Alfaxalone anaesthesia increases brain derived neurotrophic factor levels and preserves postoperative cognition by activating pregnane-X receptors: an in vitro study and a double blind randomised controlled trial.

Background: Alfaxalone is a fast acting intravenous anaesthetic with high therapeutic index. It is an analogue of the naturally-occurring neurosteroid allopregnanolone responsible for maintenance of cognition and neuroprotection by activation of brain pregnane X receptors and consequent increased production of mature brain-derived neurotrophic factor (m-BDNF). Two studies are reported here: an in vitro study investigated whether alfaxalone activates human pregnane X receptors (h-PXR) as effectively as allopregnanolone; and a clinical study that measured postoperative changes in serum m-BDNF and cognition in patients after alfaxalone anaesthesia compared with propofol and sevoflurane.

Pharmacokinetic and Pharmacodynamic Analysis of Alfaxalone Administered as a Bolus Intravenous Injection of Phaxan in a Phase 1 Randomized Trial.

Background: Previous formulations of alfaxalone have shown it to be a fast-acting intravenous anesthetic with high therapeutic index. Alfaxalone has been reformulated for human use as Phaxan, an aqueous solution of 10 mg/mL of alfaxalone and 13% betadex. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of alfaxalone given as a bolus intravenous injection of this formulation to human male volunteers.

A Phase 1c Trial Comparing the Efficacy and Safety of a New Aqueous Formulation of Alphaxalone with Propofol.

Background: Phaxan™ (PHAX, Chemic Labs, Canton, MA) is an aqueous solution of 10 mg/mL alphaxalone and 13% 7-sulfobutylether β-cyclodextrin (betadex). In preclinical studies, PHAX is a fast onset-offset IV anesthetic like propofol, but causes less cardiovascular depression. This first-in-man study was designed to find the anesthetic dose of PHAX and to compare it with an equivalent dose of propofol for safety, efficacy, and quality of recovery from anesthesia and sedation.

Long-Term Antihyperalgesic and Opioid-Sparing Effects of 5-Day Ketamine and Morphine Infusion ("Burst Ketamine") in Diabetic Neuropathic Rats.

Background: "Burst ketamine" (BK) is the long-term infusion of subanesthetic ketamine in combination with an opioid. It is used clinically with mixed success to provide long-term pain relief and improve opioid response in patients. BK has not been simulated preclinically, therefore, its effectiveness was investigated in an animal model of neuropathic pain--streptozotocin-induced diabetic neuropathy.

Alphaxalone Reformulated: A Water-Soluble Intravenous Anesthetic Preparation in Sulfobutyl-Ether-β-Cyclodextrin.

Background: Alphaxalone is a neuroactive steroid anesthetic that is poorly water soluble. It was formulated in 1972 as Althesin® using Cremophor® EL, a nonionic surfactant additive. The product was a versatile short-acting IV anesthetic used in clinical practice in many countries from 1972 to 1984.

Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis.

Objective: Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2-3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain.

Intravenous injection of leconotide, an omega conotoxin: synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain.

Objective: Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain.

Studies of synergy between morphine and a novel sodium channel blocker, CNSB002, in rat models of inflammatory and neuropathic pain.

Objective: This study determined the antihyperalgesic effect of CNSB002, a sodium channel blocker with antioxidant properties given alone and in combinations with morphine in rat models of inflammatory and neuropathic pain.

Design: Dose response curves for nonsedating doses of morphine and CNSB002 given intraperitoneally alone and together in combinations were constructed for antihyperalgesic effect using paw withdrawal from noxious heat in two rat pain models: carrageenan-induced paw inflammation and streptozotocin (STZ)-induced diabetic neuropathy.

Results: The maximum nonsedating doses were: morphine, 3.

CNSB004 (Leconotide) causes antihyperalgesia without side effects when given intravenously: a comparison with ziconotide in a rat model of diabetic neuropathic pain.

Objective: Leconotide is an omega-conotoxin that blocks neuronal voltage sensitive calcium channels. This study compared the antihyperalgesic potencies of leconotide and ziconotide given intravenously alone and in combinations with a potassium channel modulator flupirtine, given intraperitoneally, in a rat model of diabetic neuropathic pain.

