Current and Future Issues in the Development of Spinal Agents for the Management of Pain.

Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety

What goes up must come down: insights from studies on descending controls acting on spinal pain processing

Descending controls link higher processing of noxious signals to modulation of spinal cord responses to their noxious inputs. It has become possible to study one key inhibitory system in animals and humans using one painful stimulus to attenuate another distant response and so eliciting diffuse noxious inhibitory controls (DNIC) or the human counterpart, conditioned pain modulation (CPM). Here, we discuss the neuronal pathways in both species, their pharmacology and examine changes in descending controls with a focus on osteoarthritis. We will also discuss the opposing descending facilitatory system. Strong parallels between DNIC and CPM emphasize the possibility of forward and reverse translation

Future directions for the management of pain in osteoarthritis.

Osteoarthritis (OA) is the predominant form of arthritis worldwide, resulting in a high degree of functional impairment and reduced quality of life owing to chronic pain. To date, there are no treatments that are known to modify disease progression of OA in the long term. Current treatments are largely based on the modulation of pain, including NSAIDs, opiates and, more recently, centrally acting pharmacotherapies to avert pain. This review will focus on the rationale for new avenues in pain modulation, including inhibition with anti-NGF antibodies and centrally acting analgesics. The authors also consider the potential for structure modification in cartilage/bone using growth factors and stem cell therapies. The possible mismatch between structural change and pain perception will also be discussed, introducing recent techniques that may assist in improved patient phenotyping of pain subsets in OA. Such developments could help further stratify subgroups and treatments for people with OA in future

Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies

This narrative review represents an output from the International Association for the Study of Pain's global task force on the use of cannabis, cannabinoids, and cannabis-based medicines for pain management, informed by our companion systematic review and meta-analysis of preclinical studies in this area. Our aims in this review are (1) to describe the value of studying cannabinoids and endogenous cannabinoid (endocannabinoid) system modulators in preclinical/animal models of pain; (2) to discuss both pain-related efficacy and additional pain-relevant effects (adverse and beneficial) of cannabinoids and endocannabinoid system modulators as they pertain to animal models of pathological or injury-related persistent pain; and (3) to identify important directions for future research. In service of these goals, this review (1) provides an overview of the endocannabinoid system and the pharmacology of cannabinoids and endocannabinoid system modulators, with specific relevance to animal models of pathological or injury-related persistent pain; (2) describes pharmacokinetics of cannabinoids in rodents and humans; and (3) highlights differences and discrepancies between preclinical and clinical studies in this area. Preclinical (rodent) models have advanced our understanding of the underlying sites and mechanisms of action of cannabinoids and the endocannabinoid system in suppressing nociceptive signaling and behaviors. We conclude that substantial evidence from animal models supports the contention that cannabinoids and endocannabinoid system modulators hold considerable promise for analgesic drug development, although the challenge of translating this knowledge into clinically useful medicines is not to be underestimated

Calcium channel modulation as a target in chronic pain control

Neuropathic pain remains poorly treated for large numbers of patients and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (PrialtTM ) was developed and approved as a first in class synthetic version of ω-conotoxin MVIIA, a Cav 2.2 peptide blocker. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide has restricted its use to exceptional circumstances. Ziconotide exhibits no state or use dependent block of Cav 2.2 channels; activation state dependent blockers were hypothesised to circumvent the side effects of state independent blockers by selectively targeting high frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state dependent calcium channel blockers, have displayed efficacy in pre-clinical models but have subsequently disappointed in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients, and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus evoked endpoints in pre-clinical studies and a failure to utilise translatable endpoints has likely contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant based assays provide insight into sensory and affective aspects of pain in animal models, and how these may relate to chronic pain patients in order to improve bench-to-bedside translation of calcium channel modulators

Calcitonin Gene-Related Peptide Receptor Antagonists: Beyond Migraine Pain—A Possible Analgesic Strategy for Osteoarthritis?

Osteoarthritis (OA) pain is poorly understood and managed, as current analgesics have only limited efficacy and unwanted side effect profiles. A broader understanding of the pathological mechanisms driving OA joint pain is vital for the development of improved analgesics. Both clinical and preclinical data suggest an association between joint levels of the sensory neuropeptide calcitonin gene-related peptide (CGRP) and pain during OA. Whether a direct causative link exists remains an important unanswered question. Given the recent development of small molecule CGRP receptor antagonists with clinical efficacy against migraine pain, the interrogation of the role of CGRP in OA pain mechanisms is extremely timely. In this article, we provide the background to the importance of CGRP in pain mechanisms and review the emerging clinical and preclinical evidence implicating a role for CGRP in OA pain. We suggest that the CGRP receptor antagonists developed for migraine pain warrant further investigation in OA

FROM PRECLINICAL TO CLINICAL EVIDENCE: EXPLORING THE MULTIPLE PERSPECTIVES AND HEALING POWER OF BOSWELLIA SERRATA ROXB. EX COLEBR

Boswellia serrata Roxb. ex Colebr. is a species belonging to the Burseraceae family, typical of dry environments of the Indian region. The oil-gum-resin, obtained from the trunk and thick branches, is known in phytotherapy for the volatile fraction which contains up to 70% terpenes. The most important and characteristic constituents are represented by pentacyclic triterpenes, named boswellic acids. B. serrata is known for multiple beneficial effects, mainly correlated to anti-inflammatory activity. This review aims to provide a comprehensive overview on the activities and potential applications of B. serrata based on clinical and preclinical evidence. An up-to-date literature review of preclinical and clinical studies related to the applications of B. serrata preparations in different pathological conditions was conducted using the main databases of scientific literature. A body of evidence point out the role of B. serrata extracts and its active constituents in the treatment of several inflammatory diseases. In particular, clinical trials revealed its use as a topical remedy of skin diseases, such as eczema and psoriasis, and internally in the treatment of asthma, intestinal and osteoarticular inflammatory diseases. Preclinical findings highlighted the positive effects of B. serrata extracts in cardiovascular and neurodegenerative diseases, and in cancer. Finally, B. serrata finds application as a feed additive in veterinary use. Although some limitations must be overcome, such as poor bioavailability, evidence supports that B. serrata is a promising medicinal plant. Furthermore, the use of B. serrata appears to have a favorable toxicological profile, but caution may be necessary regarding potential botanical-drug interactions

The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

Pain measures traditionally used in rodents record mere reflexes evoked by sensory stimuli; the results thus may not fully reflect the human pain phenotype. Alterations in physical and emotional functioning, pain-depressed behaviors and facial pain expressions were recently proposed as additional pain outcomes to provide a more accurate measure of clinical pain in rodents, and hence to potentially enhance analgesic drug development. We aimed to review how preclinical pain assessment has evolved since the development of the tail flick test in 1941, with a particular focus on a critical analysis of some nonstandard pain outcomes, and a consideration of how sex differences may affect the performance of these pain surrogates. We tracked original research articles in Medline for the following periods: 1973-1977, 1983-1987, 1993-1997, 2003-2007, and 2014-2018. We identified 606 research articles about alternative surrogate pain measures, 473 of which were published between 2014 and 2018. This indicates that preclinical pain assessment is moving toward the use of these measures, which may soon become standard procedures in preclinical pain laboratories.FPU grant from the Spanish Ministry of Education, Culture and SportsSpanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)Ramón Areces FoundationJunta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF

Antinociceptive effects of lacosamide on spinal neuronal and behavioural measures of pain in a rat model of osteoarthritis.

Alterations in voltage-gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation, as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model