The Impact of Gabapentinoids on Pain-Related Outcomes after Knee and Hip Surgery: A Systematic Review with Meta-Analysis of Randomized Controlled Trials.

Background: Postoperative pain remains a significant challenge after knee and hip surgeries, two of the most frequently performed procedures, preventing patients from seeking timely surgical help. Gabapentinoids, gabapentin, and pregabalin, have been gaining attention in postoperative pain management. Methods: We conducted a meta-analysis to evaluate the efficacy of gabapentinoids in pain management after knee and hip surgery. PubMed, Scopus, and Cochrane Library were searched for relevant randomized controlled trials (RCTs) published before January 2023. Results: Fifteen articles reporting 1320 patients were analyzed. Cumulative pain intensity at rest and on movement was lower in the experimental group with the mean difference (MD) = -0.30 [-0.55,-0.05], p-value = 0.02, and MD = -0.41 [-0.68,-0.13], p-value = 0.004, respectively. However, the difference was not clinically meaningful and lacked statistical significance at each time period. The gabapentinoid group required less opioid consumption in morphine equivalents (MD = -6.42 [-9.07, -3.78] mg, p-value < 0.001). There was a lower incidence of postoperative nausea in the experimental group with a risk ratio (RR) of 0.69 [0.55, 0.86], p-value < 0.001. A subgroup analysis showed that gabapentinoids reduced pain on movement on postoperative day two after total knee arthroplasty but not hip arthroplasty. There was insufficient data to examine the efficacy of gabapentinoids in the reduction of chronic postoperative pain in knee/hip surgery. Conclusions: Thus, gabapentinoids were associated with a reduction in postoperative pain intensity at rest and on movement, morphine consumption, and the incidence of postoperative nausea in the early postoperative period following knee and hip surgeries. However, pain reduction was not clinically relevant. Sedation has not been evaluated in this work and, if performed, this may have influenced the conclusions. An important limitation of this study is that different gabapentinoids, their administration times and dosages, as well as varying intraoperative management protocols, were pooled together.

Patterns of gabapentinoid use among long-term opioid users.

OBJECTIVE: Understanding the clinical and demographic profile of patients on gabapentinoids can highlight areas of prescribing disparities, inform clinical practice, and guide future research to optimize effectiveness and safety of gabapentinoids for pain management. We used a national sample of Medicare beneficiaries to examine trends, patterns, and patient-level predictors of gabapentinoid use among long-term opioid users. METHODS: Using a national Medicare sample between 2014 and 2020, we examined factors associated with gabapentinoid use among long-term opioid users. We included Medicare eligible long-term opioid users with no prior gabapentinoid use. The primary outcome was gabapentinoid use after the long-term opioid use episode. Logistic regression was used to test the association with gabapentinoid use for year, age, sex, race/ethnicity, region, Medicare entitlement, low-income status, frailty, pain locations, anxiety, depression, opioid use disorder, and opioid morphine milligrams equivalent. RESULTS: Gabapentinoid use among long-term opioid users increased from 12.6% in 2014 to 16.8% in 2019 (p < .0001). Factors associated with increased gabapentinoid use were Hispanic ethnicity, back pain, nerve pain, and moderate or high opioid usage. Factors associated with decreased gabapentinoid use were older age and Medicare entitlement due to old age. CONCLUSIONS: Variation of gabapentinoid use by socio-demographics and insurance status indicates opportunities to improve pain management and a need for shared therapeutic decision making informed by discussion between pain patients and providers regarding safety and effectiveness of pain therapies. Our findings underscore the need for future research into the comparative effectiveness and safety of gabapentinoids for non-cancer chronic pain in various subpopulations.

Mechanisms and Preventative Strategies for Persistent Pain following Knee and Hip Joint Replacement Surgery: A Narrative Review.

