International Journal of Basic & Clinical Pharmacology Ba skaran P et al. Int J Basic Clin Pharmacol. 2021 Jan;10(1):133-139 http:// www.ijbcp.com pISSN 2319-2003 | eISSN 2279-0780 DOI: https://dx.doi.org/10.18203/2319-2003.ijbcp20205553 Review Article Recent advances in pain management Priyadarsini Baskaran1, Venkatraman Karthikeayan2, Anusha Natarajan3* 1Medical Monitor, Clinirx CRO, Chennai, Tamil Nadu, India 2Consultant Neuro-Immunologist, Global Hospitals, Chennai , Tamil Nadu, India 3Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India Received: 26 May 2020 Revised: 01 December 2020 Accepted: 12 December 2020 *Correspondence: Dr. Anusha Natarajan, Email: [email protected] Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT Pain is one of the most common complaints for which patients approach physicians. In spite of this there is a huge unmet need for developing medications for pain that are safe and efficacious. Owing to the heterogeneity of clinical pain and complex pathophysiology, target identification for drug development is difficult. Preclinical models have also proven unreliable for the development of novel analgesics. Recent advances in understanding the physiology of nociception has enabled the development of novel analgesics including abuse deterrent opioids, drugs targeting several receptors, ion channels and enzymes. This review will attempt to cover the physiology of nociception focusing on the novel targets, the challenges in development of novel analgesics and give an overview of the recently developed drugs and those in the pipeline for the management of pain. Keywords: Nociception, Pain therapy, Recent Advances in pain therapy INTRODUCTION Pain (including widespread pain syndromes) can be due to inflammation or tissue damage, cancer, or lesions of the The International Association for the Study of Pain defines nervous system leading to spontaneous pain, hyperalgesia pain as “an unpleasant sensory and emotional experience and allodynia. The available drugs like non-steroidal anti- associated with actual or potential tissue damage or inflammatory drugs (NSAIDS) and opioids with good described in terms of such damage.” Pain is the most analgesic efficacy are coupled with deleterious side common neurological complaint. Pain can be broadly effects. The adjuvant drugs used like amine reuptake classified as acute and chronic pain. Acute pain is usually inhibitors and anti-epileptics have poor analgesic efficacy a symptom of the underlying disease condition and has a with side effects that decrease the quality of life. protective role biologically while chronic pain lacks a biological protective role and is a disease condition in There is an unmet need for the development of novel itself, presenting with symptoms of refractory pain, effective and safe analgesics without abuse liability. functional and psychological impairment, and disability.1 An annual cost of 560–635 billion dollars is spent in direct PHYSIOLOGY OF NOCICEPTION treatment costs and lost productivity due to chronic pain causing a huge economic burden to the community.2 The physiological process by which pain is perceived is known as nociception. Nociceptors have unmyelinated (C- International Journal of Basic & Clinical Pharmacology | January 2021 | Vol 10 | Issue 1 Page 133 Baskaran P et al. Int J Basic Clin Pharmacol. 2021 Jan;10(1):133-139 fibre) or thinly myelinated (Aδ-fibre) axons. Stimulation ganglia of the spinal cord or in the trigeminal ganglia. The of afferent Aδ nociceptive fibres causes a sharp, well- nociceptors express ion-channel receptors (belonging to localized pain sensation. Activation of nociceptive C fibres the transient receptor potential (TRP) family of ion is associated with a dull, burning or aching, and poorly channel receptors) which convert the noxious stimuli into localized pain. Their cell bodies lie in the dorsal root action potentials. Figure 1: Modulation of nociceptive pathways.3 These ion channels are mostly voltage gated sodium projections that descend from the brainstem to the dorsal channels. Action potentials that result from the horn. The major inhibitory neurotransmitters in the dorsal transduction of noxious stimuli are conducted along the horn of the spinal cord are opioid peptides, norepinephrine, axon of the sensory neuron into the spinal cord where they serotonin (5-HT), glycine, and GABA. At the level of the synapse on the dorsal horn. Glutamate is released at this spinal cord, cells located in the dorsal horn modulate the synapse. The release of neurotransmitters is modulated by sensation of pain. Activation