1 5039 148 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 2 4915 43 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 3 3472 39 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 4 1160 31 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 5038 35 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 6 5028 35 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 7 5042 42 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 8 6458 36 TIME COURSE OF DNA METHYLATION IN PAIN CONDITIONS: FROM EXPERIMENTAL MODELS TO HUMANS. BACKGROUND AND OBJECTIVE: THROUGHOUT THE LAST DECADE, RESEARCH HAS UNCOVERED ASSOCIATIONS BETWEEN PAIN AND EPIGENETIC ALTERATIONS CAUSED BY ENVIRONMENTAL FACTORS. SPECIFICALLY, STUDIES HAVE DEMONSTRATED CORRELATIONS BETWEEN PAIN CONDITIONS AND ALTERED DNA METHYLATION PATTERNS. THUS, DNA METHYLATION HAS BEEN REVEALED AS A POSSIBLE MODULATOR OR CONTRIBUTOR TO PAIN CONDITIONS, PROVIDING A POTENTIAL THERAPEUTIC TARGET FOR TREATMENT BY DNA METHYLATION MODIFICATION. TO DEVELOP SUCH TREATMENTS, IT IS NECESSARY TO CLARIFY A WIDE NUMBER OF ASPECTS ON HOW DNA METHYLATION AFFECTS PAIN PERCEPTION; FIRST AND FOREMOST, THE TEMPORAL DYNAMICS. THE OBJECTIVE OF THE PRESENT REVIEW IS TO PROVIDE AN OVERVIEW OF CURRENT KNOWLEDGE ON TEMPORAL DYNAMICS OF DNA METHYLATION IN RESPONSE TO PAIN, AND TO INVESTIGATE IF A TIMEFRAME CAN BE ESTABLISHED BASED ON THE DATA OF CURRENTLY PUBLISHED STUDIES. DATABASES AND DATA TREATMENT: PUBMED, MEDLINE, GOOGLE SCHOLAR AND EMBASE WERE SEARCHED COMPREHENSIVELY FOR STUDIES OF DNA METHYLATION IN NEUROPATHIC, INFLAMMATORY AND ALTERNATIVE ANIMAL PAIN MODELS, AND IN CHRONIC PAIN PATIENTS INCLUDING COMPLEX REGIONAL PAIN SYNDROME, CHRONIC POSTSURGICAL PAIN, CHRONIC WIDESPREAD PAIN, FIBROMYALGIA AND CROHN'S DISEASE. RESULTS: WE IDENTIFIED 34 ARTICLES HIGHLIGHTING VARIATIONS IN TEMPORAL DYNAMICS OF DNA METHYLATION ACROSS SPECIES AND BETWEEN DIFFERENT TYPES OF PAIN. THESE STUDIES REPRESENT A STARTING POINT TO UNCOVER NEW INSIGHTS IN THE DNA METHYLATION TIME COURSE IN PAIN. CONCLUSIONS: NO TIMEFRAME CAN CURRENTLY BE MADE FOR THE DNA METHYLATION RESPONSE TO PAIN IN ANY OF THE REVIEWED CONDITIONS, HIGHLIGHTING AN IMPORTANT FOCUS AREA FOR FUTURE RESEARCH. 2021 9 38 33 A COMMON ROLE FOR PSYCHOTROPIC MEDICATIONS: MEMORY IMPAIRMENT. THE PSYCHOPATHOLOGIC PROFILE OF MENTAL DISORDERS IS VERY DIVERSE AND PSYCHOTROPIC MEDICATIONS USED TO TREAT THEM DIFFER IN THEIR CHEMICAL STRUCTURE. NEVERTHELESS, THESE DRUGS SHARE THESE FOUR CHARACTERISTICS: DELAYED ONSET OF CLINICAL RESPONSE, NOT ONE OF THEM CAN BE SAID TO CURE, THERE IS A HIGH NUMBER OF NON-RESPONDERS, AND THE MECHANISM RESPONSIBLE FOR THEIR THERAPEUTIC ACTION IS NOT KNOWN. IT IS HYPOTHESIZED THAT THE ACTION OF PSYCHOTROPIC MEDICATIONS IS MEMORY IMPAIRMENT, UNDERSTANDING MEMORY AS THE TRACE LEFT IN THE NERVOUS SYSTEM NOT ONLY BY INDIVIDUAL EXPERIENCES BUT ALSO BY GENETIC AND EPIGENETIC PHENOMENA. IT IS SUGGESTED THAT IT WOULD BE BENEFICIAL TO TRANSLATE SOME RESEARCH STRATEGIES FROM THE NEUROBIOLOGY OF LEARNING AND MEMORY TO THE STUDY OF THE EFFECTS OF PSYCHOTROPIC MEDICATIONS. THE HYPOTHESIS IS BRIEFLY ASSESSED ACCORDING TO THE FOLLOWING THREE CRITERIA: (A). THE COMPARISON BETWEEN THE MOLECULAR EFFECTS OF PSYCHOTROPIC MEDICATIONS AND THE SO-CALLED MOLECULAR BIOLOGY OF LEARNING AND