Unmet needs in the management of immune-mediated thrombotic thrombocytopenic purpura and the potential role of caplacizumab in the UK-A modified-Delphi study.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare, blood-clotting disorder. Management historically relies on plasma exchange and immunosuppression; however, a 10%-20% mortality rate is still observed. Caplacizumab binds to von Willebrand factor and directly inhibits platelet aggregation; addition of caplacizumab to historical treatment induced faster resolution of platelet count in clinical trials. In 2019, a modified-Delphi study was conducted with UK experts, to develop consensus statements on management of acute TTP and the potential role of caplacizumab. An unmet need was acknowledged, and areas requiring improvement included: time to diagnosis and treatment initiation; time to platelet normalisation (TTPN) during which patients remain at risk of persistent microvascular thrombosis and organ damage; and incidence of subsequent exacerbations and relapses. Caplacizumab addition to historical treatment within 24 h (after confirmatory ADAMTS13 [a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13] assay) would significantly reduce TTPN, which directly influences acute outcomes, with manageable bleeding risk and reduced burden on healthcare systems. Expert panellists agree that poor outcomes in iTTP largely result from failure to rapidly control microvascular thrombosis. Use of caplacizumab during a confirmed iTTP episode could offer better control and may plausibly improve long-term outcomes. However, this consensus must be validated with further clinical trials and robust real-world evidence.

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.

A combination pharmacotherapy of tapentadol and pregabalin to tackle centrally driven osteoarthritis pain.

BACKGROUND: Many Osteoarthritis (OA) patients report with clinical features to their pain that cannot be explained by purely peripheral mechanisms. Yet, the analgesic agents available that tackle centrally driven chronic pain often provide only partial pain relief, or have dose-limiting side effects. We explored a combination therapy of the centrally acting analgesic agents tapentadol and pregabalin, to investigate if they could be used in combination to provide superior analgesia. METHODS: Using electrophysiological single-unit recordings taken from spinal wide dynamic range neurons, Diffuse Noxious Inhibitory Controls (DNIC) were assessed as a marker of potential changes in descending controls in a monoiodoacetate (MIA) model of OA. We investigated if a subcutaneous injection of tapentadol or pregabalin, both alone and in combination, inhibited neuronal responses and restored the expression of DNIC, quantified as a reduction in neuronal firing in the presence of a conditioning noxious stimulus. RESULTS: Tapentadol restored DNIC-induced neuronal inhibition in MIA animals, while pregabalin inhibited pre-conditioned mechanically evoked neuronal responses but did not restore DNIC. Given in combination, tapentadol and pregabalin restored DNIC expression and also inhibited spinal neuronal responses. CONCLUSIONS: We propose that there is both central sensitization and an imbalance in inhibitory and facilitatory descending controls in MIA animals. The combination therapy of tapentadol and pregabalin restored descending noradrenergic inhibitory tone and also inhibited nociceptive transmission at the level of the spinal cord. SIGNIFICANCE: This study shows that pregabalin and tapentadol target different mechanisms of centrally driven chronic pain associated with osteoarthritis, and that when administered together can restore descending inhibitory tone whilst also tackling spinal neuronal hyperexcitability and may therefore provide superior analgesia.

Neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype: A back-translational study of oxcarbazepine.

BACKGROUND: The term 'irritable nociceptor' was coined to describe neuropathic patients characterized by evoked hypersensitivity and preservation of primary afferent fibres. Oxcarbazepine is largely ineffectual in an overall patient population, but has clear efficacy in a subgroup with the irritable nociceptor profile. We examine whether neuropathy in rats induced by spinal nerve injury shares overlapping pharmacological sensitivity with the irritable nociceptor phenotype using drugs that target sodium channels. METHODS: In vivo electrophysiology was performed in anaesthetized spinal nerve ligated (SNL) and sham-operated rats to record from wide dynamic range (WDR) neurones in the ventral posterolateral thalamus (VPL) and dorsal horn. RESULTS: In neuropathic rats, spontaneous activity in the VPL was substantially attenuated by spinal lidocaine, an effect that was absent in sham rats. The former measure was in part dependent on ongoing peripheral activity as intraplantar lidocaine also reduced aberrant spontaneous thalamic firing. Systemic oxcarbazepine had no effect on wind-up of dorsal horn neurones in sham and SNL rats. However, in SNL rats, oxcarbazepine markedly inhibited punctate mechanical-, dynamic brush- and cold-evoked neuronal responses in the VPL and dorsal horn, with minimal effects on heat-evoked responses. In addition, oxcarbazepine inhibited spontaneous activity in the VPL. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic oxcarbazepine, supporting a peripheral locus of action. CONCLUSIONS: We provide evidence that ongoing activity in primary afferent fibres drives spontaneous thalamic firing after spinal nerve injury and that oxcarbazepine through a peripheral mechanism exhibits modality-selective inhibitory effects on sensory neuronal processing. SIGNIFICANCE: The inhibitory effects of lidocaine and oxcarbazepine in this rat model of neuropathy resemble the clinical observations in the irritable nociceptor patient subgroup and support a mechanism-based rationale for bench-to-bedside translation when screening novel drugs.

Age-dependent plasticity in endocannabinoid modulation of pain processing through postnatal development.

Significant age- and experience-dependent remodelling of spinal and supraspinal neural networks occur, resulting in altered pain responses in early life. In adults, endogenous opioid peptide and endocannabinoid (ECs) pain control systems exist which modify pain responses, but the role they play in acute responses to pain and postnatal neurodevelopment is unknown. Here, we have studied the changing role of the ECs in the brainstem nuclei essential for the control of nociception from birth to adulthood in both rats and humans. Using in vivo electrophysiology, we show that substantial functional changes occur in the effect of microinjection of ECs receptor agonists and antagonists in the periaqueductal grey (PAG) and rostroventral medulla (RVM), both of which play central roles in the supraspinal control of pain and the maintenance of chronic pain states in adulthood. We show that in immature PAG and RVM, the orphan receptor, GPR55, is able to mediate profound analgesia which is absent in adults. We show that tissue levels of endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol, within the PAG and RVM are developmentally regulated (using mass spectrometry). The expression patterns and levels of ECs enzymes and receptors were assessed using quantitative PCR and immunohistochemistry. In human brainstem, we show age-related alterations in the expression of key enzymes and receptors involved in ECs function using PCR and in situ hybridisation. These data reveal that significant changes on ECs that to this point have been unknown and which shed new light into the complex neurochemical changes that permit normal, mature responses to pain.