Chronic postsurgical pain (CPSP) following total knee arthroplasty (TKA) and total hip arthroplasty (THA) is a prevalent complication of joint replacement surgery which has the potential to decrease patient satisfaction, increase financial burden, and lead to long-term disability. The identification of risk factors for CPSP following TKA and THA is challenging but essential for targeted preventative therapy. Recent meta-analyses and individual studies highlight associations between elevated state anxiety, depression scores, preoperative pain, diabetes, sleep disturbances, and various other factors with an increased risk of CPSP, with differences observed in prevalence between TKA and THA. While the etiology of CPSP is not fully understood, several factors such as chronic inflammation and preoperative central sensitization have been identified. Other potential mechanisms include genetic factors (e.g., catechol-O-methyltransferase (COMT) and potassium inwardly rectifying channel subfamily J member 6 (KCNJ6) genes), lipid markers, and psychological risk factors (anxiety and depression). With regards to therapeutics and prevention, multimodal pharmacological analgesia, emphasizing nonopioid analgesics like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), has gained prominence over epidural analgesia. Nerve blocks and local infiltrative anesthesia have shown mixed results in preventing CPSP. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, exhibits antihyperalgesic properties, but its efficacy in reducing CPSP is inconclusive. Lidocaine, an amide-type local anesthetic, shows tentative positive effects on CPSP. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have mixed results, while gabapentinoids, like gabapentin and pregabalin, present hopeful data but require further research, especially in the context of TKA and THA, to justify their use for CPSP prevention.

Pain Control Associated With Gabapentinoid Prescription After Elective Total Knee Arthroplasty.

BACKGROUND: Gabapentinoid (GABA) prescribing has substantially increased as a nonopioid analgesics for surgical conditions. We examined the effectiveness of GABA use for postoperative pain control among patients receiving total knee arthroplasty (TKA). METHODS: This retrospective cohort study using 2016 to 2019 data from a 20% national sample of Medicare enrollees included patients aged 66 and over years who received an elective TKA, were discharged to home, received home health care, and had both admission and discharge assessments of pain (n = 35,186). Study outcomes were pain score difference between admission and discharge and less-than-daily pain interfering with activity at discharge. Opioid and GABA prescriptions after surgery and receipt of nerve block within 3 days of surgery were also assessed. RESULTS: There were 30% of patients who had a pain score decrease of 3 to 4 levels and 55.8% had pain score decreases of 1 to 2 levels. In multivariable analyses, receiving a nerve block was significantly associated with pain score reduction. A GABA prescription increased the magnitude of pain score reduction among those receiving a nerve block. Results from inverse probability weighted analysis with propensity score showed that coprescribing of GABA and low-dose opioid was associated with significantly lower pain scores. CONCLUSIONS: Post-TKA opioid use was not associated with pain score reduction. Receiving a nerve block was associated with a modest pain score reduction. Co-prescribing GABA with low-dose opioid or receiving a nerve block was associated with increasing magnitudes of pain reduction. Further research should identify alternatives to opioid use for managing postoperative TKA pain.

Signal detection of adverse events associated with gabapentinoid use for chronic pain.

INTRODUCTION: Gabapentinoids (GABA) prescribing as a potential and conceivably safer substitute for opioids has substantially increased. Understanding all potential adverse drug events (ADEs) associated with GABA will guide clinical decision-making for pain management. METHODS: A 20% sample of Medicare enrollees with new chronic pain diagnoses in 2017-2018 was selected. GABA users were those with >=30 consecutive days prescription in a year without opioid prescription. Opioid users were similarly defined. The control group used neither of these drugs. Propensity score match across three groups based on demographics and comorbidity was performed. We used proportional reporting ratio (PRR), Gamma Poisson Shrinker, and tree-based scan statistic (TBSS) to detect ADEs within 3, 6, and 12 months of follow-up. RESULTS: Immunity disorder was detected within 3 months of follow-up by PRR compared to opioid use (PRR:2.33), and by all three methods compared to controls. Complications of transplanted organs/tissues and schizophrenia spectrum/other psychotic disorders were consistently detected by PRR and TBSS within 3 months. Skin disorders were detected by TBSS; and stroke was detected by PRR within 3 months compared to opioid use (PRR:4.74). Some malignancies were detected by PRR within 12 months. Other signals detected in GABA users were neuropathy and nerve disorders. CONCLUSIONS: Our study identified expected and unexpected ADE signals in GABA users. Neurological signals likely related to indications for GABA use. Signals for immunity, mental/behavior, and skin disorders were found in the FDA adverse event reporting system database. Unexpected signals of stroke and cancer require further confirmatory analyses to verify.

