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Fibromyalgia Syndrome: Canadian Clinical Working Case Definition, Diagnostic and Treatment Protocols–A Consensus Document
Published in I. Jon Russell, The Fibromyalgia Syndrome: A Clinical Case Definition for Practitioners, 2020
Anil Kumar Jain, Bruce M. Carruthers, Maijorie I. van de Sande, Stephen R. Barron, C. C. Stuart Donaldson, James V. Dunne, Emerson Gingrich, Dan S. Heffez, Y.-K. Frances Leung, Daniel G. Malone, Thomas J. Romano, I. Jon Russell, David Saul, Donald G. Seibel
Other endorphins: Other endogenous endorphins were considered as possible contributors to the pathogenesis of FMS (307). Neither CSF β-endorphin [mp-opioid receptor] nor dynorphin A [kappa-opioid receptor] were low in FMS CSF. Actually, the surprise was that the concentration of dynorphin A in FMS CSF was elevated. That finding could indicate an attempt on the part of the endogenous opioid system to balance the increased nociception. Alternatively, it could have very different implications that could not have been predicted in 1991.
Classes of Compounds with GI Tract Toxicity
Published in Shayne C. Gad, Toxicology of the Gastrointestinal Tract, 2018
Amy L. Mihalchik, Erica N. Rogers
Opiate drugs are widely used for management of pain resulting from cancer, postoperative pain, and chronic non-cancer pain, despite known potential for habituation and addiction. A variety of therapeutic and adverse effects associated with endogenous opioids and opiate drugs are primarily mediated through receptor binding to three major classes of G-protein coupled receptors including the ∂-opioid receptor (OP1), kappa opioid receptor (OP2), and µ-opioid receptor (OP3), which are localized to the CNS and peripheral tissues including the gastrointestinal tract. OP1 is associated with mediating spinal and supraspinal analgesia, in addition to dopamine release required for amphetamine associated motor activity. OP2 is active within the spinal cord and brain, and results in pupil constriction, spinal analgesia, and inhibition of anti-diuretic hormone when activated. OP3 activity plays a role in supraspinal analgesia, respiratory depression, psychoactive effects, and a number of gastrointestinal effects. In humans, the most prevalent receptor in the gastrointestinal tract is the OP3 receptor, which may interact with endogenous opioid peptides such as met-enkaphalin, leu-enkephalin, ß-endorphin, and dynorphin as well as opiate agonists, partial agonists, and antagonist compounds. In the presence of opiate agonists in the GI tract, OP3 receptor-ligand complexes are endocytosed in a concentration-dependent manner and evoke constipation and slowed GI transit due to decreased peristalsis, which may be severe enough to warrant cessation of opiate use in some patients (Holzer, 2007; Pathan & Williams, 2012; Seifert, 2004; Smith, 2009).
Chronic abdominal, groin, and perineal pain of visceral origin
Published in Peter R Wilson, Paul J Watson, Jennifer A Haythornthwaite, Troels S Jensen, Clinical Pain Management, 2008
As in any chronic pain disorder, an important (but not particularly testable) component to the management of IBS is a stable, trusting patient–physician relationship. Life-threatening pathology may be simply ruled out without an exhaustive investigation and the patient needs to be assured that their symptoms are believed. Therapeutic options for IBS are listed in Box 40.7. As part of a diagnostic/therapeutic trial, patients are generally advised to engage in dietary modifications such as avoiding milk products, avoiding excessive legume consumption (associated with gas production), increasing fiber and bran in those with constipation,86, 93 avoiding caffeine- or sorbitol-containing foods, and establishing a stable dietary pattern in the hope of establishing a stable evacuation routine. Anticholinergics/antidiarrheals have been extensively employed clinically and extensively studied. Reviews of the efficacy of these agents have concluded that their benefit is unproven.93 Traditional advice has been to keep analgesic therapy to a minimum with the use of opioids particularly discouraged. Recently, various antidepressants have been demonstrated to have efficacy in controlled studies.90, 91, 92 Drugs acting via serotonin receptors as either 5HT-3 antagonists (alosetron) or 5HT-4 agonists (tegaserod) have been utilized in clinical practice95 but ischemic colitis has proven to be a problematic side effect96 resulting in some restriction of use. Peripherally