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Nature Communications Jun 2023Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other...
Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Na channels, the binding mode of most Na-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na channels summarized from the present and previous structures.
Topics: Humans; Analgesics; Carbamazepine; Lacosamide; Pain; Protein Domains; Voltage-Gated Sodium Channels; Voltage-Gated Sodium Channel Blockers
PubMed: 37270609
DOI: 10.1038/s41467-023-38942-3 -
JAMA Network Open Aug 2023Dural-puncture epidural (DPE) and standard epidural are common modes of neuraxial labor analgesia. Little is known about conversion of DPE-initiated labor analgesia to... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Dural-Puncture Epidural vs Standard Epidural for Epidural Extension on Onset Time of Surgical Anesthesia in Elective Cesarean Delivery: A Randomized Clinical Trial.
IMPORTANCE
Dural-puncture epidural (DPE) and standard epidural are common modes of neuraxial labor analgesia. Little is known about conversion of DPE-initiated labor analgesia to surgical anesthesia for cesarean delivery.
OBJECTIVE
To determine whether DPE provides a faster onset and better-quality block compared with the standard epidural technique for cesarean delivery.
DESIGN, SETTING, AND PARTICIPANTS
This double-blind, randomized clinical trial was conducted between April 2019 and October 2022 at a tertiary care university hospital (University of Arkansas for Medical Sciences). Participants included women aged 18 years and older undergoing scheduled cesarean delivery with a singleton pregnancy.
INTERVENTIONS
Participants were randomized to receive DPE or standard epidural in the labor and delivery room. A T10 sensory block was achieved and maintained using a low concentration of bupivacaine with fentanyl through the epidural catheter until the time of surgery. Epidural extension anesthesia was initiated in the operating room.
MAIN OUTCOMES AND MEASURES
The primary outcome was the time taken from chloroprocaine administration to surgical anesthesia (T6 sensory block). The secondary outcome was the quality of epidural anesthesia, as defined by a composite of the following factors: (1) failure to achieve a T10 bilateral block preoperatively in the delivery room, (2) failure to achieve a surgical block at T6 within 15 minutes of chloroprocaine administration, (3) requirement for intraoperative analgesia, (4) repeat neuraxial procedure, and (5) conversion to general anesthesia.
RESULTS
Among 140 women (mean [SD] age, 30.1 [5.2] years), 70 were randomized to the DPE group, and 70 were randomized to the standard epidural group. The DPE group had a faster onset time to surgical anesthesia compared with the standard epidural group (median [IQR], 422 [290-546] seconds vs 655 [437-926] seconds; median [IQR] difference, 233 [104-369] seconds). The composite rates of lower quality anesthesia were 15.7% (11 of 70 women) in the DPE group and 36.3% (24 of 66 women) in the standard epidural group (odds ratio, 0.33; 95% CI, 0.14-0.74; P = .007).
CONCLUSIONS AND RELEVANCE
Anesthesia initiated following a DPE technique resulted in faster onset and improved block quality during epidural extension compared with initiation with a standard epidural technique. Further studies are needed to confirm these findings in the setting of intrapartum cesarean delivery.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03915574.
