1 5042 108 PHARMACOGENOMICS IN PAIN TREATMENT. THE EXPERIENCE OF CHRONIC PAIN IS ONE OF THE COMMONEST REASONS FOR SEEKING MEDICAL ATTENTION, BEING A MAJOR ISSUE IN CLINICAL PRACTICE. WHILE PAIN IS A UNIVERSAL EXPERIENCE, ONLY A SMALL PROPORTION OF PEOPLE WHO FELT PAIN DEVELOP PAIN SYNDROMES. IN ADDITION, PAINKILLERS ARE ASSOCIATED WITH WIDE INTER-INDIVIDUAL VARIABILITY IN THE ANALGESIC RESPONSE. THIS MAY BE PARTLY EXPLAINED BY THE PRESENCE OF SINGLE NUCLEOTIDE POLYMORPHISMS IN GENES ENCODING MOLECULAR ENTITIES INVOLVED IN PHARMACODYNAMICS AND PHARMACOKINETICS. HOWEVER, UPTAKE OF THIS INFORMATION HAS BEEN SLOW DUE IN LARGE PART TO THE LACK OF ROBUST EVIDENCES DEMONSTRATING CLINICAL UTILITY. FURTHERMORE, NOVEL THERAPIES, INCLUDING TARGETING OF EPIGENETIC CHANGES AND GENE THERAPY-BASED APPROACHES ARE FURTHER BROADENING FUTURE OPTIONS FOR THE TREATMENT OF CHRONIC PAIN. THE AIM OF THIS ARTICLE IS TO REVIEW THE EVIDENCES BEHIND PHARMACOGENETICS (PGX) TO INDIVIDUALIZE THERAPY (BOOSTING THE EFFICACY AND MINIMIZING POTENTIAL TOXICITY) AND GENES IMPLICATED IN PAIN MEDICINE, IN TWO PARTS: (I) GENETIC VARIABILITY WITH PAIN SENSITIVITY AND ANALGESIC RESPONSE; AND (II) PHARMACOLOGICAL CONCEPTS APPLIED ON PGX. 2016 2 1686 35 DRUGGING THE PAIN EPIGENOME. MORE THAN 20% OF ADULTS WORLDWIDE EXPERIENCE DIFFERENT TYPES OF CHRONIC PAIN, WHICH ARE FREQUENTLY ASSOCIATED WITH SEVERAL COMORBIDITIES AND A DECREASE IN QUALITY OF LIFE. SEVERAL APPROVED PAINKILLERS ARE AVAILABLE, BUT CURRENT ANALGESICS ARE OFTEN HAMPERED BY INSUFFICIENT EFFICACY AND/OR SEVERE ADVERSE EFFECTS. CONSEQUENTLY, NOVEL STRATEGIES FOR SAFE, HIGHLY EFFICACIOUS TREATMENTS ARE HIGHLY DESIRABLE, PARTICULARLY FOR CHRONIC PAIN. EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND MICRORNAS (MIRNAS) STRONGLY AFFECT THE REGULATION OF GENE EXPRESSION, POTENTIALLY FOR LONG PERIODS OVER YEARS OR EVEN GENERATIONS, AND HAVE BEEN ASSOCIATED WITH PATHOPHYSIOLOGICAL PAIN. SEVERAL STUDIES, MOSTLY IN ANIMALS, REVEALED THAT INHIBITORS OF DNA METHYLATION, ACTIVATORS AND INHIBITORS OF HISTONE MODIFICATION AND MODULATORS OF MIRNAS REVERSE A NUMBER OF PATHOLOGICAL CHANGES IN THE PAIN EPIGENOME, WHICH ARE ASSOCIATED WITH ALTERED EXPRESSION OF PAIN-RELEVANT GENES. THIS EPIGENETIC MODULATION MIGHT THEN REDUCE THE NOCICEPTIVE RESPONSE AND PROVIDE NOVEL THERAPEUTIC OPTIONS FOR ANALGESIC THERAPY OF CHRONIC PAIN STATES. HOWEVER, A NUMBER OF CHALLENGES, SUCH AS NONSPECIFIC EFFECTS AND POOR DELIVERY TO TARGET CELLS AND TISSUES, HINDER THE RAPID DEVELOPMENT OF SUCH ANALGESICS. IN THIS REVIEW, WE CRITICALLY SUMMARIZE DATA ON EPIGENETICS AND PAIN, FOCUSING ON CHALLENGES IN CLINICAL DEVELOPMENT AS WELL AS POSSIBLE NEW APPROACHES TO THE DRUG MODULATION OF THE PAIN EPIGENOME. 2017 3 5038 29 PHARMACOGENETICS OF CHRONIC PAIN AND ITS TREATMENT. THIS PAPER REVIEWS THE IMPACT OF GENETIC VARIABILITY OF DRUG METABOLIZING ENZYMES, TRANSPORTERS, RECEPTORS, AND PATHWAYS INVOLVED IN CHRONIC PAIN PERCEPTION ON THE EFFICACY AND SAFETY OF ANALGESICS AND OTHER DRUGS USED FOR CHRONIC PAIN TREATMENT. