état de résultats secondaires. La qualité des données probantes était faible.Conclusions: Les données probantes de faible qualité indiquent un bénéfice analgésique de la NRFP du NGO pour la névralgie occipitale et la migraine chronique, mais son rôle pour d'autres types de céphalées doit être davantage étudié. La cible et les paramétres optimaux de la NRFP restent floues. Des essais contrôlés randomisés de haute qualité sont nécessaires pour explorer davantage le rôle de cette intervention.

Safety and Efficacy of the Combination of Propofol and Ketamine for Procedural Sedation/Anesthesia in the Pediatric Population: A Systematic Review and Meta-analysis.

BACKGROUND: Drugs such as propofol and ketamine are used alone or in combination to provide sedation for medical procedures in children. The purpose of this systematic review was to compare the safety and effectiveness of propofol and ketamine to other drug regimens. METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Web of Science, and the grey literature (meta-Register of Controlled Trials, ClinicalTrials.gov, and Google Scholar) for randomized controlled studies comparing intravenous propofol and ketamine to any other single or combination drug regimen administered to children undergoing diagnostic or therapeutic procedures. Meta-analyses were performed for primary (hemodynamic and respiratory adverse events) and secondary outcomes using RevMan 5.3. We assessed the risk of bias and the certainty (quality) evidence for all outcomes using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Twenty-nine studies were included for analysis. Based on low-to-moderate quality evidence, we concluded that the use of propofol and ketamine may result in a slight-to-small reduction in the risk of hypotension, bradycardia, and apnea, and a slight increase in the risk of tachycardia, hypertension, and other respiratory adverse events, such as cough or laryngospasm. The ratio of propofol to ketamine and comparator drug regimen subgroups effects were important for desaturation and some secondary outcomes. CONCLUSIONS: The use of propofol and ketamine had a minimal effect on the incidence of adverse events and other secondary outcomes. Large-scale studies are required to more accurately estimate adverse event rates and the effects of propofol and ketamine on patient-important outcomes.

Intravenous Lidocaine for Acute Pain: A Single-Institution Retrospective Study.

BACKGROUND: In the perioperative period, intravenous lidocaine has been used as an opioid-sparing systemic analgesic with additional anti-inflammatory and anti-hyperalgesic properties. OBJECTIVE: The aim of this retrospective study was to review the utilization, efficacy, and safety of intravenous lidocaine on our Acute Pain Service (APS) and identify surgical and patient populations where this intervention was found to be useful. PATIENTS AND METHODS: This retrospective study was designed to assess acute pain management in patients who received an intravenous lidocaine infusion between February 2013 and December 2017. Data collected included demographics, surgery type, infusion duration, pain scores, analgesic consumption, and adverse effects. Pain scores included rest and active pain scores and were analyzed by surgical model and subgroups. Clinically important differences (CIDs) in pain were determined by changes in pain score difference of ≥ 2 (11-point scale) or ≥ 30% reduction in pain intensity. A patient was considered to have a true CID if a CID was observed with rest and/or active pain scores at both first to second (4-24 h) and first to final time point (4 h to infusion end) comparisons. RESULTS: In total, 544 patients received intravenous lidocaine during this period, and 394 were included in the final analysis. The average (± standard deviation) duration of infusion was 68.60 ± 49.52 h. Surgical specialties included gastrointestinal surgery (41%), orthopedics (28%), neurosurgery (15%), vascular surgery (10%), and others (6%). Overall, 56.1% of the study population experienced a CID, with reduced pain scores at rest and/or with activity. CIDs were also observed in patients with chronic pain (53.5%) and when intravenous lidocaine was used as a rescue technique (69.6%). Within the rescue cohort, opioid-dependent and opioid-naïve patients experienced 23.0% and 45.6% reductions, respectively, in their 8-h intravenous opioid consumption. In total, 37 patients in the study experienced transient signs of mild local anesthetic toxicity, which resolved with infusion titration (conservative) management. One serious adverse event required intervention, and the patient was successfully resuscitated. CONCLUSIONS: This retrospective study at a single institution with an APS policy for intravenous lidocaine in the postoperative period identifies benefits of intravenous lidocaine in certain surgical and patient populations. The findings need to be confirmed with further research.

Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis.

Importance: Harms and benefits of opioids for chronic noncancer pain remain unclear. Objective: To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain. Data Sources and Study Selection: The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control. Data Extraction and Synthesis: Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence. Main Outcomes and Measures: The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting. Results: Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], -0.69 cm [95% CI, -0.82 to -0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low- to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, -0.60 cm [95% CI, -1.54 to 0.34 cm]; physical functioning: WMD, -0.90 points [95% CI, -2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, -0.13 cm [95% CI, -0.99 to 0.74 cm]; physical functioning: WMD, -5.31 points [95% CI, -13.77 to 3.14 points]), and anticonvulsants (pain: WMD, -0.90 cm [95% CI, -1.65 to -0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, -5.77 to 6.66 points]). Conclusions and Relevance: In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.

Limited responsiveness related to the minimal important difference of patient-reported outcomes in rare diseases.