Topics: Pregnancy; Female; Humans; Adult; Analgesia, Obstetrical; Labor, Obstetric; Anesthesia, Epidural; Punctures
PubMed: 37526934
DOI: 10.1001/jamanetworkopen.2023.26710 -
Journal of Clinical Medicine Apr 2024: In the context of the current opioid crisis, non-pharmacologic approaches to pain management have been considered important alternatives to the use of opioids or... (Review)
Review
: In the context of the current opioid crisis, non-pharmacologic approaches to pain management have been considered important alternatives to the use of opioids or analgesics. Advancements in nano and quantum technology have led to the development of several nanotransporters, including nanoparticles, micelles, quantum dots, liposomes, nanofibers, and nano-scaffolds. These modes of nanotransporters have led to the development of new drug formulations. In pain medicine, new liposome formulations led to the development of DepoFoam™ introduced by Pacira Pharmaceutical, Inc. (Parsippany, NJ, USA). This formulation is the base of DepoDur™, which comprises a combination of liposomes and extended-release morphine, and Exparel™, which comprises a combination of liposomes and extended-release bupivacaine. In 2021, Heron Therapeutics (San Diego, CA, USA) created Zynrelef™, a mixture of bupivacaine and meloxicam. Advancements in nanotechnology have led to the development of devices/patches containing millions of nanocapacitors. Data suggest that these nanotechnology-based devices/patches reduce acute and chronic pain. : Google and PubMed searches were conducted to identify studies, case reports, and reviews of medical nanotechnology applications with a special focus on acute and chronic pain. This search was based on the use of keywords like nanotechnology, nano and quantum technology, nanoparticles, micelles, quantum dots, liposomes, nanofibers, nano-scaffolds, acute and chronic pain, and analgesics. This review focuses on the role of nanotechnology in acute and chronic pain. : (1) Nanotechnology-based transporters. DepoDur™, administered epidurally in 15, 20, or 25 mg single doses, has been demonstrated to produce significant analgesia lasting up to 48 h. Exparel™ is infiltrated at the surgical site at the recommended dose of 106 mg for bunionectomy, 266 mg for hemorrhoidectomy, 133 mg for shoulder surgery, and 266 mg for total knee arthroplasty (TKA). Exparel™ is also approved for peripheral nerve blocks, including interscalene, sciatic at the popliteal fossa, and adductor canal blocks. The injection of Exparel™ is usually preceded by an injection of plain bupivacaine to initiate analgesia before bupivacaine is released in enough quantity from the depofoarm to be pharmacodynamically effective. Finally, Zynrelef™ is applied at the surgical site during closure. It was initially approved for open inguinal hernia, abdominal surgery requiring a small-to-medium incision, foot surgery, and TKA. (2) Nanotechnology-based devices/patches. Two studies support the use of nanocapacitor-based devices/patches for the management of acute and chronic pain. A randomized study conducted on patients undergoing unilateral primary total knee (TKA) and total hip arthroplasty (THA) provided insight into the potential value of nanocapacitor-based technology for the control of postoperative acute pain. The results were based on 2 studies, one observational and one randomized. The observational study was conducted in 128 patients experiencing chronic pain for at least one year. This study suggested that compared to baseline, the application of a nanocapacitor-based Kailo™ pain relief patch on the pain site for 30 days led to a time-dependent decrease in pain and analgesic use and an increase in well-being. The randomized study compared the effects of standard of care treatment to those of the same standard of care approach plus the use of two nanocapacitor-based device/patches (NeuroCuple™ device) placed in the recovery room and kept in place for three days. The study demonstrated that the use of the two NeuroCuple™ devices was associated with a 41% reduction in pain at rest and a 52% decrease in the number of opioid refills requested by patients over the first 30 days after discharge from the hospital. : For the management of pain, the use of nano-based technology has led to the development of nano transporters, especially focus on the use of liposome and nanocapacitors. The use of liposome led to the development of DepoDur™, bupivacaine Exparel™ and a mixture of bupivacaine and meloxicam (Zynrelef™) and more recently lidocaine liposome formulation. In these cases, the technology is used to prolong the duration of action of drugs included in the preparation. Another indication of nanotechnology is the development of nanocapacitor device or patches. Although, data obtained with the use of nanocapacitors are still limited, evidence suggests that the use of nanocapacitors devices/patches may be interesting for the treatment of both acute and chronic pain, since the studies conducted with the NeuroCuple™ device and the based Kailo™ pain relief patch were not placebo-controlled, it is clear that additional placebo studies are required to confirm these preliminary results. Therefore, the development of a placebo devices/patches is necessary. : Increasing evidence supports the concept that nanotechnology may represent a valuable tool as a drug transporter including liposomes and as a nanocapacitor-based device/patch to reduce or even eliminate the use of opioids in surgical patients. However, more studies are required to confirm this concept, especially with the use of nanotechnology incorporated in devices/patches.
PubMed: 38731140
DOI: 10.3390/jcm13092611 -
Anesthesiology May 2024
Topics: Bupivacaine; Liposomes
PubMed: 38592359
DOI: 10.1097/ALN.0000000000004935 -
Anesthesiology May 2024
Topics: Bupivacaine
PubMed: 38592361
DOI: 10.1097/ALN.0000000000004934