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We have read the article "The value of interdisciplinary treatment for sickness absence in chronic pain: A nationwide register-based cohort study" by LoMartire et al (1) with great interest but also great concern. We, a group of experienced specialists, clinicians and scientists in Pain Medicine, welcome well-designed good quality studies on the treatment of chronic pain, a major health problem. Valid evidence on the benefits of interventions is of great importance for healthcare and Society. A critical appraisal of current standard of care methods is certainly warranted in order to promote continuous improvement. However, the present study has in our opinion several critical issues to which we would like to draw your attention.
Learn More >Metformin is an oral hypoglycemic drug widely used in the management of type 2 diabetes mellitus. We have recently demonstrated that metformin exhibits activity in models of nociceptive and neuropathic pain. However, little is known about its effects in experimental models of inflammation and inflammatory pain. Thus, the present study aimed to evaluate the activity of metformin in experimental models of inflammation and inflammatory pain in mice, as well as the underlying mechanisms. Previous (1 h) per os (p.o.) administration of metformin (250, 500 or 1000 mg/kg) inhibited the mechanical allodynia and paw edema induced by intraplantar (i.pl.) injection of carrageenan (600 μg) and also the pleurisy induced by this stimulus (200 μg, intrapleural). In the model of mechanical allodynia and paw edema induced by carrageenan, metformin also exhibited activity when administered after (1 h) the inflammatory stimulus. Metformin (1000 mg/kg) reduced the production of tumor necrosis factor-α induced by i.pl. injection of carrageenan. Metformin antiallodynic effect was not affected by previous administration of naltrexone (5 or 10 mg/kg, intraperitoneal) or cyproheptadine (5 or 10 mg/kg, p.o). However, this effect was abolished by previous administration of glibenclamide (20 or 40 mg/kg, p.o). In conclusion, the results demonstrate the activity of metformin in models of inflammation and inflammatory pain. In addition, the results indicate that the activity of metformin may be mediated by activation of ATP-sensitive potassium channels and reduction of production of inflammatory mediators. Altogether, these results stimulate the conduction of studies aiming to evaluate whether metformin may be repositioned in the treatment of patients with painful and inflammatory disorders.
Learn More >Osteoarthritis (OA) is the most common form of arthritis. It is characterized by progressive destruction of articular cartilage and the development of chronic pain and constitutes a considerable socioeconomic burden. Currently, pharmacological treatments mostly aim to relieve the OA symptoms associated with inflammation and pain. However, with increasing understanding of OA pathology, several potential therapeutic targets have been identified, enabling the development of disease-modifying OA drugs (DMOADs). By targeting inflammatory cytokines, matrix-degrading enzymes, the Wnt pathway, and OA-associated pain, DMOADs successfully modulate the degenerative changes in osteoarthritic cartilage. Moreover, regenerative approaches aim to counterbalance the loss of cartilage matrix by stimulating chondrogenesis in endogenous stem cells and matrix anabolism in chondrocytes. Emerging strategies include the development of senolytic drugs or RNA therapeutics to eliminate the cellular or molecular sources of factors driving OA. This review describes the current developmental status of DMOADs and the corresponding results from preclinical and clinical trials and discusses the potential of emerging therapeutic approaches to treat OA.
Learn More >The pathophysiology of osteoarthritis (OA) includes the destruction of subchondral bone tissue and inflammation of the synovium. Thus, an effective disease-modifying treatment should act on both of these pathogenetic components. It is known that cSrc kinase is involved in bone and cartilage remodeling, and SYK kinase is associated with the inflammatory component. Thus the aim of this study was to characterize the mechanism of action and efficacy of a small molecule multikinase inhibitor MT-SYK-03 targeting SYK and cSrc kinases among others in different in vitro and in vivo arthritis models. The selectivity of MT-SYK-03 kinase inhibition was assayed on a panel of 341 kinases. The compound was evaluated in a set of in vitro models of OA and in vivo OA and RA models: surgically-induced arthritis (SIA), monosodium iodoacetate-induced arthritis (MIA), collagen-induced arthritis (CIA), adjuvant-induced arthritis (AIA). MT-SYK-03 inhibited cSrc and SYK with IC of 14.2 and 23 nM respectively. Only five kinases were inhibited > 90% at 500 nM of MT-SYK-03. In in vitro OA models MT-SYK-03 reduced hypertrophic changes of chondrocytes, bone resorption, and inhibited SYK-mediated inflammatory signaling. MT-SYK-03 showed preferential distribution to joint and bone tissue (in rats) and revealed disease-modifying activity in vivo by halving the depth of cartilage erosion in rat SIA model, and increasing the pain threshold in rat MIA model. Chondroprotective and antiresorptive effects were shown in a monotherapy regime and in combination with methotrexate (MTX) in murine and rat CIA models; an immune-mediated inflammation in rat AIA model was decreased. The obtained preclinical data support inhibition of cSrc and SYK as a viable strategy for disease-modifying treatment of OA. A Phase 2 clinical study of MT-SYK-03 is to be started.
