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1 UST College of Science Department of Biological Sciences UST College of Science Department of Biological Sciences 1 Pharmacogenomics of Myofascial Pain Syndrome An Undergraduate Thesis Submitted to the Department of Biological Sciences College of Science University of Santo Tomas In Partial Fulfillment of the Requirements for the Degree of Bachelor of Science in Biology Jose Marie V. Lazaga Marc Llandro C. Fernandez May 2021 UST College of Science Department of Biological Sciences 2 PANEL APPROVAL SHEET This undergraduate research manuscript entitled: Pharmacogenomics of Myofascial Pain Syndrome prepared and submitted by Jose Marie V. Lazaga and Marc Llandro C. Fernandez, was checked and has complied with the revisions and suggestions requested by panel members after thorough evaluation. This final version of the manuscript is hereby approved and accepted for submission in partial fulfillment of the requirements for the degree of Bachelor of Science in Biology. Noted by: Asst. Prof. Marilyn G. Rimando, PhD Research adviser, Bio/MicroSem 602-603 Approved by: Bio/MicroSem 603 panel member Bio/MicroSem 603 panel member Date: Date: UST College of Science Department of Biological Sciences 3 DECLARATION OF ORIGINALITY We hereby affirm that this submission is our own work and that, to the best of our knowledge and belief, it contains no material previously published or written by another person nor material to which a substantial extent has been accepted for award of any other degree or diploma of a university or other institute of higher learning, except where due acknowledgement is made in the text. We also declare that the intellectual content of this undergraduate research is the product of our work, even though we may have received assistance from others on style, presentation, and language expression. Jose Marie V. Lazaga Marc Llandro C. Fernandez Date: May 6, 2021 Date: May 6, 2021 Asst. Prof. Marilyn G. Rimando, PhD Research adviser Date: May 6, 2021 UST College of Science Department of Biological Sciences 4 ABSTRACT Myofascial pain syndrome (MPS) is a musculoskeletal pain condition characterised by localized deep pains in the skeletal muscle and fascia, known as trigger points. It is a top contributor to global disability, with a lifetime prevalence of up to 85%, increasing the rate of other health-related concerns. Some of the current pharmacological treatment modalities for MPS and other musculoskeletal pain (MSP)-related conditions show some favourable outcomes in pain. The genetic make-up of patients however may affect drug treatment response. Also, signalling cascades are affected due to the adverse gene-drug- drug-gene interactions. The signalling cascades of G-proteins, such as in cAMP pathway, are also highly linked to MPS and other diseases and conditions, which often present chronic pain complications. A secondary analysis systematic review, using structured mining was conducted to determine the top genes, drugs, and conditions associated with MPS. The data sets surveyed were sourced from several databases including Comparative Toxicogenomics Database (CTD) and GeneCards Suite Databases (GeneCards, MalaCards, PathCards). The purpose of this review is to provide information on the current knowledge on the pharmacogenomics of MPS to direct the focus of future studies to disease-gene-drug associations for better patient treatment and intervention outcomes. Further studies are necessary to better improve the quality of life of patients with MPS, including the minimisation of adverse drug reactions and maximisation of drug efficacy. Keywords: chronic pain, myofascial pain syndrome, pharmacogenomics UST College of Science Department of Biological Sciences 5 INTRODUCTION Chronic pain (Institute of Medicine (IoM), 2011) is amongst the most reported medical conditions in adults (Interagency Pain Research Coordinating Committee (IPRCC), 2016). Approximately 70% to 80% of patients with chronic pain have chronic musculoskeletal pain (MSP) disorder as the underlying diagnosis (James et al., 2018). Chronic MSP conditions are the top contributors to global disability, increasing the rate of other health-related concerns, including anxiety and depression, and opioid dependence (Cieza et al., 2020; Gatchel & Schultz, 2014; Groves et al., 1998; Ho et al., 2018; IoM, 2011; Hutson & Ward, 2015; IPRCC, 2016; James et al., 2018; Mills et al., 2019; Smith et al., 2001). Numerous treatment interventions are used in chronic pain management, including pharmacologic treatment modalities, such as nonsteroidal anti-inflammatory drugs (NSAIDs) and muscle relaxants (Gatchel & Schultz, 2014; Groves et al., 1998; Ho et al., 2018; Hutson & Ward, 2015), and non-pharmacologic treatment modalities, such as rehabilitation interventions (Gatchel & Schultz, 2014; Kamper