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED IN THE LITERATURE, WHILE THERE IS USUALLY ONLY LIMITED CLINICAL EVIDENCE SUBSTANTIATING FOR THE PENETRATION OF THE TESTING FOR THESE CANDIDATE BIOMARKERS INTO THE CLINICAL PRACTICE. FURTHER, THE PAIN-PERCEPTION REGULATION AND MODULATION ARE STILL NOT FULLY UNDERSTOOD, AND THUS MORE COMPLEX KNOWLEDGE OF GENETIC AND EPIGENETIC BACKGROUND FOR ANALGESIA WILL BE NEEDED PRIOR TO THE CLINICAL USE OF THE CANDIDATE GENETIC BIOMARKERS. 2013 4 1160 25 CONTINUING WAR ON PAIN: A PERSONALIZED APPROACH TO THE THERAPY WITH NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS. SUCCESSFUL PAIN MANAGEMENT REQUIRES THE DELIVERY OF ANALGESIA WITH MINIMAL RISK OF ADVERSE DRUG REACTIONS. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS REMAIN THE MAINSTAY OF TREATMENT FOR THE MAJORITY OF PATIENTS. UNFORTUNATELY, ALMOST 50% OF ALL PATIENTS EXPERIENCE INADEQUATE PAIN RELIEF AND SERIOUS SIDE EFFECTS. ALLELIC VARIANTS IN GENES CODING FOR TARGET PROTEINS, TRANSPORTERS AND ENZYMES, WHICH GOVERN ANALGESIC DRUGS ACTION AND THEIR FATE IN THE ORGANISM, MIGHT EXPLAIN INTER-INDIVIDUAL VARIABILITY IN PAIN SEVERITY AND IN DRUG-INDUCED PAIN RELIEF AND TOXICITIES. ADDITIONALLY, IT SEEMS THAT EPIGENETIC CHANGES CONTRIBUTE TO THE HIGHLY VARIABLE RESPONSE TO PAIN TREATMENT. THEREFORE, PHARMACOGENOMIC TESTING MIGHT BE A VALUABLE TOOL FOR PERSONALIZATION OF PAIN TREATMENT, WITH A MULTIDISCIPLINARY TEAM APPROACH INVOLVED. 2019 5 6807 23 [EPIGENETICS AND PAIN]. CHRONIC PAIN AFFECTS APPROXIMATELY 20 % OF ADULTS WORLDWIDE AND IS OFTEN ASSOCIATED WITH A DECREASE IN THE QUALITY OF LIFE AND VARIOUS COMORBIDITIES. CONVENTIONAL ANALGESIC THERAPIES ARE FREQUENTLY INSUFFICIENT AND SOMETIMES LEAD TO SEVERE SIDE EFFECTS. THEREFORE, GREAT EFFORTS ARE STILL BEING MADE TO ELUCIDATE THE SIGNALLING PATHWAYS IN PAIN AND TO DEVELOP NEW, SAFE AND EFFECTIVE THERAPIES. EPIGENETIC MECHANISMS WHICH INTERFERE WITH THE REGULATION OF GENE EXPRESSION ARE INVOLVED IN THE PATHOGENESIS OF SEVERAL DISEASES AND ARE GAINING INCREASING IMPETUS IN MEDICAL RESEARCH. AS THEY ARE ALSO INVOLVED IN PAIN PROCESSING, A MODULATION OF THESE MECHANISMS MIGHT REPRESENT A NOVEL OPTION FOR THE THERAPY OF PAIN PATIENTS. 2014 6 1291 30 DECODING THE ROLE OF EPIGENETICS AND GENOMICS IN PAIN MANAGEMENT. PERSISTENT PAIN IS A COSTLY EPIDEMIC, AFFECTING >50 MILLION AMERICANS WITH ESTIMATED EXPENDITURES OF >$200 BILLION ANNUALLY FOR DIRECT CARE AND LOST PRODUCTIVITY. RECENT ADVANCES IN EPIGENETIC/GENOMIC UNDERSTANDING OF PAIN AND ANALGESIC RESPONSE MAY LEAD TO IMPROVEMENTS IN PAIN MANAGEMENT AND HELP CURTAIL COSTS BY PROVIDING MORE PRECISE DETECTION OF THE PAIN MECHANISMS INVOLVED AND THEREBY MORE PERSONALIZED AND EFFECTIVE TREATMENTS. HOWEVER, THE TRANSLATION OF EPIGENETIC AND GENOMIC STRATEGIES FOR PAIN MANAGEMENT INTO CLINICAL PRACTICE WILL DEPEND ON UNDERSTANDING THEIR POTENTIAL APPLICATIONS. THE PURPOSE OF THIS ARTICLE IS TO EXAMINE CURRENT KNOWLEDGE ABOUT EPIGENETIC AND GENOMIC MECHANISMS OF PERSISTENT PAIN AND POTENTIAL OPPORTUNITIES FOR IMPROVING PAIN MANAGEMENT. THE INITIAL DISCUSSION FOCUSES ON PRESENT UNDERSTANDING OF NOCICEPTIVE PATHWAYS AND ALTERATIONS THAT LEAD TO PATHOLOGIC PAIN. THE DISCUSSION THEN MOVES TO A REVIEW OF EPIGENETIC MECHANISMS THAT HAVE BEEN IDENTIFIED IN THE TRANSITION TO AND MAINTENANCE OF PERSISTENT PAIN AS WELL AS IN THE INDIVIDUAL'S RESPONSE TO ANALGESICS. POTENTIAL APPLICATIONS OF EPIGENETICS/GENOMICS TO IDENTIFY PEOPLE AT RISK AND POSSIBLY PREVENT PERSISTENT PAIN AND GUIDE DIAGNOSIS AND THE SELECTION OF THERAPEUTIC MODALITIES ARE PRESENTED. 