restricted kappa opioid receptor agonists have found some utility in experimental trials.94 Gastrokinetic agents, anti-diarrheals, serotonin receptor antagonists, osmotic laxatives, naloxone, cholecystokinin antagonists, and peppermint oil have all been proposed as effective. Injection therapies have not been generally employed in the treatment of IBS but a neurolytic celiac plexus block has been reported as useful in the treatment of idiopathic abdominal pain.97 Behavioral treatments such as hypnosis, cognitive-behavioral therapy, and supportive psychotherapy have proven valuable, especially if pain is intermittent and there is identified psychiatric disease such as anxiety or depression.87 Swedlund et al.,88 in a prospective, randomized study of 99 patients with the diagnosis of IBS, demonstrated that those patients who received eight psychotherapy sessions (and antispasmotics and bulking agents) had less abdominal pain, better bowel movements, and less psychological distress at both three and 15 months following treatment than similar patients treated only with antispasmotics and bulking agents. Other studies have been less supportive of behavioral treatments.89
An evaluation of difelikefalin as a treatment option for moderate-to-severe pruritus in end stage renal disease
Published in Expert Opinion on Pharmacotherapy, 2021
Zoe M. Lipman, Gil Yosipovitch
Third generation kappa opioid receptor agonists are tetrapeptides made up of 4 hydrophilic/lipophobic amino acids that aim to prevent blood-brain barrier crossing and enhance peripheral specificity [35]. Two third generation kappa opioid receptor agonists that are of particular interest are CR665 (D‐Phe‐D‐Phe‐D‐Nle‐D‐Arg‐NH‐4‐Picolyl; previously FE‐200665, JNJ‐38488502) and DFK/CR845 (D‐Phe‐D‐Phe‐D‐Leu‐D‐Lys‐[γ‐(4‐N‐piperidinyl) amino carboxylic acid; FE-202845) [34]. As CR665 was found to not be very orally active and had disappointing clinical results [36], DFK was designed to increase multimodal bioactivity while maintaining similar KOR specificity. Through clinical trials run by CARA Pharmaceuticals starting in 2008, DFK has been investigated for the indications of acute post-operative pain and CKD-aP [37].
Fragment-based screening with natural products for novel anti-parasitic disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
The Dictionary of Natural Products database has been computationally divided into 64,650 fragment sized (MW 100–300 Da) and 145,623 natural products with an MW > 300. SPiDER software [27] predicted the targets of 23,340 (36%) of the low MW natural products compared to 31,556 (22% of the 145,623 larger natural products). The concept of target prediction for fragment-like natural products through a comparison with drug-like small molecules was undertaken with sparteine for a prospective experiment. In addition to weakly inhibiting p38α mitogen-activated protein kinase, sparteine was previously shown to bind to the muscarinic and nicotinic receptors [28]. SPiDER predicted these two targets among the top three predictions. The kappa opioid receptor was listed as the second-most-confidently predicted target. Binding and functional assays confirmed the prediction and revealed sparteine as a ligand-efficient fragment for further development (ligand efficiency = 0.30) [29].
Choice of intrathecal drug in the treatment of neuropathic pain – new research and opinion
Published in Expert Review of Clinical Pharmacology, 2019
Timothy R. Deer, Mark Malinowski, Vishal Varshney, Jason Pope
Quinoxaline-based kappa-opioid receptor agonists have acquired increasing attention in research and have emerged as an alternative target for the development of safer analgesics [28]. Specifically targeting the kappa-opioid receptor can result in stronger analgesia but does not lead to typical mu-opioid receptor side effects such as euphoria, dependence and respiratory depression [29]. In animal models, the intrathecal delivery of kappa-opioid receptor agonists has been shown to downregulate the proliferation, activation, and secretion of cytokines in immune cells, suggesting anti-inflammatory activity [28]. As neuropathic pain involves neural damage, it is known that after neural damage, inflammatory mediators are produced by peripheral immune cells in the spinal cord and contribute to neuropathic pain by activating nociceptive neurons [7]. Thus, the development of novel kappa-opioid receptor agonists delivered intrathecally may provide a mechanism to treat neuroinflammation and resulting neuropathic pain.