Postmastectomy Pain Syndrome: A Narrative Review.

Postmastectomy pain syndrome is a very common disorder in breast cancer survivors. The impact on the quality of patients' lives is significantly adverse. The precise pathophysiology has not been determined as yet though various risk factors have been identified that make the patient vulnerable. Required preoperative work includes the identification and possible elimination of risk factors. Treatment is multidisciplinary involving surgical and non-surgical modalities. There is a great scope of research in this field.

Preoperative pregabalin prevents succinylcholine-induced fasciculation and myalgia: A meta-analysis of randomized trials.

Succinylcholine is the gold standard neuromuscular blocker for rapid sequence induction; however, its use is associated with fasciculation and myalgia. We performed a systematic review and meta-analysis of randomized controlled clinical trials comparing gabapentinoids versus placebo for the prevention of fasciculations and succinylcholine-induced myalgias. Six randomized clinical studies were included with a total of 481 patients - 241 in the intervention group and 240 in the placebo group. Gabapentinoids reduced the incidence of succinylcholine-induced myalgia (RR = 0.69, 95% CI 0.56-0.84, P < .001), which remained statistically significant for pregabalin (RR = 0.71, 95% CI 0.54-0.93, P = .013) and gabapentin (RR = 0.61, 95% CI 0.45-0.82, P = .001) separately. There was no difference in fasciculations between the groups (RR = 0.92, 95% CI 0.82-1.03, P = .148). Preoperative use of gabapentinoids is associated with lower incidence of succinylcholine-induced myalgias within the first 24 h of surgery.

Novel Drug Targets and Emerging Pharmacotherapies in Neuropathic Pain.

Neuropathic pain is a debilitating condition characterized by abnormal signaling within the nervous system, resulting in persistent and often intense sensations of pain. It can arise from various causes, including traumatic nerve injury, neuropathy, and certain diseases. We present an overview of current and emerging pharmacotherapies for neuropathic pain, focusing on novel drug targets and potential therapeutic agents. Current pharmacotherapies, including tricyclic antidepressants, gabapentinoids, and serotonin norepinephrine re-uptake inhibitors, are discussed, as are emerging treatments, such as ambroxol, cannabidiol, and N-acetyl-L-cysteine. Additionally, the article highlights the need for further research in this field to identify new targets and develop more effective and targeted therapies for neuropathic pain management.

The use of gabapentinoids and opioids and risk of developing opioid-induced respiratory depression among older breast cancer survivors with neuropathic pain.

PURPOSE: To estimate the combined effect of gabapentinoid and opioid therapy compared to opioid monotherapy on the risk of developing opioid-induced respiratory depression among breast cancer survivors with neuropathic pain. METHOD: A nested case-control study of Medicare female breast cancer survivors with neuropathic pain receiving both opioids and gabapentinoids, opioid monotherapy, gabapentinoid monotherapy, and none of these drugs was conducted using SEER-Medicare between 2007 and 2015. Cases were survivors with respiratory depression and were matched with controls on the event date (± 1 year), age at diagnosis (± 5 years), and stage at diagnosis. Exposure to opioids and gabapentinoids was assessed 120 days before the event date. Conditional logistic regression was used to assess the impact of exposure among cases and controls. RESULTS: A total of 657 cases and 11,471 controls were identified. After matching, 656 cases and 5612 controls were retained, and cases were more likely to be diagnosed with mental health disorders (24.4% vs 10.5%, p < 0.0001) than controls. In the primary adjusted analysis, combined opioids and gabapentin use were associated with an increased risk of respiratory depression compared to opioid monotherapy (Adj. OR: 1.513; 95% CI: 1.473-2.350). Additionally, under secondary analysis, combined opioids and gabapentin use were associated with an increased risk of respiratory depression compared to receiving neither of these classes. (Adj. OR: 1.595; 95% CI: 1.050-2.421). CONCLUSION: There is a need for dose titration strategies of gabapentinoids and caution when co-prescribing opioids and gabapentinoids in older cancer survivors.

Misuse of gabapentinoids (pregabalin and gabapentin) in patients with neuropathic pain related to spinal cord injury.