2013 7 5028 33 PERSONALIZING PEDIATRIC PAIN MEDICINE: USING POPULATION-SPECIFIC PHARMACOGENETICS, GENOMICS, AND OTHER -OMICS APPROACHES TO PREDICT RESPONSE. PERSONALIZED MEDICINE IS THE SCIENCE OF INDIVIDUALIZED PREVENTION AND THERAPY. THE NOTION THAT "ONE SIZE FITS ALL" HAS BEEN REPLACED BY THE IDEA OF PATIENT-TAILORED HEALTH CARE. WITHIN THIS PARADIGM, THE RESEARCH COMMUNITY HAS TURNED TO EXAMINE GENETIC PREDICTORS OF DISEASE AND TREATMENT RESPONSES. PAIN RESEARCHERS HAVE PRODUCED GENETIC STUDIES OVER THE LAST DECADE THAT EVALUATE THE ASSOCIATION OF GENETIC VARIABILITY WITH PAIN SENSITIVITY AND ANALGESIC RESPONSE. WHILE MOST OF THESE STUDIES HAVE BEEN CONDUCTED AMONG COHORTS OF SUBJECTS OF EUROPEAN DESCENT, SOME HAVE INCLUDED OTHER RACIAL AND ETHNIC GROUPS, PROVIDING EVIDENCE OF VARIABLE RESPONSES TO ANALGESICS. SIMULTANEOUSLY, THERE IS AN INCREASED RECOGNITION REGARDING THE COMPLEXITY OF PAIN RESEARCH, ACKNOWLEDGING THE ADDITIONAL ROLE OF EPIGENETIC, TRANSCRIPTOMIC, PROTEOMIC, AND METABOLOMIC FACTORS IN THE DEVELOPMENT, EXPERIENCE, AND TREATMENT OF PAIN. THIS ARTICLE PROVIDES AN INTRODUCTION TO POPULATION-SPECIFIC PHARMACOGENETICS, PROTEOMICS AND OTHER "-OMICS" TECHNOLOGIES TO PREDICT DRUG RESPONSE TO PAIN MEDICATIONS IN CHILDREN. IT AIMS TO PROVIDE ANESTHESIOLOGISTS WITH THE BASIC KNOWLEDGE TO UNDERSTAND THE POTENTIAL IMPLICATIONS OF GENETIC AND EPIGENETIC FACTORS MANAGING THE PAIN OF PEDIATRIC PATIENTS. 2015 8 4915 38 PAIN, ANALGESIA AND GENETICS. OBJECTIVES: IN THE CLINICAL SETTING, THERE IS MARKED INTERSUBJECT VARIABILITY IN THE INTENSITY OF PAIN REPORTED BY PATIENTS WITH APPARENTLY SIMILAR PAIN STATES, AS WELL AS WIDELY DIFFERING ANALGESIC DOSING REQUIREMENTS BETWEEN INDIVIDUALS TO PRODUCE SATISFACTORY PAIN RELIEF WITH TOLERABLE SIDE-EFFECTS. GENETIC AND ENVIRONMENTAL FACTORS AS WELL AS THEIR INTERACTION ARE IMPLICATED, AND THESE ARE DISCUSSED IN THIS REVIEW. KEY FINDINGS: PIONEERING WORK UNDERTAKEN IN MICE MORE THAN A DECADE AGO, SHOWED A STRONG GENETIC CONTRIBUTION TO LEVELS OF NOCICEPTION/HYPERSENSITIVITY AS WELL AS LEVELS OF ANTINOCICEPTION PRODUCED BY COMMONLY AVAILABLE ANALGESIC AGENTS. TO DATE MORE THAN 300 CANDIDATE 'PAIN' GENES HAVE BEEN IDENTIFIED AS POTENTIALLY CONTRIBUTING TO HERITABLE DIFFERENCES IN PAIN SENSITIVITY AND ANALGESIC RESPONSIVENESS IN ANIMALS AND HUMANS, WITH THIS INFORMATION AVAILABLE IN A PUBLICLY ACCESSIBLE DATABASE HTTP://WWW.JBLDESIGN.COM/JMOGIL/ENTER.HTML. SINCE THEN, MANY GENETIC ASSOCIATION STUDIES HAVE BEEN CONDUCTED IN HUMANS TO INVESTIGATE THE POSSIBILITY THAT SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) IN AN INDIVIDUAL GENE MAY EXPLAIN DRUG INEFFICACY OR EXCESSIVE TOXICITY EXPERIENCED BY A SMALL SUBSET OF THE WHOLE POPULATION WHO HAVE THE RARE ALLELE FOR A PARTICULAR SNP. SUMMARY: DESPITE THE FACT THAT SNPS IN MORE THAN 20 GENES THAT AFFECT PAIN SENSITIVITY OR CONTRIBUTE TO INTERINDIVIDUAL VARIABILITY IN RESPONSES TO ANALGESIC MEDICATIONS HAVE BEEN IDENTIFIED IN THE HUMAN GENOME, MUCH OF THE DATA IS CONFLICTING. APART FROM DEFICIENCIES IN THE DESIGN AND CONDUCT OF HUMAN GENETIC ASSOCIATION STUDIES, RECENT RESEARCH FROM OTHER FIELDS HAS IMPLICATED EPIGENETIC MECHANISMS THAT FACILITATE DYNAMIC GENE-ENVIRONMENT COMMUNICATION, AS A POSSIBLE EXPLANATION. 