of non-nociceptive afferent N-type voltage gated calcium channels. The dorsal horn fibres may suppress the nociceptive transmission in the neurons send projections to supra-spinal areas in the spinal cord. This is the basis of “the gate control theory of brainstem, hypothalamus, and thalamus and then, through pain”. Descending inhibitory pathways from the brain relay neurons, to the cortex where the sensation of pain is further modulate pain transmission. The inhibitory perceived. Glutamate and substance P are the major pathways include opioid, noradrenergic and serotonergic transmitters involved in pain transmission. systems. CENTRAL MODULATION OF PAIN2 CHRONIC PAIN2 Synaptic transmission in the spinal cord is regulated by the On repeated painful stimuli to the nociceptors, the actions of both local inhibitory interneurons and threshold for their activation is decreased. This is called International Journal of Basic & Clinical Pharmacology | January 2021 | Vol 10 | Issue 1 Page 134 Baskaran P et al. Int J Basic Clin Pharmacol. 2021 Jan;10(1):133-139 auto-sensitisation. As the painful stimulus continues there of pain with even minor/ no stimulus. This property of the is increased membrane excitability. Finally gene alteration neurons to change is called neuronal plasticity. takes place leading to prolonged and increased perception Figure 2: Newer targets being explored for development of analgesics.4 DRUGS ACTING ON OPIOID RECEPTOR LIKE CB2 receptors showed promise as analgesics in preclinical RECEPTOR-1 (ORL-1) trials. Olorinab, a highly potent CB2 agonist has completed phase 2a trials for treatment of visceral pain. ORL-1 is also known as nociception receptor. It is Tedalinab, another potent and highly selective CB2 expressed in the central nervous system (CNS). On agonist has also shown analgesic and anti-inflammatory activation by its ligand nociceptin, it causes closure of effects in phase 1 trials. Other molecules like LY2828360, voltage gated calcium channels and opening of potassium S-777469, KHK6188 were discontinued for lack of channels reducing excitability.5 Cebranopadol is a low efficacy in clinical trials. selectivity ORL-1 agonist and was found to be as effective as tapentadol and superior to placebo in phase 2 trials. Angiotensin type 2 receptor (AT2R) inhibitors Buprenorphine also has ORL-1 agonist activity.6 The AT2 receptors are expressed in the sensory neurons of HISTAMINE RECEPTORS humans and have been implicated in the development of neuropathic pain. AT2R inhibitors are being developed for The H3 receptor subtype (H3R) is an inhibitory the treatment of neuropathic pain. The molecule EMA-401 autoreceptor located on both pre and postsynaptic neurons. is now in phase 2b of clinical development. It is being Activation of H3Rs in the skin reduces calcitonin gene- investigated for the treatment of painful diabetic related peptide (CGRP) and substance P release, leading to neuropathy (EMPADINE trial) and post herpetic neuralgia 7,8 an anti-inflammatory response. The compound (EMPHENE trial). GSK189254 (H3 agonists) was found effective in animal models of neuropathic pain.5 Alpha (α2) adrenergic receptors agonists DRUGS TARGETING G-PROTEIN COUPLED α2 adrenergic receptors inhibit the presynaptic release of RECEPTORS neuropeptides in the spinal cord and bring about reduction in pain. Phase 2 trials of an inhaled formulation of The receptor systems involved in pain pathways include dexmedetomidine showed efficacy in reducing cannabinoid receptors, angiotensin type 2 receptors and α2 postoperative pain but was accompanied by adverse 5 adrenergic receptors. effects like hypotension and bradycardia. Cannabinoid receptors agonists7 Chemokine receptors The CB1 and CB2 receptors have been investigated as Chemokines activate and sensitize the sodium channels potential targets for management of pain. CB1 receptors and TRPV1 receptors. They help in maintenance of pain. have severe psychomimetic effects and abuse potential but They’re also implicated in the causation of opioid International Journal of Basic & Clinical Pharmacology | January 2021 | Vol 10 | Issue 1 Page 135 Baskaran P et al. Int J Basic Clin Pharmacol. 2021 Jan;10(1):133-139 tolerance and opioid induced hyperalgesia. CCR2 receptor Calcium channels antagonist AZD242 was developed and showed promise in preclinical rodent models but did not show any analgesic Voltage dependent calcium channels regulate cellular efficacy in human studies.5 excitability and mediate release of synaptic vesicles. The commonly used therapeutic agents gabapentin and DRUGS TARGETING ION CHANNELS