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Differences in pain processing, muscle structure and function have been reported in patients with low back pain (LBP) with different grades of pain chronicity.
Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.
Over the past number of years, N-methyl-D-aspartate (NMDA) inhibitory drugs, like ketamine, have been introduced as adjuvant treatments for postoperative acute pain, within a multimodal approach. A further extension of this strategy could be the use of opioids with NMDA receptor (NMDAr) antagonism activity for control of postoperative pain. Methadone has a unique pharmacodynamic profile: it is both a μ-agonist and an NMDAr-blocker.
Synthetic opioids, including fentanyl and its analogues, have therapeutic efficacy in analgesia and anesthesia. However, their illicit use in the U.S. has increased, and contributed to the number one cause of death for adults 18-50 years old. Fentanyl and the heroin metabolite, morphine, induce respiratory depression that can be treated with the mu opioid receptor (MOR) antagonist, naloxone. With higher or more rapid dosing, fentanyl, more than morphine, causes chest wall rigidity, and can also induce rapid onset laryngospasm. Because non-MORs could mediate differing clinical manifestations, we examined the interactions of fentanyl and morphine at recombinant human neurotransmitter transporters, G protein-coupled receptors, and the NMDA glutamate receptor. Both drugs were agonists at MOR, kappa, and delta opioid receptors. Morphine had little or no affinity at other human receptors and transporters (Ki or IC value >100μM). However, fentanyl had Ki values of 1,407nM and 1,100nM at α1A and α1B adrenoceptor subtypes, respectively, Ki values of 1,049nM and 1,670nM at dopamine D4.4 and D1 receptor subtypes, respectively, and also blocked [H]neurotransmitter uptake by the vesicular monoamine transporter 2 (VMAT2) (IC = 911nM). Pharmacokinetic models indicate that these Ki and IC values are pharmacologically relevant. Fentanyl had little affinity for other receptors or transporters. Thus, noradrenergic disposition at specific receptor subtypes in relevant organs may play a role in respiratory and cardiothoracic effects of fentanyl. Data suggest that less selective fentanyl receptor pharmacology could play a role in the different clinical effects of morphine compared to fentanyl, including fentanyl-induced deaths following illicit use. SIGNIFICANCE STATEMENT: The synthetic opioid, fentanyl, induces different clinical effects including rapid onset muscular rigidity, vocal cord closure and rapid death, than the heroin metabolite, morphine. Our data indicate for the first time that the two drugs have very different effects at recombinant human neurotransmitter receptors and transporters that might explain those clinical differences.
The goal of this research is the identification of new treatments for neuropathic pain. We characterized the GABAergic system of immortalized mouse and human microglia using electrophysiology and qRT-PCR. Cells from both species exhibited membrane current changes in response to γ-aminobutyric acid, with an EC50 of 260 nM and 1940 nM, respectively. Human microglia expressed high levels of the γ-aminobutyric acid type A receptor (GABAAR) α3 subunit, which can assemble with β1 and γ2/δ subunits to form functional GABAARs. Mouse microglia contained α2, α3 and α5, in addition to β1-3, γ1-2 and δ, mRNA, enabling a more diverse array of GABAARs than human microglia. Benzodiazepines are well-established modulators of GABAAR activity, prompting a screen of a library of diverse benzodiazepines in microglia for cellular effects. Several active compounds were identified by reduction of nitric oxide (NO) in interferon gamma and lipopolysaccharide activated microglia. However, further investigation with GABAAR antagonists flumazenil, picrotoxin, and bicuculline demonstrated that GABAARs were not linked to the NO response. A screen of 48 receptors identified the κ-opioid receptor and to a lesser extent the µ-opioid receptor as molecular targets, with opioid receptor antagonist norbinaltorphimine reversing benzodiazepine induced reduction of microglial NO. Functional assays identified the downregulation of inducible NO synthase as the mode of action of imidazodiazepines MP-IV-010 and GL-IV-03. Like other κ-opioid receptor agonists, GL-IV-03 reduced the agitation response in both phases of the formalin nociception test. However, unlike other κ-opioid receptor agonists, MP-IV-010 and GL-IV-03 did not impair sensorimotor coordination in mice. Thus, MP-IV-010 and GL-IV-03 represent a new class of non-sedative drug candidates for inflammatory pain.
The role of voltage-gated sodium (Na) channels in pain perception is indisputable. Of particular interest as targets for the development of pain therapeutics are the tetrodotoxin-resistant isoforms Na1.8 and Na1.9, based on animal as well as human genetic studies linking these ion channel subtypes to the pathogenesis of pain. However, only a limited number of inhibitors selectively targeting these channels have been reported. HSTX-I is a peptide toxin identified from saliva of the leech Haemadipsa sylvestris. The native 23-residue peptide, stabilised by two disulfide bonds, has been reported to inhibit rat Na1.8 and mouse Na1.9 with low micromolar activity, and may therefore represent a scaffold for development of novel modulators with activity at human tetrodotoxin-resistant Na isoforms. We synthetically produced this hydrophobic peptide in high yield using a one-pot oxidation and single step purification and determined the three-dimensional solution structure of HSTX-I using NMR solution spectroscopy. However, in our hands, the synthetic HSTX-I displayed only very modest activity at human Na1.8 and Na1.9, and lacked analgesic efficacy in a murine model of inflammatory pain.
To examine whether sleep disturbance modifies the association between physical activity and incident pain.
The aetiology of painful diabetic neuropathy is unclear. We have evaluated vitamin D levels in diabetic patients with and without painful neuropathy. Forty-three patients with type 1 diabetes and painless (DPN) (n = 20) or painful (PDN) (n = 23) neuropathy and 14 non-diabetic healthy control subjects (C) underwent assessment of neurologic deficits, quantitative sensory testing (QST), electrophysiology, skin biopsy, corneal confocal microscopy (CCM) and measurement of serum 25(OH)D. There were no significant differences for age, BMI, HbA1c, lipids, neurological deficits, QST, electrophysiology, intra-epidermal nerve fibre density (IENFD) and corneal nerve morphology between patients with DPN and PDN. Both positive (hyperalgesia and allodynia) and negative symptoms (paraesthesia and numbness) of diabetic neuropathy were greater in PDN compared to DPN (P = 0.009 and P = 0.02 respectively). Serum 25(OH)D level were significantly lower in PDN (24.0 ± 14.1 ng/mL) compared to DPN (34.6 ± 15.0 ng/mL, P = 0.01) and controls (34.1 ± 8.6 ng/mL, P = 0.03). The odds ratio in favour of painful diabetic neuropathy was 9.8 (P = 0.003 (95% CI 2.2-76.4) for vitamin D deficiency (<20 ng/mL) and 4.4 (P = 0.03 [95% CI 1.1-19.8]) for vitamin D insufficiency (<30 ng/mL). This study suggests that vitamin D deficiency and insufficiency are associated with painful diabetic neuropathy. This article is protected by copyright. All rights reserved.
Opioid use has increased to epidemic levels over the past decade within the United States, particularly among vulnerable populations. This retrospective study aimed to evaluate rates of prolonged opioid use in the Veteran population after thoracic surgery and identify specific risk clusters.