2011 9 5926 30 TARGETING EPIGENETIC MECHANISMS FOR CHRONIC PAIN: A VALID APPROACH FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. CHRONIC PAIN IS A MULTIFACETED AND COMPLEX CONDITION. BROADLY CLASSIFIED INTO SOMATIC, VISCERAL, OR NEUROPATHIC PAIN, IT IS POORLY MANAGED DESPITE ITS PREVALENCE. CURRENT DRUGS USED FOR THE TREATMENT OF CHRONIC PAIN ARE LIMITED BY TOLERANCE WITH LONG-TERM USE, ABUSE POTENTIAL, AND MULTIPLE ADVERSE SIDE EFFECTS. THE PERSISTENT NATURE OF PAIN SUGGESTS THAT EPIGENETIC MACHINERY MAY BE A CRITICAL FACTOR DRIVING CHRONIC PAIN. IN THIS REVIEW, WE DISCUSS THE LATEST INSIGHTS INTO EPIGENETIC PROCESSES, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS, AND WE DESCRIBE THEIR INVOLVEMENT IN THE PATHOPHYSIOLOGY OF CHRONIC PAIN AND WHETHER EPIGENETIC MODIFICATIONS COULD BE APPLIED AS FUTURE THERAPEUTIC TARGETS FOR CHRONIC PAIN. WE PROVIDE EVIDENCE FROM EXPERIMENTAL MODELS AND TRANSLATIONAL RESEARCH IN HUMAN TISSUE THAT HAVE ENHANCED OUR UNDERSTANDING OF EPIGENETIC PROCESSES MEDIATING NOCICEPTION, AND WE THEN SPECULATE ON THE POTENTIAL FUTURE USE OF MORE SPECIFIC AND SELECTIVE AGENTS THAT TARGET EPIGENETIC MECHANISMS TO ATTENUATE PAIN. 2016 10 5039 42 PHARMACOGENETICS OF CHRONIC PAIN MANAGEMENT. OBJECTIVE: THE EXPERIENCE OF CHRONIC PAIN IS ONE OF THE COMMONEST REASONS INDIVIDUALS SEEK MEDICAL ATTENTION, MAKING THE MANAGEMENT OF CHRONIC PAIN A MAJOR ISSUE IN CLINICAL PRACTICE. DRUG METABOLISM AND RESPONSES ARE AFFECTED BY MANY FACTORS, WITH GENETIC VARIATIONS OFFERING ONLY A PARTIAL EXPLANATION OF AN INDIVIDUAL'S RESPONSE. THERE IS A PAUCITY OF EVIDENCE FOR THE BENEFITS OF PHARMACOGENETIC TESTING IN THE CONTEXT OF PAIN MANAGEMENT. DESIGN AND METHODS: WE REVIEWED THE LITERATURE BETWEEN 2000 AND 2013, AND REFERENCES CITED THEREIN, USING VARIOUS KEYWORDS RELATED TO PAIN MANAGEMENT, PHARMACOLOGY AND PHARMACOGENETICS. RESULTS: OPIOIDS CONTINUE TO BE THE MAINSTAY OF CHRONIC PAIN MANAGEMENT. SEVERAL NON-OPIOID BASED THERAPIES, SUCH AS TREATMENT WITH CANNABINOIDS, GENE THERAPY AND EPIGENETIC-BASED APPROACHES ARE NOW AVAILABLE FOR THESE PATIENTS. ADJUVANT THERAPIES WITH ANTIDEPRESSANTS, BENZODIAZEPINES OR ANTICONVULSANTS CAN ALSO BE USEFUL IN MANAGING PAIN. CURRENTLY, LABORATORY MONITORING OF PAIN MANAGEMENT PATIENTS, IF PERFORMED, IS LARGELY THROUGH URINE DRUG MEASUREMENTS. CONCLUSIONS: DRUG HALF-LIFE CALCULATIONS CAN BE USED AS FUNCTIONAL MARKERS OF THE CUMULATIVE EFFECT OF PHARMACOGENETICS AND DRUG-DRUG INTERACTIONS. ASSESSMENT OF HALF-LIFE AND THERAPEUTIC EFFECTS MAY BE MORE USEFUL THAN GENETIC TESTING IN PREVENTING ADVERSE DRUG REACTIONS TO PAIN MEDICATIONS, WHILE ENSURING EFFECTIVE ANALGESIA. DEFINITIVE, MASS SPECTROMETRY-BASED METHODS, CAPABLE OF MEASURING PARENT DRUG AND METABOLITE LEVELS, ARE THE MOST USEFUL ASSAYS FOR THIS PURPOSE. URINE DRUG MEASUREMENTS DO NOT NECESSARILY CORRELATE WITH SERUM DRUG CONCENTRATIONS OR THERAPEUTIC EFFECTS. THEREFORE, THEY ARE LIMITED IN THEIR USE IN MONITORING EFFICACY AND TOXICITY. 