Design: Rats were given streptozotocin (150 mg/kg ip) to induce diabetic neuropathy and hyperalgesia.

Prevention and reversal of morphine tolerance by the analgesic neuroactive steroid alphadolone.

Objective: Alphadolone is a neuroactive steroid that causes antinociception in rats and analgesia in humans by interaction with spinal cord GABA(A) receptors. This study investigated whether alphadolone could affect morphine tolerance.

Methods: Morphine tolerance was induced in rats with subcutaneous sustained release morphine emulsion (M-SR; 125 mg/kg/day).

Combination therapy with flupirtine and opioid: open-label case series in the treatment of neuropathic pain associated with cancer.

Objectives: This study is a case series that was designed to provide data on the efficacy and the incidence and duration of adverse effects of flupirtine in the treatment of cancer-related neuropathic pain.

Design: This was an 8-day, open-label study of palliative care patients with neuropathic pain despite maximal opioid treatment. They received an initial dose of flupirtine 100 mg orally four times daily (QID) that could be titrated.

Combination therapy with flupirtine and opioid: studies in rat pain models.

Objectives: Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ2-3 potassium channel opener. These experiments were performed to see if this property could be useful in treating pain states characterized by central sensitization with the drug either given alone or in combination with morphine.

Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain[ISRCTN83088383].

BACKGROUND: Despite preclinical evidence suggesting a synergistic interaction between ketamine and opioids promoting analgesia, several clinical trials have not identified dosing regimens capable of eliciting a benefit in the co-administration of ketamine with opioids. METHODS: Ten healthy volunteers participated in a double blinded, randomised, placebo controlled, crossover laboratory study in order to determine whether a low dose of ketamine potentiated the antinociceptive effect of fentanyl without causing an increase in sedative effects. A battery of tests was used to assess both nociception and sedation including electrical current, pressure, thermal stimuli, psychometric tests, and both subjective and objective scores of sedation.

A simple, fast, easy method to identify the evidence base in pain-relief research: validation of a computer search strategy used alone to identify quality randomized controlled trials.

Unlabelled: Clinicians need a simple, fast, reliable, and inexpensive way of identifying the evidence base relevant to their clinical practice. It is often believed that the only way to identify all relevant evidence is to perform hand-searches of the literature to supplement computer searches; this is complex and labor intensive. However, most of quality randomized controlled trials cited in systematic reviews in pain medicine are listed in computer databases.

Intrathecal midazolam II: combination with intrathecal fentanyl for labor pain.

Unlabelled: Recent investigations have sought to improve intrathecal analgesia by combining opioids with other classes of analgesics. In this study we assessed the ability of intrathecal midazolam to increase the potency and duration of the analgesic effects of intrathecal fentanyl without causing adverse effects. Thirty parturients with cervical dilations 2-6 cm were randomized to receive either intrathecal midazolam 2 mg, fentanyl 10 micro g, or both combined to initiate analgesia.

Intrathecal midazolam I: a cohort study investigating safety.

Unlabelled: Despite conflicting evidence regarding the safety of intrathecal midazolam from animal investigations, its clinical use is increasing. We investigated the potential of intrathecal midazolam to produce symptomatology suggestive of neurological damage. This study compared two cohorts of patients who received intrathecal anesthesia with or without intrathecal midazolam (2 mg).

The spinal antinociceptive effects of cholinergic drugs in rats: receptor subtype specificity in different nociceptive tests.

Background: Several studies have shown that muscarinic cholinergic agonists cause antinociception in humans and animals when given by both spinal and non-spinal parenteral routes. It is uncertain which subtype of muscarinic receptor is involved in spinally mediated antinociceptive effects caused by these drugs. The cholinergic receptor agonists McN-A-343 (M1 selective; 3.

Intrathecal midazolam for the treatment of chronic mechanical low back pain: a controlled comparison with epidural steroid in a pilot study.

This paper describes a prospective, double blind, randomised and dummy-controlled trial in 28 patients with chronic mechanical low back pain presenting to the York Pain Clinic. The therapeutic effects of epidural methyl prednisolone (80 mg) were compared with intrathecal midazolam (2 mg). All the patients had pain for a considerable length of time (range: 1-35 years) and all had received previous treatments which had failed.