et al., 2015). Myofascial Pain Syndrome Myofascial pain syndrome (MPS) is one of the common MSP conditions, described as localised deep pains and “complex of sensory, motor, and autonomic symptoms” in the skeletal muscle and fascia, caused by myofascial trigger points (MTrPs) (Friction et al., 1985; Gatchel & Schultz, 2014; Hutson & Ward, 2015; Kamper et al., 2015; Simons, 1975). Simons (1975) referred to MTrPs as “spots of exquisite tenderness and hyperirritability in muscles or their fascia, localised in taut, palpable bands”. MPS also presents neurologic and otologic associations, including muscle weakness, paraesthesia, UST College of Science Department of Biological Sciences 6 and hampered vision (Friction et al., 1985; Hutson & Ward, 2015; Simons, 1975). Due to the clinical similarities between MPS and other MSP conditions, most esp. fibromyalgia syndrome (FMS), it is postulated that later stages of MPS result in FMS (Friction et al., 1985; Gatchel & Schultz, 2014; Hutson & Ward, 2015; Simons, 1975). Prevalence of MPS The existing literature regarding the exact prevalence of MPS has been exceedingly rare (Tantanatip & Chang, 2020). A cross-sectional study conducted by Fleckenstein et al. (2010) reported that MPS has a lifetime prevalence of up to 85% amongst the general population, primarily affecting sedentary individuals (Vazquez-Delgado et al., 2009) and has a positive age correlation, with peak age prevalence between 59 to 74 years old (Bergman et al., 2001). There are no reports of significant differences in presentation between males and females. However, it is described that MPS is more prevalent in females than in males (Vazquez-Delgado et al., 2009; Galasso et al., 2020), but the difference was also not of statistical significance (Wolfe et al., 2013). MPS is the leading diagnosis of chronic and persistent localised pain in pain management clinics, with a prevalence of up to 90% (Fleckenstein et al., 2010). Aetiology and Pathophysiology of MPS The exact developmental mechanisms of MTrPs are unknown, but it is believed to be initiated by systemic or ergonomic factors, including gross or repetitive muscle trauma and psychological stress (Borg-Stein & Iaccarino, 2014; Gatchel & Schultz, 2014; Hutson & Ward, 2015; Orhan et al., 2018; Schneider, 1995; Tantanatip & Chang, 2020). Most common factors include fatigue, improper posture, osteoarthritis, and hypothyroidism. An UST College of Science Department of Biological Sciences 7 increased rate of acetylcholine synthesis, which, in turn, increases the activity of neuromuscular junctions occurs as a physiological response to physical muscle trauma and leads to a cascade of other biochemical responses, such as the release of vasoactive and inflammatory factors (Borg-Stein & Iaccarino, 2014; Hutson & Ward, 2015; Schneider, 1995; Shah et al., 2008; Tantanatip & Chang, 2020). The results of the trial conducted by Srbely et al. (2010) implied that neurogenic inflammation could facilitate the formation of MTrPs even in the absence of localised muscle injury. Combined evidence (Smith & Haythornthwaite, 2004) of longitudinal and micro longitudinal studies suggests that sleep disturbance exacerbates MPS. The main mechanistic hypothesis put forth in describing MPS is central sensitisation (Hocking, 2013; Hutson & Ward, 2015; Latremoliere & Woolf, 2009; Tantanatip & Chang, 2020), such as hyperalgesia and allodynia, and characterised by a pain persisting for more than three months (Hutson & Ward, 2015; Rivers et al., 2015; Tantanatip & Chang, 2020). However, various hypotheses surrounding chronic MSP conditions are being stipulated. This considers MSP disorders, such as MPS, a biopsychosocial condition, wherein biological, psychological, and social factors significantly affect the belief, behaviour, and cognition towards pain (Orhan et al., 2018). Diagnosis Travell and D. G. Simons (1983; … L.S Simons, 1999) proposed the initial set of diagnostic criteria for MPS. The primary diagnostic features of MPS include patterned localised pain, palpable taut band and focal tenderness within it, restricted locomotion in the pain region, and weakness without atrophy. The secondary criteria involve chief pain UST College of Science Department of Biological Sciences 8 complaints after applied pressure on MTrP nodules, generation of local twitch response upon introduction of snapping palpation and diminishing or relief from pain following muscular treatment. Despite the origination of this diagnostic manual defining clear signs and symptoms, there is yet to be a uniformly accepted diagnostic protocol for the diagnosis of MPS. One of diagnostic challenges is the poor reliability in detecting taut bands (Hutson & Ward, 2015; Myburgh et al., 2008; Simons et al., 1999; Tough et al., 20017; Travel & Simons,
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