2014 11 2611 26 EPIGENETICS: A PROMISING PARADIGM FOR BETTER UNDERSTANDING AND MANAGING PAIN. EPIGENETIC REGULATION OF GENE EXPRESSION IS A RAPIDLY GROWING AREA OF RESEARCH. CONSIDERING THE LONGEVITY AND PLASTICITY OF NEURONS, THE STUDIES ON EPIGENETIC PATHWAYS IN THE NERVOUS SYSTEM SHOULD BE OF SPECIAL INTEREST FOR BOTH EPIGENETICISTS AND NEUROSCIENTISTS. ACTIVATION OR INACTIVATION OF DIFFERENT EPIGENETIC PATHWAYS BECOMES MORE PRONOUNCED WHEN THE CELLS EXPERIENCE RAPID CHANGES IN THEIR ENVIRONMENT, AND SUCH CHANGES CAN BE EASILY CAUSED BY INJURY AND INFLAMMATION, RESULTING IN PAIN PERCEPTION OR DISTORTION OF PAIN PERCEPTION (EG, HYPERALGESIA). THEREFORE, IN THIS REGARD, THE FIELD OF PAIN IS AT AN ADVANTAGE TO STUDY THE EPIGENETIC PATHWAYS. MORE IMPORTANTLY, UNDERSTANDING PAIN FROM AN EPIGENETICS POINT OF VIEW WOULD PROVIDE A NEW PARADIGM FOR DEVELOPING DRUGS OR STRATEGIES FOR PAIN MANAGEMENT. IN THIS REVIEW, WE INTRODUCE BASIC CONCEPTS OF EPIGENETICS, INCLUDING CHROMATIN DYNAMICS, HISTONE MODIFICATIONS, DNA METHYLATION, AND RNA-INDUCED GENE SILENCING. IN ADDITION, WE PROVIDE EVIDENCE FROM PUBLISHED STUDIES SUGGESTING WIDE IMPLICATION OF DIFFERENT EPIGENETIC PATHWAYS WITHIN PAIN PATHWAYS. PERSPECTIVE: THIS ARTICLE PROVIDES A BRIEF OVERVIEW OF EPIGENETIC PATHWAYS FOR GENE REGULATION AND HIGHLIGHTS THEIR INVOLVEMENT IN PAIN. OUR GOAL IS TO EXPOSE THE READERS TO THESE CONCEPTS SO THAT PAIN-RELATED PHENOTYPES CAN BE INVESTIGATED FROM THE EPIGENETIC POINT OF VIEW. 2013 12 3472 26 IDENTIFICATION AND MANAGEMENT OF PAIN MEDICATION ABUSE AND MISUSE: CURRENT STATE AND FUTURE DIRECTIONS. LONG-TERM OPIOID THERAPY POSES A RISK FOR ABUSE AND MISUSE IN SOME PATIENTS. IDENTIFYING WHICH PATIENTS MAY POTENTIALLY BE AT RISK PRIOR TO INITIATION OF THERAPY, AND IDENTIFYING PATIENTS IN WHOM THESE PROBLEMS DEVELOP DURING THERAPY, ARE SIGNIFICANT CHALLENGES. OUTCOME PREDICTION IS IMPEDED BY THE COMPLEXITY OF THE PROBLEM, WHERE CONSIDERABLE HETEROGENEITY RESULTS FROM PSYCHOLOGICAL AND SOCIOECONOMIC FACTORS, AS WELL AS INTERINDIVIDUAL VARIATION IN BIOLOGICAL PATHWAYS DUE TO GENETIC AND EPIGENETIC FACTORS. SCREENING TOOLS DESIGNED TO DETECT OPIOID MISUSE AND URINE DRUG TESTING ARE BOTH USED CLINICALLY; SCANT EVIDENCE CURRENTLY EXISTS TO ALLOW THE FORMULATION OF AN ALGORITHM FOR JUDICIOUS USE OF THESE TOOLS. MOREOVER, THESE TOOLS MAY NOT BE ADDRESSING THE UNDERLYING ALTERATIONS IN BIOLOGICAL PATHWAYS THAT OCCUR OWING TO THE DEVELOPMENT OF CHRONIC PAIN OR IN RESPONSE TO CHRONIC OPIOID ADMINISTRATION. AN EVIDENCE-BASED ALGORITHMIC APPROACH TO RISK MITIGATION THAT CAN BE APPLIED IN A COST-EFFECTIVE MANNER TO GUIDE THERAPY IS URGENTLY NEEDED. 