OBJECTIVE: To investigate the misuse of gabapentinoids (pregabalin and gabapentin) in patients with neuropathic pain related to spinal cord injury. STUDY DESIGN: Cross-sectional study. SETTING: Outpatient clinic in a physical therapy and rehabilitation hospital. PARTICIPANTS: 127 patients, aged 18-70 years, who had neuropathic pain related to spinal cord injury (SCI) and disease duration of at least 12 months. OUTCOME MEASURES: Gabapentinoid use disorder of the patients was determined based on the DSM-5 diagnostic criteria for substance-related disorders. Patients were divided into 2 groups as those with drug misuse and those without drug misuse. Demographic and clinical information of the patients were compared between the groups. Factors associated with drug misuse were analyzed. RESULTS: The misuse rate was 81.9% in patients using pregabalin and 69.69% in patients using gabapentin. Duration of disease and the Leeds assessment of neuropathic symptoms and signs (LANSS) score were statistically significantly higher in the drug misuse group. A statistically significant difference was found between the groups in terms of marital status, education and income level, and smoking and alcohol use. A statistically significant relationship was observed between drug misuse and duration of disease and LANSS score. CONCLUSION: Misuse of gabapentinoids is prevalent in patients with neuropathic pain related to spinal cord injury. The duration of disease and the severity of NP are associated with misuse. Clinicians should exercise caution when prescribing gabapentinoids to patients with SCI.

Gabapentinoid Prescribing for Carpal Tunnel Syndrome.

BACKGROUND: Gabapentinoids, including gabapentin and pregabalin, are commonly prescribed for neuropathic pain, but robust evidence recommends against using gabapentinoids for the treatment of carpal tunnel syndrome (CTS). We aimed to quantify national prescribing patterns of gabapentinoids for CTS. METHODS: We performed a retrospective population-based cohort study using claims data of gabapentinoid-naïve patients with a new diagnosis of CTS (2009-2016). Our primary outcome was a new gabapentinoid fill for CTS. We assessed temporal trends and characteristics associated with a gabapentinoid fill. Multivariable logistic regression was used to evaluate the association between patient-level factors and a new gabapentinoid fill for CTS. RESULTS: Of the 248 324 previously gabapentinoid-naïve patients with CTS, 9589 patients (4%) filled a gabapentinoid prescription. Sixty-one percent were prescribed by primary care providers or medical subspecialists. Patients with a history of neck pain (odds ratio [OR]: 1.31, 95% confidence interval [CI], 1.25-1.38), back pain (OR: 1.25, 95% CI, 1.20-1.31), arthritis (OR: 1.25, 95% CI, 1.18-1.31), and other pain conditions (OR: 1.26, 95% CI, 1.20-1.31) were associated with an increased odds of a new gabapentinoid fill. In addition, patients with a history of alcohol or substance use disorder were significantly associated with a new gabapentinoid prescription fill (OR: 1.33, 95% CI, 1.20-1.47). CONCLUSIONS: Despite evidence recommending against the use of gabapentinoids for CTS, gabapentinoids were frequently initiated among those with higher risk for misuse, including substance use disorders. Given the effectiveness of bracing or surgery for CTS and the risks associated with gabapentinoids, efforts aimed at disseminating evidence-based treatment for CTS are critical to minimize the harms of gabapentinoid misuse.

Analgesic Efficacy of Gabapentin and Pregabalin in Patients Undergoing Laparoscopic Bariatric Surgeries: a Systematic Review and Meta-analysis.

This meta-analysis investigated the effect of oral gabapentinoids (i.e., pregabalin and gabapentin) on analgesic consumption (i.e., primary outcome) and pain relief (i.e., secondary outcome) in patients following bariatric surgery. Analysis of five eligible trials published between 2010 and 2019 including 363 participants receiving gabapentinoids revealed a significantly lower morphine consumption [mean difference (MD) = - 15.1 mg, p = 0.004; evidence certainty: low] and risk of nausea/vomiting [risk ratio (RR) = 0.49, p = 0.002; evidence certainty: high] at postoperative 6-24 h. There was also a lower pain score at postoperative 0-4 h (MD = - 1.41, p < 0.00001; evidence certainty: low) and 6-12 h (MD = - 0.9, p = 0.007; evidence certainty: low) compared with controls, while pain severity at postoperative 24 h was comparable between two groups. In summary, preoperative oral gabapentinoids optimized postoperative pain outcomes and reduced risk of nausea/vomiting following bariatric surgery.

