Novel pain therapeutics

Rationale

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Chronic pain is a major health care problem that affects some 30%-50% of the world population and almost 20% of the Europeans actually suffers from chronic or intermittent pain; the latter results in suffering and disability for patients and increasing economic loss for society. In Italy, pain prevalence is estimated to be 21,7% and it is calculated that only 1/3 of patients receives pain relief from current analgesics, like nonsteroidal anti-inflammatory drugs (NSAIDs), local anaesthetics, some antidepressants and anticonvulsants, including carbamazepine and gabapentin, opiates. Advancements in the understanding of the mechanisms that produce pain have disclosed new potential therapeutic targets for the development of more effective drugs. For instance, validation of experimental  models recapitulating allodynia contributed a great deal of precious information on the long-term plasticity changes occurring in pain transmission and modulation. Thus, changes of long-term potentiation (LTP) of excitatory synaptic transmission have been described to occur at spinal and supra-spinal central nervous system (CNS) regions. Likewise, at cellular level, changes in the activation of postsynaptic signaling pathways and of a host of genes and synthesis of new proteins, including some that can generate permanent structural changes, have also been reported. Release of soluble mediators by non neuronal cells might play an important role in initiating and modulating activity in primary afferent nociceptors; recently, the influence of CNS glial cells (including microglia, astrocytes and oligodendrocytes) on pain processing has also been recognized and investigated. The evidence gathered so far implicates that CNS glia, via modulating fundamental mechanisms of neuronal function and synaptic communication, can contribute to sensitization and pain-related behavior though its translational value to clinic remains to be established. Recent application of functional image analysis technique (fMRI) to the study of pain has proven extremely useful to the study of pharmacologic modulation of pain related brain activity in humans. Thus, it has been reported that, under conditions recapitulating  sensitization occurring in neuropathic pain, gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing  deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.  The latter should also be considered an important example of how basic knowledge is nowadays rapidly translated into valuable therapeutic advancements. Indeed, in spite of the development of specific drugs for neuropathic pain, the treatment of severe pain relies on the use of opioids. Unfortunately, addiction, overdose and death from opioid prescriptions and the development of diversion and illicit activities still characterize opioid use; the latter disorders may stem from inappropriate prescription (see CDC guidelines for treatment of pain unrelated to cancer) and limited pharmacodynamic and safety characteristics of opioids.  Among the most disabling chronic pain conditions, one of the hardest challenges is represented by migraine. In this field, botulinum toxin has emerged as noteworthy pharmacological tool for the study of pain and the development of biotechnological drugs (e.g. mAbs) raised against the signalling of calcitonin gene related peptide (CGRP), reaffirming the fundamental role for basic research in drug discovery. Higher prevalence of pain is registered in aging (over 65 patients) since it predisposes to chronic conditions as muskuloskeletal disorders, osteoporosis, osteoarthirtis, diabetes, herpes zoster, frequent traumas, often accompanied by the development of chronic pain. Moreover, aging is characterized by slower healing and poorer recovery from acute injury. This problem becomes even more burdensome in patients suffering from dementia, due to the impaired communication capabilities which make pain often underdiagnosed and undertreated. Unrelieved pain accounts for the development in 40 to 60% of these patients of neuropsychiatric symptoms of dementia (BPSDs) like agitation; this is managed through off label use of atypical antipsychotics increasing (approx 2 fold) the risk of mortality whilst Cochrane metanalyses of randomized clinical trials support the efficacy of some botanicals.  Fundamental is the effort of the Italian consensus conference on pain in neurorehabilitation for the clinical management of chronic pain. Collectively, these and other subjects will form matter of discussion at the forthcoming international meeting on “Novel Pain Therapeutics: From Basic Research to Clinical Translation and Rehabilitation” to be held at the University Club of the University of Calabria (Rende, CS, Italy). This collaborative meeting is organized in the frame of a scientific and academic agreement signed among the Tohoku Medical and Pharmaceutical University (Sendai, Japan), the Daiichi Pharmaceutical University (Fukuoka, Japan) and the University of Calabria (Rende, Cosenza, Italy); it will host some twenty scientists from several Universities of Japan, including Tokyo, Sendai, Wakayama, Fukuoka etc that will join researchers of international caliber. The conference is organized under the aegis of the Italian and Japanese Societies of Pharmacology (SIF & JPS) and the Italian Society of Neurological Rehabilitation (SIRN).