2012 13 1204 28 COULD TARGETING EPIGENETIC PROCESSES RELIEVE CHRONIC PAIN STATES? PURPOSE OF REVIEW: ABERRATIONS IN THE EPIGENETIC LANDSCAPE HAVE PREVIOUSLY BEEN ASSOCIATED WITH HUMAN DISEASES SUCH AS CANCER AND SCHIZOPHRENIA, AND DRUGS THAT TARGET EPIGENETIC PROCESSES ARE CURRENTLY USED AS THERAPEUTIC AGENTS. THIS ARTICLE WILL REVIEW THE EVIDENCE OBTAINED FROM ANIMAL STUDIES INDICATING THAT EPIGENETIC PROCESSES MIGHT REGULATE LONG-TERM PAIN STATES AND THEN DISCUSS THE POSSIBILITY THAT TARGETING EPIGENETIC MECHANISMS MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. RECENT FINDINGS: RECENT ANIMAL STUDIES HAVE REPORTED INJURY-INDUCED CHANGES IN EPIGENETIC PROCESSES IN THE CENTRAL NERVOUS SYSTEM. THE PICTURE THAT HAS EMERGED IS THAT OF VERY COMPLEX EPIGENETIC PROGRAMS THAT DEPEND ON THE INJURY. HOWEVER, SOME STUDIES HAVE REPORTED THE SUCCESSFUL USE OF NONSPECIFIC EPIGENETIC TOOLS TO IMPROVE THE HYPERSENSITIVITY THAT DEVELOPS IN ANIMAL MODELS OF LONG-TERM PAIN STATES. SUMMARY: THE FIELD OF EPIGENETICS AND PAIN IS RAPIDLY EMERGING BUT FURTHER INVESTIGATION IS NEEDED TO FULLY COMPREHEND THE CONTRIBUTION OF EPIGENETIC PROCESSES TO CHRONIC PAIN STATES. ALTHOUGH THERAPEUTIC APPROACHES TARGETING THESE MECHANISMS MIGHT SEEM WORTHWHILE, WE CANNOT ASSERT THAT CURRENTLY AVAILABLE GLOBAL TOOLS SUCH AS HISTONE DEACETYLASE INHIBITORS CAN BE USED SUCCESSFULLY FOR THE LONG-TERM TREATMENT OF CHRONIC PAIN STATES. 2015 14 1984 27 EPIGENETIC ALTERATIONS IN PRESCRIPTION OPIOID MISUSE: NEW STRATEGIES FOR PRECISION PAIN MANAGEMENT. PRESCRIPTION OPIOIDS ARE USED FOR SOME CHRONIC PAIN CONDITIONS. HOWEVER, GENERALLY, LONG-TERM THERAPY HAS UNWANTED SIDE EFFECTS WHICH MAY TRIGGER ADDICTION, OVERDOSE, AND EVENTUALLY CAUSE DEATHS. OPIOID ADDICTION AND CHRONIC PAIN CONDITIONS HAVE BOTH BEEN ASSOCIATED WITH EVIDENCE OF GENETIC AND EPIGENETIC ALTERATIONS. DESPITE INTENSE RESEARCH INTEREST, MANY QUESTIONS ABOUT THE CONTRIBUTION OF EPIGENETIC CHANGES TO THIS TYPOLOGY OF ADDICTION VULNERABILITY AND DEVELOPMENT REMAIN UNANSWERED. THE AIM OF THIS REVIEW WAS TO SUMMARIZE THE EPIGENETIC MODIFICATIONS DETECTED IN SPECIFIC TISSUES OR BRAIN AREAS AND ASSOCIATED WITH OPIOID PRESCRIPTION AND MISUSE IN PATIENTS WHO HAVE INITIATED PRESCRIBED OPIOID MANAGEMENT FOR CHRONIC NON-CANCER PAIN. THE REVIEW CONSIDERS THE EFFECTS OF OPIOID EXPOSURE ON THE EPIGENOME IN CENTRAL AND PERIPHERAL TISSUES IN ANIMAL MODELS AND HUMAN SUBJECTS AND HIGHLIGHTS THE MECHANISMS IN WHICH OPIOID EPIGENETICS MAY BE INVOLVED. THIS WILL IMPROVE OUR CURRENT UNDERSTANDING, PROVIDE THE BASIS FOR TARGETED, PERSONALIZED PAIN MANAGEMENT, AND THUS BALANCE OPIOID RISKS AND BENEFITS IN MANAGING CHRONIC PAIN. 2021 15 3108 26 GENOMICS OF PAIN IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) ACCOUNTS FOR THE MAJORITY OF THE DISEASE BURDEN FOR MUSCULOSKELETAL DISORDERS AND IS ONE OF THE LEADING CAUSES OF DISABILITY WORLDWIDE. THIS DISABILITY IS THE RESULT NOT OF THE CARTILAGE LOSS THAT DEFINES OA RADIOGRAPHICALLY, BUT OF THE CHRONIC PAIN WHOSE PRESENCE DEFINES SYMPTOMATIC OA. IT IS BECOMING CLEAR THAT MANY GENES, EACH WITH A SMALL EFFECT SIZE, CONTRIBUTE TO THE RISK OF DEVELOPING OA. HOWEVER, THE GENETICS OF OA PAIN ARE ONLY JUST STARTING TO BE EXPLORED. THIS REVIEW WILL DESCRIBE THE FIRST GENES TO HAVE BEEN IDENTIFIED IN GENOMIC STUDIES OF OA PAIN, AS WELL AS THE POSSIBLE DUAL ROLES OF GENES PREVIOUSLY IDENTIFIED IN GENOMIC STUDIES OF OA IN THE CONTEXT OF PAIN. DIFFICULTIES ASSOCIATED WITH ATTEMPTING TO CHARACTERISE THE GENETICS OF OA PAIN WILL BE DISCUSSED AND PROMISING FUTURE AVENUES OF RESEARCH INTO GENETIC AND EPIGENETIC FACTORS AFFECTING OA PAIN DESCRIBED. 