Use of epidurography in the perioperative and acute pain setting.

Ensuring proper placement of epidural catheters is critical to improving their reliability for pain control and maintaining confidence in their continued use. This article will seek to address the role of objective confirmation of successful epidural placement via either single view or continuous epidural contrast studies, each creating an 'epidurogram.' Furthermore, the pertinent anatomical corollaries of continuous fluoroscopy used frequently in chronic pain medicine, from which these techniques emerged, will be addressed. Technical radiographic information needed to better understand and troubleshoot these studies is also included. Image examples which highlight the patterns key for successful interpretation of epidurograms will be provided. The aim of this paper was to provide an anesthesiologist unfamiliar with fluoroscopic evaluation of epidural catheters with the tools necessary to successfully conduct and interpret such an examination.

Impact of a perioperative oral opioid substitution protocol during the nationwide intravenous opioid shortage: A single center, interrupted time series with segmented regression analysis.

INTRODUCTION: To mitigate the recent nationwide shortage of intravenous opioids, we developed a standardized perioperative oral opioid guideline anchored with appropriate use of nonopioid analgesia, neuraxial and loco-regional techniques. We hypothesize that adoption of this new guideline was associated with: 1) equivalent patient reported pain scores in the post-anesthesia care unit (PACU); and 2) equivalent total opioid use (oral and parenteral) during the perioperative period. METHODS: Cases performed from July 1, 2017 to May 31, 2019 were screened. All opioids administered were converted to intravenous morphine milligram equivalents. Segmented regression analyses of interrupted time series were performed examining the change in opioid use, PACU pain scores and number of non-opioid analgesic medications used before and after the protocol implementation in April 2018. RESULTS: After exclusions, 29, 621 cases were included in the analysis. No significant differences in demographic, ASA status, case length and surgical procedure type were present in the pre and post-intervention period. A significant decrease in total (Estimate: -39.9 mg, SE: 6.9 mg, p < 0.001) and parenteral (Estimate: -51.6 mg, SE: 7.1 mg, p < 0.001) opioid use with a significant increase in oral opioid use (Estimate: 9.4 mg, SE: 1.1 mg, p < 0.001) was noted after the intervention. Pain scores were not significantly different between the pre- and post-intervention period (Estimate: 0.05, SE: 0.13, p = 0.69). CONCLUSION: We report our experience with a primary perioperative oral based opioid regimen that is associated with decreased total opioid consumption and equivalent patient reported pain scores.

A review and survey of policies utilized for interventional pain procedures: a need for consensus.

BACKGROUND: Other than the newly published anticoagulation guidelines, there are currently few recommendations to assist pain medicine physicians in determining the safety parameters to follow when performing interventional pain procedures. Little information exists regarding policies for oral intake, cumulative steroid dose limits, driving restrictions with and without sedation, and routine medication use for interventional procedures. METHODS: A 16-question survey was developed on common policies currently in use for interventional pain procedures. The questionnaire was distributed through the American Society of Regional Anesthesia and Pain Medicine and American Academy of Pain Medicine. We sought to statistically analyze the range of policies being used by pain medicine physicians and to determine if there are any commonly accepted standards. RESULTS: A total of 337 physicians out of 4037 members responded to our survey with a response rate of 8.4%. A total of 82% of these respondents used a sedative agent while performing an interventional pain procedure. The majority of respondents required drivers after procedures, except after trigger points. A total of 47% indicated that they have an nil per os (NPO) policy for procedures without sedation. A total of 98% reported that they had an anticoagulation policy before an interventional procedure. A total of 17% indicated that the interval between steroid doses was <2 weeks, while 53% indicated that they waited 2-4 weeks between steroid doses. CONCLUSION: Our study has clearly demonstrated a wide variation in the current practice among physicians regarding sedation, NPO status, steroid administration, and the need for designated drivers. There was much higher endorsement of policies regarding anticoagulation. There is an obvious need for evidence-based guidelines for these aspects of interventional pain care to improve patient safety and minimize the risk of adverse events.

Hyperexcitability of rat thalamocortical networks after exposure to general anesthesia during brain development.

Prevailing literature supports the idea that common general anesthetics (GAs) cause long-term cognitive changes and neurodegeneration in the developing mammalian brain, especially in the thalamus. However, the possible role of GAs in modifying ion channels that control neuronal excitability has not been taken into consideration. Here we show that rats exposed to GAs at postnatal day 7 display a lasting reduction in inhibitory synaptic transmission, an increase in excitatory synaptic transmission, and concomitant increase in the amplitude of T-type calcium currents (T-currents) in neurons of the nucleus reticularis thalami (nRT). Collectively, this plasticity of ionic currents leads to increased action potential firing in vitro and increased strength of pharmacologically induced spike and wave discharges in vivo. Selective blockade of T-currents reversed neuronal hyperexcitability in vitro and in vivo. We conclude that drugs that regulate thalamic excitability may improve the safety of GAs used during early brain development.

