Ketamine for Non-Neuropathic Pain

Chronic pain is one of the leading causes of years lost to disability, as most of the time it is refractory to conventional treatment. Recent advances in understanding the pain mechanisms have favored the use of ketamine as a rescue agent in refractory chronic pain conditions, as it has potential modulating effect on both sensory-discriminative and affective motivational components of pain. Preclinical studies also suggested the antinociceptive effect of sub anesthetic dose of ketamine against central and peripheral neuropathic pain conditions and non-neuropathic pain conditions such as inflammatory and nociceptive pain states. Subanesthetic infusion of ketamine along with adjuvants such as midazolam and clonidine is found to reduce the psychomimetic and cardiovascular side effects of ketamine. Even though the consensus guidelines for intravenous use of ketamine for chronic pain advocate the use of ketamine only for complex regional pain syndrome, various other clinical studies suggested its role in other refractory painful conditions. Hence the present topic focuses specifically on the effect of ketamine on non-neuropathic pain conditions such as complex regional pain syndrome, fibromyalgia, headache, ischemic limb pain, etc. Many studies had shown that ketamine not only reduces the pain scores but also the analgesic medications, which further improves the well-being and quality of life.

Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent

Background One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. Methods A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. Results A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01–0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. Conclusions Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

Severe neonatal pulmonary artery hypertension rescued with vasopressin

An inborn term neonate weighing 2600 g developed meconium aspiration syndrome at birth. Baby had respiratory failure requiring high-frequency oscillatory ventilation support at 15 hours of life. He additionally developed hypotension with left ventricular dysfunction noted on point-of-care echocardiography (POCE), which required dopamine and epinephrine infusions. At 28 hours of life, he was started on inhaled nitric oxide (iNO), followed by milrinone due to hypoxaemic respiratory failure and the POCE revealed severe pulmonary artery hypertension (PAH). As PAH was refractory to iNO and milrinone, vasopressin was added which resulted in rapid improvement in oxygenation and normalisation of pulmonary artery pressures. Baby was weaned off from vasoactive support in the next 120 hours. Vasopressin proved to be the rescue agent in this case of iNO refractory PAH without any side effects during therapy. Baby was successfully extubated on day 18 and was discharged with a normal neurological examination finding.

An engineered factor Va prevents bleeding induced by direct-acting oral anticoagulants by different mechanisms

Control of bleeding with direct-acting oral anticoagulants (DOACs) remains an unmet clinical need. Activated superFactor V (superFVa) is an engineered activated protein C (APC)–resistant FVa variant with enhanced procoagulant activity resulting from an A2/A3 domain disulfide bond and was studied here for control of DOAC-induced bleeding. SuperFVa reversed bleeding induced by FXa inhibitors (rivaroxaban, apixaban), and the FIIa inhibitor dabigatran in BalbC mice. The blocking anti-protein C and APC [(A)PC] antibody SPC-54 also reduced FXa inhibitor induced bleeding similar to superFVa, whereas dabigatran-induced bleeding was not affected. This indicated that sufficient APC was generated to contribute to bleeding in the presence of FXa inhibitors, but not in the presence of dabigatran, suggesting that mechanisms contributing to bleeding differed for FXa and FIIa inhibitors. Despite different mechanisms contributing to bleeding, superFVa effectively reduced bleeding for all DOACs, indicating the versatility of superFVa’s properties that contribute to its universal prohemostatic effects for DOAC associated bleeding. Supported by thrombin generation assays on endothelial cells in normal plasma spiked with DOACs and patient plasma anticoagulated with DOACs, 3 complementary mechanisms were identified by which superFVa achieved DOAC class-independent prohemostatic efficiency. These mechanisms are resistance to inactivation by APC, overcoming the FV activation threshold, and maximizing the efficiency of the prothrombinase complex when the available FXa is increased by FVIIa-based prohemostatics. In summary, it is this versatility of superFVa that delineates it from other prohemostatic agents as a promising class-independent rescue agent in bleeding situations associated with DOACs.

Sugammadex: Efficacy and Practicality in the Dental Office

Sugammadex is a novel drug capable of reversing paralysis induced by the common steroidal nondepolarizing neuromuscular blocking drugs, rocuronium and vecuronium. Reversal is complete at any depth of blockade dependent on the dose of sugammadex administered. This allows rocuronium to be used as a rescue agent in scenarios where succinylcholine is contraindicated. Sugammadex is considered a safe drug with minimal side effects compared with traditional reversal with neostigmine and glycopyrrolate. This article features a case report where succinylcholine was undesirable and rapid reversal of paralysis with sugammadex was used during general anesthesia for dentistry.