Review of Voltage-gated Calcium Channel α2δ Subunit Ligands for the Treatment of Chronic Neuropathic Pain and Insight into Structure-activity Relationship (SAR) by Pharmacophore Modeling.

BACKGROUND: Neuropathic pain (NP) is a complex symptom related to nerve damage. The discovery of new drugs for treating chronic NP has been continuing for several decades, while more progress is still needed because of the unsatisfactory efficacy and the side effects of the currently available drugs. Among all the approved drugs for chronic NP, voltage- gated calcium channel (VGCC) α2δ subunit ligands, also known as gabapentinoids, are among the first-line treatment and represent a class of efficacious and relatively safe therapeutic agents. However, new strategies are still needed to be explored due to the unsatisfied response rate. OBJECTIVE: The aim of the study is to review the latest status of the discovery and development of gabapentinoids for the treatment of chronic NP by covering both the marketed and the preclinical/clinical ones. Moreover, it aims to analyze the structure-activity relationship (SAR) of gabapentinoids to facilitate the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit. METHODS: We searched PubMed Central, Embase, Cochrane Library, Web of Science, Scopus, and Espacenet for the literature and patents on diabetic peripheral neuropathic pain, postherpetic neuralgia, fibromyalgia, voltage-gated calcium channel α2δ subunit and related therapeutic agents from incipient to June 10, 2021. The SAR of gabapentinoids was analyzed by pharmacophore modeling using the Phase module in the Schrödinger suite. RESULTS: A variety of gabapentinoids were identified as VGCC α2δ ligands that have ever been under development to treat chronic NP. Among them, four gabapentinoids are marketed, one is in the active late clinical trials, and eight have been discontinued. Pharmacophore models were generated using the phase module in the Schrödinger suite, and common pharmacophores were predicted based on pharmacophoric features and analyzed. CONCLUSION: The latest progress in the discovery and development of gabapentinoids for the treatment of chronic NP was reviewed. Moreover, the structure-activity relationship (SAR) of gabapentinoids has been analyzed by pharmacophore modeling, which will be valuable for the future design of structurally novel therapeutic agents targeting the VGCC α2δ subunit.

Simultaneous quantitative analysis of 39 common toxicological drugs for increased efficiency in an ante- and postmortem laboratory.

BACKGROUND: A novel forensic method was developed to quantitate 39 drugs of toxicological interest for ante-mortem and postmortem analysis. This method was created to combine and replace four existing quantitation methods as well as add three additional compounds of interest and serves to drastically increase the efficiency of the criminalists and reduce the case backlog. The method is currently applied to ante-mortem blood, postmortem blood, urine, liver, brain, and gastric contents. METHODS: The extraction was performed by using a protein precipitation and DPX WAX-S tips with analysis on a Waters® i-class Acquity ultra-performance liquid chromatography with a Phenomenex Kinetex® Column (1.7 µm Biphenyl Å, 2.1 ×100 mm) followed by a Waters® XeVo-TQS tandem mass spectrometer using positive electrospray ionization in multiple reaction monitor mode. The sample volume required for analysis was 0.5 mL, or 0.5 g, an improvement from 4 mL when performing previous methods utilized in the laboratory. RESULTS: The improved method incorporated the 2017 recommended cut-offs for toxicological investigation of driving under the influence of drugs and was validated following the SWGTOX and ANSI/ASB guidelines of method validation. The advantages of analyzing low volume cases and/or detecting drugs previously outside the laboratory's scope of analysis, (such as gabapentin, pregabalin and baclofen) will be presented in two case studies. CONCLUSION: The multi-drug quantitation method allowed for the analysis of 39 drugs including a hydrolysis step, if needed, with only 0.5 mL or 0.5 g of sample. The method condensed two previously un-validated quantitative methods and two additional qualitative methods, which detected many commonly seen drugs, all into a single method. Three additional analytes of interest, gabapentin, pregabalin and baclofen, which it had previously been unable to detect, were added to the new method. The added benefit of these new drugs added both the coroner's investigators in cause of death determination and driving under the influence of drugs investigation especially with the high prevalence of gabapentin.