Learn More >Typically, migraine prevention trials focus on reducing migraine days. This narrow focus may not capture all that is important to people with migraine. Inconsistency in outcome selection across trials limits the potential for data pooling and evidence synthesis. In response, we describe the development of core outcome set for migraine (COSMIG).
Learn More >Osteoarthritis (OA) is a chronic joint disease in which cartilage degeneration leads to chronic pain. The endocannabinoid system has attracted attention as an emerging drug target for OA. However, the therapeutic potential of cannabinoids is limited by psychoactive side-effects related to CB1 activation and tolerance development for analgesic effects. β-Caryophyllene (BCP) is a low-efficacy natural agonist of CB2 and a common constituent of human diet with well-established anti-inflammatory properties. The results presented herein show the anti-nociceptive and chondroprotective potential of BCP in an animal model of OA induced by intra-articular injection of monoiodoacetate (MIA). Behavioural assessment included pressure application measurement and kinetic weight bearing tests. Histological assessment of cartilage degeneration was quantified using OARSI scoring. Experiments established the dose-response effects of BCP and pharmacological mechanisms of the antinociceptive action dependent on CB2 and opioid receptors. Chronic BCP treatment was able to hamper cartilage degeneration without producing tolerance for the analgesic effects. The data presented herein show that BCP is able to produce both acute and prolonged antinociceptive and chondroprotective effects. Together with the safety profile and legal status of BCP, these results indicate a novel and promising disease-modifying strategy for treating OA.
Learn More >Increased sympathetic nerve excitability has been reported to aggravate a variety of chronic pain conditions, and an increase in the number of sympathetic nerve fibers in the dorsal root ganglion (DRG) has been found in neuropathic pain (NP) models. However, the mechanism of the neurotransmitter norepinephrine (NE) released by sympathetic nerve fiber endings on the excitability of DRG neurons is still controversial, and the adrenergic receptor subtypes involved in this biological process are also controversial. In our study, we have two objectives: (1) To determine the effect of the neurotransmitter NE on the excitability of different neurons in DRG; (2) To determine which adrenergic receptors are involved in the excitability of DRG neurons by NE released by sprouting sympathetic fibers. In this experiment, a unique field potential recording method of spinal cord dorsal horn was innovatively adopted, which can be used for electrophysiological study in vivo. The results showed that： Forty days after SNI, patch clamp and field potential recording methods confirmed that NE enhanced the excitability of ipsilateral DRG large neurons, and then our in vivo electrophysiological results showed that the α receptor blocker Yohimbine could block the excitatory effect of NE on A-fiber and the inhibitory effect on C-fiber, while the α-adrenergic receptor agonist guanfacine (100 μM) had the same biological effect as NE. Finally, we concluded that NE from sympathetic fiber endings is involved in the regulation of pain signaling by acting on α-adrenergic receptors in DRG.
Learn More >Chemotherapy-induced neuropathic pain (CINP) is among the most common clinical complications associated with the use of anti-cancer drugs. CINP occurs in nearly 68.1% of the cancer patients receiving chemotherapeutic drugs. Most of the clinically available analgesics are ineffective in the case of CINP patients as the pathological mechanisms involved with different chemotherapeutic drugs are distinct from each other. CINP triggers the somatosensory nervous system, increases the neuronal firing and activation of nociceptive mediators including transient receptor protein vanilloid 1 (TRPV1). TRPV1 is widely present in the peripheral nociceptive nerve cells and it has been reported that the higher expression of TRPV1 in DRGs serves a critical role in the potentiation of CINP. The therapeutic glory of TRPV1 is well recognized in clinics which gives a promising insight into the treatment of pain. But the adverse effects associated with some of the antagonists directed the scientists towards RNA interference (RNAi), a tool to silence gene expression. Thus, ongoing research is focused on developing small interfering RNA (siRNA)-based therapeutics targeting TRPV1. In this review, we have discussed the involvement of TRPV1 in the nociceptive signaling associated with CINP and targeting this nociceptor, using siRNA will potentially arm us with effective therapeutic interventions for the clinical management of CINP.
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