OBJECTIVES: To explore the responsiveness of patient-reported outcomes (PROs) in interventional studies involving patients with rare lysosomal storage diseases (LSDs). STUDY DESIGN AND SETTING: We searched eight databases for experimental and nonexperimental studies. Pairs of trained reviewers independently screened articles and subsequently extracted data from the eligible studies. Among studies with 10 or more patients using a valid PRO, we assessed the responsiveness of PROs based on a reanalysis of the data using minimal important difference estimates. Our analyses focused on statistically significant within-group differences in PROs for observational studies or the statistically significant between-group differences in PRO scores for controlled studies. RESULTS: Of 2,679 unique records, 62 interventional studies addressing patients with Fabry (55%), Gaucher (19%), Pompe (16%), and mucopolysaccharidoses (11%) proved eligible. The most frequently used PROs were the Short-Form-36 (25 studies), Brief Pain Inventory (20 studies), EuroQoL-5D (9 studies), and the Fatigue Severity Scale (6 studies). Observational studies suggest that PROs sometimes detect significant within-group changes when present. Randomized trials raise questions regarding the responsiveness of PROs to small differences between groups. CONCLUSIONS: Most studies have relied on generic PROs to evaluate quality of life and symptoms in patients with rare LSDs. PROs appear more responsive in observational studies than randomized trials.

Complex disease and phenotype mapping in the domestic dog.

The domestic dog is becoming an increasingly valuable model species in medical genetics, showing particular promise to advance our understanding of cancer and orthopaedic disease. Here we undertake the largest canine genome-wide association study to date, with a panel of over 4,200 dogs genotyped at 180,000 markers, to accelerate mapping efforts. For complex diseases, we identify loci significantly associated with hip dysplasia, elbow dysplasia, idiopathic epilepsy, lymphoma, mast cell tumour and granulomatous colitis; for morphological traits, we report three novel quantitative trait loci that influence body size and one that influences fur length and shedding. Using simulation studies, we show that modestly larger sample sizes and denser marker sets will be sufficient to identify most moderate- to large-effect complex disease loci. This proposed design will enable efficient mapping of canine complex diseases, most of which have human homologues, using far fewer samples than required in human studies.

Genetic structure in village dogs reveals a Central Asian domestication origin.

Dogs were the first domesticated species, originating at least 15,000 y ago from Eurasian gray wolves. Dogs today consist primarily of two specialized groups--a diverse set of nearly 400 pure breeds and a far more populous group of free-ranging animals adapted to a human commensal lifestyle (village dogs). Village dogs are more genetically diverse and geographically widespread than purebred dogs making them vital for unraveling dog population history. Using a semicustom 185,805-marker genotyping array, we conducted a large-scale survey of autosomal, mitochondrial, and Y chromosome diversity in 4,676 purebred dogs from 161 breeds and 549 village dogs from 38 countries. Geographic structure shows both isolation and gene flow have shaped genetic diversity in village dog populations. Some populations (notably those in the Neotropics and the South Pacific) are almost completely derived from European stock, whereas others are clearly admixed between indigenous and European dogs. Importantly, many populations--including those of Vietnam, India, and Egypt-show minimal evidence of European admixture. These populations exhibit a clear gradient of short--range linkage disequilibrium consistent with a Central Asian domestication origin.

Genomic analysis establishes correlation between growth and laryngeal neuropathy in Thoroughbreds.

BACKGROUND: Equine recurrent laryngeal neuropathy (RLN) is a bilateral mononeuropathy with an unknown pathogenesis that significantly affects performance in Thoroughbreds. A genetic contribution to the pathogenesis of RLN is suggested by the higher prevalence of the condition in offspring of RLN-affected than unaffected stallions. To better understand RLN pathogenesis and its genetic basis, we performed a genome-wide association (GWAS) of 282 RLN-affected and 268 control Thoroughbreds. RESULTS: We found a significant association of RLN with the LCORL/NCAPG locus on ECA3 previously shown to affect body size in horses. Using height at the withers of 505 of these horses, we confirmed the strong association of this locus with body size, and demonstrated a significant phenotypic and genetic correlation between height and RLN grade in this cohort. Secondary genetic associations for RLN on ECA18 and X did not correlate with withers height in our cohort, but did contain candidate genes likely influencing muscle physiology and growth: myostatin (MSTN) and integral membrane protein 2A (ITM2A). CONCLUSIONS: This linkage between body size and RLN suggests that selective breeding to reduce RLN prevalence would likely reduce adult size in this population. However, our results do not preclude the possibility of modifier loci that attenuate RLN risk without reducing size or performance, or that the RLN risk allele is distinct but tightly linked to the body size locus on ECA3. This study is both the largest body size GWAS and the largest RLN GWAS within Thoroughbred horses to date, and suggests that improved understanding of the relationship between genetics, equine growth rate, and RLN prevalence may significantly advance our understanding and management of this disease.

Genetic recombination is targeted towards gene promoter regions in dogs.

The identification of the H3K4 trimethylase, PRDM9, as the gene responsible for recombination hotspot localization has provided considerable insight into the mechanisms by which recombination is initiated in mammals. However, uniquely amongst mammals, canids appear to lack a functional version of PRDM9 and may therefore provide a model for understanding recombination that occurs in the absence of PRDM9, and thus how PRDM9 functions to shape the recombination landscape. We have constructed a fine-scale genetic map from patterns of linkage disequilibrium assessed using high-throughput sequence data from 51 free-ranging dogs, Canis lupus familiaris. While broad-scale properties of recombination appear similar to other mammalian species, our fine-scale estimates indicate that canine highly elevated recombination rates are observed in the vicinity of CpG rich regions including gene promoter regions, but show little association with H3K4 trimethylation marks identified in spermatocytes. By comparison to genomic data from the Andean fox, Lycalopex culpaeus, we show that biased gene conversion is a plausible mechanism by which the high CpG content of the dog genome could have occurred.