2013 16 6447 31 THERAPEUTIC PROSPECTS FOR EPIGENETIC MODULATION. INTRODUCTION: EPIGENETICS DESCRIBES THE PHENOMENON OF HERITABLE CHANGES IN GENE REGULATION GOVERNED BY NON-MENDELIAN PROCESSES, PRIMARILY THROUGH BIOCHEMICAL MODIFICATIONS TO CHROMATIN THAT OCCUR DURING CELL DIFFERENTIATION AND DEVELOPMENT. ABNORMAL LEVELS OF DNA AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. DRUGS THAT TARGET THE PROTEINS CONTROLLING THESE CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS WITH SINGLE TARGET PHARMACOLOGIES THAT ARE SUSCEPTIBLE TO BIOCHEMICAL PATHWAY DEGENERACY. AREAS COVERED: THIS ARTICLE REVIEWS RESEARCH CHARACTERIZING DYSREGULATION OF EPIGENETIC PROCESSES IN CANCER, IMMUNO-INFLAMMATORY, PSYCHIATRIC, NEUROLOGICAL, METABOLIC AND VIROLOGY DISEASE AREAS, AND SUMMARIZES RECENT DEVELOPMENTS IN IDENTIFYING SMALL MOLECULE MODULATORS THAT ARE BEING USED TO INFORM TARGET DISCOVERY AND INITIATE DRUG DISCOVERY PROJECTS. EXPERT OPINION: THERE ARE NUMEROUS POTENTIAL OPPORTUNITIES FOR EPIGENETIC MODULATORS IN TREATING A WIDE RANGE OF CHRONIC DISEASES; HOWEVER, THE FIELD IS COMPLEX, INVOLVING > 300 PROTEINS, AND MUCH WORK IS STILL REQUIRED TO PROVIDE TOOLS TO UNRAVEL THE FUNCTIONS OF INDIVIDUAL PROTEINS, PARTICULARLY IN VIVO. THIS GROUNDWORK IS ESSENTIAL TO ALLOW THE DRUG DISCOVERY COMMUNITY TO FOCUS ON THOSE EPIGENETIC PROTEINS MOST LIKELY TO BE SUITABLE TARGETS FOR SAFE, EFFICACIOUS NEW THERAPIES. 2011 17 4911 19 PAIN IMAGING: FUTURE APPLICATIONS TO INTEGRATIVE CLINICAL AND BASIC NEUROBIOLOGY. WE HAVE ENTERED A NEW ERA IN UNDERSTANDING CNS CIRCUITRY INVOLVED IN ACUTE AND CHRONIC PAIN. THE ABILITY TO OBJECTIVELY MEASURE A PAIN OR ANALGESIC STATE OF THE BRAIN USING NON-INVASIVE METHODS THAT DEFINE NEURAL ACTIVATION PROVIDES THE POSSIBILITY FOR TOP-DOWN APPROACHES TO DRUG DISCOVERY. THESE BRAIN MAPS REPRESENT THE SPECIFIC BRAIN STATE. IN THE FUTURE, CORRELATIONS WITH SUCH STATES AND BEHAVIORAL, GENETIC, EPIGENETIC OR OTHER CHEMICAL MARKERS MAY HELP DEFINE SPECIFIC DIAGNOSTIC TOOLS AND NOVEL APPROACHES TO DRUG DISCOVERY. 2003 18 6124 30 THE EPIGENETIC MECHANISMS INVOLVED IN CHRONIC PAIN IN RODENTS: A MINI- REVIEW. CHRONIC PAIN IS A COMMON DISTRESSING NEUROLOGICAL DISORDER AND ABOUT 30% OF THE GLOBAL POPULATION SUFFERS FROM IT. IN ADDITION TO BEING HIGHLY PREVALENT, CHRONIC PAIN CAUSES A HEAVY ECONOMIC AND SOCIAL BURDEN. ALTHOUGH SUBSTANTIAL PROGRESS HAS BEEN ACHIEVED TO DISSECT THE UNDERLYING MECHANISM OF CHRONIC PAIN IN THE PAST FEW DECADES, THE INCIDENCE AND TREATMENT OF THIS NEUROLOGICAL ILLNESS IS YET NOT PROPERLY MANAGED IN CLINICAL PRACTICE. WHILE NERVE INJURY-, CHEMOTHERAPY- OR INFLAMMATION-INDUCED FUNCTIONAL REGULATION OF GENE EXPRESSION IN THE DORSAL ROOT GANGLION AND SPINAL CORD ARE EXTENSIVELY REPORTED TO BE INVOLVED IN THE PATHOGENIC PROCESS OF CHRONIC PAIN, THE SPECIFIC MECHANISM OF THESE ALTERED TRANSCRIPTIONAL PROFILE STILL REMAINS UNCLEAR. RECENT STUDIES HAVE SHOWN