Multimodal analgesia in neurosurgery: a narrative review.

Pain following brain surgery can compromise the result of surgery. Several pharmacological interventions have been used to prevent postoperative pain in adults undergoing brain surgery. Pain following craniotomy is considered to be moderate to severe during the first two post-operative days. Opioids have been historically the mainstay and are the current prominent strategy for pain treatment. They produce analgesia but may alter respiratory, cardiovascular, gastrointestinal, and neuroendocrine functions. All these side effects may affect the normal postoperative course of craniotomy by affecting neurological function and increasing intracranial pressure. Therefore, their use in neurosurgery is limited, and opioids are used in case of strict necessity or as rescue medication. In addition to opioids, drugs with differing mechanisms of actions target pain pathways, resulting in additive and/or synergistic effects. Some of these agents include acetaminophen/non-steroidal anti-inflammatory drugs (NSAIDs), alpha-2 agonists, NMDA receptor antagonists, gabapentinoids, and local anesthesia techniques. Multimodal analgesia should be a balance between adequate analgesia and less drug-induced sedation, respiratory depression, hypercapnia, nausea, and vomiting, which may increase intracranial pressure. Non-opioid analgesics can be an useful pharmacological alternative in multimodal regimes to manage post-craniotomy pain. This narrative review aims to outline the current clinical evidence of multimodal analgesia for post craniotomy pain control.

Association Between Gabapentinoids and Postoperative Pulmonary Complications in Patients Undergoing Thoracic Surgery.

OBJECTIVE: Perioperative gabapentinoids in general surgery have been associated with an increased risk of postoperative pulmonary complications (PPCs), while resulting in equivocal pain relief. This study's aim was to examine the utilization of gabapentinoids in thoracic surgery to determine the association of gabapentinoids with PPCs and perioperative opioid utilization. DESIGN: A multicenter retrospective cohort study. SETTING: Hospitals in the Premier Healthcare Database from 2012 to 2018. PARTICIPANTS: A total of 70,336 patients undergoing elective open thoracotomy, video-assisted thoracic surgery, and robotic-assisted thoracic surgery. INTERVENTIONS: Propensity score analyses were used to assess the association between gabapentinoids on day of surgery and the primary composite outcome of PPCs, defined as respiratory failure, pneumonia, reintubation, pulmonary edema, and noninvasive and invasive ventilation. Secondary outcomes included invasive and noninvasive ventilation, hospital mortality, length of stay, opioid consumption on day of surgery, and average daily opioid consumption after day of surgery. RESULTS: Overall, 8,142 (12%) patients received gabapentinoids. The prevalence of gabapentin on day of surgery increased from 3.8% in 2012 to 15.9% in 2018. Use of gabapentinoids on day of surgery was associated with greater odds of PPCs (odds ratio [OR] 1.19, 95% CI 1.11-1.28), noninvasive mechanical ventilation (OR 1.30, 95% CI 1.16-1.45), and invasive mechanical ventilation (OR 1.14, 95% CI 1.02-1.28). Secondary outcomes indicated no clinically meaningful associations of gabapentinoid use with opioid consumption, hospital mortality, or length of stay. CONCLUSIONS: Perioperative gabapentinoid administration in elective thoracic surgery may be associated with a higher risk of PPCs and no opioid-sparing effect.

A Systematic Review of the Clinical Use of Gabapentin and Pregabalin in Bipolar Disorder.

Despite its prevalence and disease burden, several chasms still exist with regard to the pharmacotherapy of bipolar disorder (BD). Polypharmacy is commonly encountered as a significant proportion of patients remain symptomatic, and the management of the depressive phase of the illness is a particular challenge. Gabapentin and pregabalin have often been prescribed off-label in spite of a paucity of evidence and clinical practice guidelines to support its use. This systematic review aimed to synthesize the available human clinical trials and inform evidence-based pharmacological approaches to BD management. A total of six randomized, controlled trials (RCTs) and 13 open-label trials involving the use of gabapentin and pregabalin in BD patients were reviewed. Overall, the studies show that gabapentin and its related drug pregabalin do not have significant clinical efficacy as either monotherapy or adjunctive therapy for BD. Gabapentin and pregabalin are probably ineffective for acute mania based on the findings of RCT, with only small open-label trials to support its potential adjunctive role. However, its effects on the long-term outcomes of BD remain to be elucidated. The evidence base was significantly limited by the generally small sample sizes and the trials also had heterogeneous designs and generally high risk of bias.