Reversal of neuropathic pain in diabetes by targeting glycosylation of Ca(V)3.2 T-type calcium channels.

It has been established that Ca(V)3.2 T-type voltage-gated calcium channels (T-channels) play a key role in the sensitized (hyperexcitable) state of nociceptive sensory neurons (nociceptors) in response to hyperglycemia associated with diabetes, which in turn can be a basis for painful symptoms of peripheral diabetic neuropathy (PDN). Unfortunately, current treatment for painful PDN has been limited by nonspecific systemic drugs with significant side effects or potential for abuse. We studied in vitro and in vivo mechanisms of plasticity of Ca(V)3.2 T-channel in a leptin-deficient (ob/ob) mouse model of PDN. We demonstrate that posttranslational glycosylation of specific extracellular asparagine residues in Ca(V)3.2 channels accelerates current kinetics, increases current density, and augments channel membrane expression. Importantly, deglycosylation treatment with neuraminidase inhibits native T-currents in nociceptors and in so doing completely and selectively reverses hyperalgesia in diabetic ob/ob mice without altering baseline pain responses in healthy mice. Our study describes a new mechanism for the regulation of Ca(V)3.2 activity and suggests that modulating the glycosylation state of T-channels in nociceptors may provide a way to suppress peripheral sensitization. Understanding the details of this regulatory pathway could facilitate the development of novel specific therapies for the treatment of painful PDN.

TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent.

Several agents that are preferential T-type calcium (T-channel) blockers have shown promise as being effective in alleviating acute and chronic pain, suggesting an urgent need to identify even more selective and potent T-channel antagonists. We used small, acutely dissociated dorsal root ganglion (DRG) cells of adult rats to study the in vitro effects of 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), a derivative of 4-aminomethyl-4-fluoropiperdine, on T currents, as well as other currents known to modulate pain transmission. We found that TTA-P2 potently and reversibly blocked DRG T currents with an IC(50) of 100 nM and stabilized channel in the inactive state, whereas high-voltage-activated calcium and sodium currents were 100- to 1000-fold less sensitive to channel blocking effects. In in vivo studies, we found that intraperitoneal injections of 5 or 7.5 mg/kg TTA-P2 reduced pain responses in mice in phases 1 and 2 of the formalin test. Furthermore, TTA-P2, at 10 mg/kg i.p., selectively and completely reversed thermal hyperalgesia in diabetic rats treated with streptozocin but had no effect on the nociceptive response of healthy animals. The antihyperalgesic effects of TTA-P2 in diabetic rats were completely abolished by administration of oligonucleotide antisense for Ca(V)3.2 isoform of T channels. Thus, TTA-P2 is not only the most potent and selective blocker of T channels in sensory neurons yet described, but it also demonstrates the potential for the pharmacological effectiveness of this approach in addressing altered nociceptive responses in animal models of both inflammatory and neuropathic pain.

Free radical signalling underlies inhibition of CaV3.2 T-type calcium channels by nitrous oxide in the pain pathway.

Nitrous oxide (N2O, laughing gas) has been used as an anaesthetic and analgesic for almost two centuries, but its cellular targets remain unclear. Here, we present a molecular mechanism of nitrous oxide's selective inhibition of CaV3.2 low-voltage-activated (T-type) calcium channels in pain pathways. Using site-directed mutagenesis and metal chelators such as diethylenetriamine pentaacetic acid and deferoxamine, we reveal that a unique histidine at position 191 of CaV3.2 participates in a critical metal binding site, which may in turn interact with N2O to produce reactive oxygen species (ROS). These free radicals are then likely to oxidize H191 of CaV3.2 in a localized metal-catalysed oxidation reaction. Evidence of hydrogen peroxide and free radical intermediates is given in that N2O inhibition of CaV3.2 channels is attenuated when H2O2 is neutralized by catalase. We also use the adrenochrome test as an indicator of ROS in vitro in the presence of N2O and iron. Ensuing in vivo studies indicate that mice lacking CaV3.2 channels display decreased analgesia to N2O in response to formalin-induced inflammatory pain. Furthermore, a superoxide dismutase and catalase mimetic, EUK-134, diminished pain responses to formalin in wild-type mice, but EUK-134 and N2O analgesia were not additive. This suggests that reduced ROS levels led to decreased inflammation, but without the presence of ROS, N2O was not able to provide additional analgesia. These findings reveal a novel mechanism of interaction between N2O and ion channels, furthering our understanding of this widely used analgesic in pain processing.