THAT EPIGENETIC MECHANISMS, INCLUDING DNA/RNA METHYLATION, HISTONE MODIFICATION AND CIRCULAR RNAS REGULATION, ARE INVOLVED IN THE OCCURRENCE AND DEVELOPMENT OF CHRONIC PAIN. IN THIS REVIEW, WE PROVIDE A DESCRIPTION OF RESEARCH ON THE ROLE OF EPIGENETIC MECHANISM IN CHRONIC PAIN, SUMMARIZE THE LATEST CLINICAL AND PRECLINICAL ADVANCE IN THIS FIELD, AND PROPOSE THE POTENTIAL DIRECTIONS FOR FURTHER RESEARCH TO ELUCIDATE THE MOLECULAR MECHANISM UNDERLYING THE PATHOGENESIS OF CHRONIC PAIN. 2022 19 2551 29 EPIGENETICS IN PAIN AND ANALGESIA: AN IMMINENT RESEARCH FIELD. HERITABLE PHENOTYPES RESULTING FROM ENVIRONMENT-CAUSED CHANGES IN A CHROMOSOME WITHOUT ALTERATIONS IN THE DNA SEQUENCE ARE INCREASINGLY RECOGNIZED AS A BASIS OF PERSONALIZED THERAPY. EPIGENETIC MECHANISMS INCLUDE COVALENT MODIFICATIONS OF THE DNA (METHYLATION) OR OF THE DNA-PACKAGING HISTONES (E.G., DEACETYLATION OR PHOSPHORYLATION). IN ADDITION, REGULATORY NON-CODING RNA MOLECULES (MICRO-RNAS) EXERT EPIGENETIC ACTIONS. THIS LEADS TO DISRUPTION OR OTHERWISE MODIFIED EXPRESSION OF GENES. ENVIRONMENTAL INFLUENCES SUCH AS NUTRITIONAL FACTORS, EXPOSURE TO CHEMICALS OR DRUGS, BUT ALSO SOCIAL FACTORS APPEAR TO EXERT EPIGENETIC ACTIONS. HISTONE MODIFICATIONS AND DNA METHYLATION ARE ASSOCIATED WITH THE SUBJECT'S AGE. EPIGENETIC MECHANISMS CAN SILENCE THE EXPRESSION OF PRO- OR ANTINOCICEPTIVE GENES. TO THE EPIGENETIC CONTROL OF NOCICEPTION ADDS ITS CONTROL OF THE PHARMACODYNAMICS OR PHARMACOKINETICS OF ANALGESICS BY EPIGENETIC CONTROL OF DRUG TARGETS AND ANALGESICS METABOLIZING ENZYMES. ALTHOUGH EPIGENETICS-BASED STRATEGIES FOR PAIN THERAPY ARE NOT YET AVAILABLE, EXPERIMENTS IN RODENTS SUGGEST THAT RNA INTERFERENCE MAY BECOME A NEW THERAPY APPROACH FOR NEUROPATHIC AND OTHER PAIN. ANOTHER EPIGENETIC APPROACH TO ANALGESIC TREATMENT EMPLOYS INHIBITORS OF HISTONE DEACETYLASE THAT ACT ON THE EPIGENOME BY INDIRECTLY REMODELING THE SPATIAL CONFORMATION OF THE CHROMATIN. FINALLY, EPIGENETIC TECHNIQUES SUCH AS RNA INTERFERENCE HAVE BEEN EMPLOYED IN PAIN RESEARCH TO PROOF THE CONTRIBUTION OF CERTAIN PROTEINS TO NOCICEPTION. THUS, THE NEW FIELD OF EPIGENETICS BECOMES INCREASINGLY USED IN RESEARCH AND MANAGEMENT OF PAIN AND WILL COMPLEMENT GENETICS. THIS ARTICLE INTRODUCES EPIGENETICS TO PAIN AND SUMMARIZES THE CURRENT AND FUTURE UTILITY. 2011 20 5928 25 TARGETING EPIGENETIC MECHANISMS FOR PAIN RELIEF. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS TO CHROMATIN THAT MODULATE GENE ACTIVITY WITHOUT ALTERING THE DNA SEQUENCE. WHILE RESEARCH ON EPIGENETICS HAS GROWN EXPONENTIALLY OVER THE PAST FEW YEARS, VERY FEW STUDIES HAVE INVESTIGATED EPIGENETIC MECHANISMS IN RELATION TO PAIN STATES. HOWEVER, EPIGENETIC MECHANISMS ARE CRUCIAL TO MEMORY FORMATION THAT REQUIRES SIMILAR SYNAPTIC PLASTICITY TO PAIN PROCESSING, INDICATING THAT THEY MAY PLAY A KEY ROLE IN THE CONTROL OF PAIN STATES. THIS ARTICLE REVIEWS THE EARLY EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS ARE ENGAGED AFTER INJURY AND IN CHRONIC PAIN STATES, AND THAT DRUGS USED CLINICALLY TO TARGET THE EPIGENETIC MACHINERY FOR THE TREATMENT OF CANCER MIGHT BE USEFUL FOR THE MANAGEMENT OF CHRONIC PAIN. 2012