α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly.

Many neurological disorders show an increased prevalence of GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs), which dramatically alters synaptic function. However, the molecular mechanism underlying this distinct synaptic plasticity remains enigmatic. Here, we show that nerve injury potentiates postsynaptic, but not presynaptic, CP-AMPARs in the spinal dorsal horn via α2δ-1. Overexpressing α2δ-1, previously regarded as a Ca2+ channel subunit, augments CP-AMPAR levels at the cell surface and synapse. Mechanistically, α2δ-1 physically interacts with both GluA1 and GluA2 via its C terminus, inhibits the GluA1/GluA2 heteromeric assembly, and increases GluA2 retention in the endoplasmic reticulum. Consequently, α2δ-1 diminishes the availability and synaptic expression of GluA1/GluA2 heterotetramers in the spinal cord in neuropathic pain. Inhibiting α2δ-1 with gabapentin or disrupting the α2δ-1-AMPAR complex fully restores the intracellular assembly and synaptic dominance of heteromeric GluA1/GluA2 receptors. Thus, α2δ-1 is a pivotal AMPAR-interacting protein that controls the subunit composition and Ca2+ permeability of postsynaptic AMPARs.

Association between preoperative administration of gabapentinoids and 30-day hospital readmission: A retrospective hospital registry study.

STUDY OBJECTIVE: To evaluate the effectiveness of preoperative gabapentinoid administration. DESIGN: Retrospective hospital registry study. SETTING: Tertiary referral center (Boston, MA). PATIENTS: 111,008 adult non-emergency, non-cardiac surgical patients between 2014 and 2018. INTERVENTIONS: Preoperative administration of gabapentinoids (gabapentin or pregabalin). MEASUREMENTS: We tested the primary hypothesis that preoperative gabapentinoid use was associated with lower odds of hospital readmission within 30 days. Contingent on this hypothesis, we examined whether lower intraoperative opioid utilization mediated this effect. Secondary outcome was postoperative respiratory complications. MAIN RESULTS: Gabapentinoid administration was associated with lower odds of readmission (adjusted odds ratio [ORadj] 0.80 [95% CI, 0.75-0.85]; p < 0.001). This effect was in part mediated by lower intraoperative opioid utilization in patients receiving gabapentinoids (8.2% [2.4-11.5%]; p = 0.012). Readmissions for gastrointestinal disorders (ORadj 0.74 [0.60-0.90]; p = 0.003), neuro-psychiatric complications (ORadj 0.66 [0.49-0.87]; p = 0.004), non-surgical site infections (ORadj 0.68 [0.52-0.88; p = 0.004) and trauma or poisoning (ORadj 0.25 [0.16-0.41]; p < 0.001) occurred less frequently in patients receiving gabapentinoids. The risk of postoperative respiratory complications was lower in patients receiving gabapentinoids (ORadj 0.77 [0.70-0.85]; p < 0.001). Lower doses of pregabalin (< 75 mg) and gabapentin (< 300 mg) compared to both, no and high-dose administration of gabapentinoids, were associated with a lower risk of postoperative respiratory complications (ORadj 0.61 [0.50-0.75]; p < 0.001 and ORadj 0.70 [0.53-0.92]; p = 0.012, respectively). These lower gabapentinoid doses prevented 30-day readmission (ORadj 0.74 [0.65-0.85]; p < 0.001). The results were robust in several sensitivity analyses including surgical procedure defined subgroups and patients undergoing ambulatory surgery. CONCLUSIONS: The preoperative use of pregabalin and gabapentin, up to doses of 75 and 300 mg respectively, mitigates the risks of hospital readmission and postoperative respiratory complications which can in part be explained by lower intraoperative opioid use. Further research is warranted to elucidate mechanisms of the preventive action.