MEMORY, (B). THE EFFECTS OF THESE DRUGS, PREFERENTIALLY AFTER CHRONIC USE, ON MEMORY TESTS, AND (C). THE EFFECTS OF DRUGS THAT IMPAIR MEMORY ON TESTS USED FOR SCREENING PSYCHOTROPIC MEDICATIONS. FINALLY, SOME GENERAL SUGGESTIONS FOR FUTURE RESEARCH ARE POINTED OUT. 2003 10 2108 38 EPIGENETIC FACTORS RELATED TO LOW BACK PAIN: A SYSTEMATIC REVIEW OF THE CURRENT LITERATURE. LOW BACK PAIN (LBP) IS ONE OF THE MOST COMMON CAUSES OF PAIN AND DISABILITY. AT PRESENT, TREATMENT AND INTERVENTIONS FOR ACUTE AND CHRONIC LOW BACK PAIN OFTEN FAIL TO PROVIDE SUFFICIENT LEVELS OF PAIN RELIEF, AND FULL FUNCTIONAL RESTORATION CAN BE CHALLENGING. CONSIDERING THE SIGNIFICANT SOCIO-ECONOMIC BURDEN AND RISK-TO-BENEFIT RATIO OF MEDICAL AND SURGICAL INTERVENTION IN LOW BACK PAIN PATIENTS, THE IDENTIFICATION OF RELIABLE BIOMARKERS SUCH AS EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN COULD BE USEFUL IN CLINICAL PRACTICE. THE AIM OF THIS STUDY WAS TO REVIEW THE AVAILABLE LITERATURE REGARDING THE EPIGENETIC FACTORS ASSOCIATED WITH LOW BACK PAIN. THIS REVIEW WAS CARRIED OUT IN ACCORDANCE WITH PREFERENTIAL REPORTING ITEMS FOR SYSTEMATIC REVIEWS AND META-ANALYSES (PRISMA) GUIDELINES. THE SEARCH WAS CARRIED OUT IN OCTOBER 2022. ONLY PEER-REVIEWED ARTICLES WERE CONSIDERED FOR INCLUSION. FOURTEEN STUDIES WERE INCLUDED AND SHOWED PROMISING RESULTS IN TERMS OF RELIABLE MARKERS. EPIGENETIC MARKERS FOR LBP HAVE THE POTENTIAL TO SIGNIFICANTLY MODIFY DISEASE MANAGEMENT. MOST RECENT EVIDENCE SUGGESTS THAT EPIGENETICS IS A MORE PROMISING FIELD FOR THE IDENTIFICATION OF FACTORS ASSOCIATED WITH LBP, OFFERING A RATIONALE FOR FURTHER INVESTIGATION IN THIS FIELD WITH THE LONG-TERM GOAL OF FINDING EPIGENETIC BIOMARKERS THAT COULD CONSTITUTE BIOLOGICAL TARGETS FOR DISEASE MANAGEMENT AND TREATMENT. 2023 11 6807 28 [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 12 5040 32 PHARMACOGENETICS OF PAIN AND ANALGESIA. PAIN SEVERITY RATINGS AND THE ANALGESIC DOSING REQUIREMENTS OF PATIENTS WITH APPARENTLY SIMILAR PAIN CONDITIONS MAY DIFFER CONSIDERABLY BETWEEN INDIVIDUALS. CONTRIBUTING FACTORS INCLUDE THOSE OF GENETIC AND ENVIRONMENTAL ORIGIN WITH EPIGENETIC MECHANISMS THAT ENABLE DYNAMIC GENE-ENVIRONMENT INTERACTION, MORE RECENTLY IMPLICATED IN PAIN MODULATION. INSIGHT INTO GENETIC FACTORS UNDERPINNING INTER-PATIENT VARIABILITY IN PAIN SENSITIVITY HAS COME FROM RODENT HERITABILITY STUDIES AS WELL AS FAMILIAL AGGREGATION AND TWIN STUDIES IN HUMANS. INDEED, MORE THAN 350 CANDIDATE PAIN GENES HAVE BEEN IDENTIFIED AS POTENTIALLY CONTRIBUTING TO HERITABLE DIFFERENCES IN PAIN SENSITIVITY. A LARGE NUMBER OF GENETIC ASSOCIATION STUDIES CONDUCTED IN PATIENTS WITH A VARIETY OF CLINICAL PAIN TYPES OR IN HUMANS EXPOSED TO EXPERIMENTALLY INDUCED PAIN STIMULI IN THE LABORATORY SETTING, HAVE EXAMINED THE IMPACT OF SINGLE-NUCLEOTIDE POLYMORPHISMS IN VARIOUS TARGET GENES ON PAIN SENSITIVITY AND/OR ANALGESIC DOSING REQUIREMENTS. HOWEVER, THE FINDINGS OF SUCH STUDIES HAVE GENERALLY FAILED TO REPLICATE OR HAVE BEEN ONLY PARTIALLY REPLICATED BY INDEPENDENT INVESTIGATORS. DEFICIENCIES IN STUDY CONDUCT INCLUDING USE OF SMALL SAMPLE SIZE, INAPPROPRIATE STATISTICAL METHODS AND INADEQUATE ATTENTION TO THE POSSIBILITY THAT BETWEEN-STUDY DIFFERENCES IN ENVIRONMENTAL FACTORS MAY ALTER PAIN PHENOTYPES THROUGH EPIGENETIC MECHANISMS, HAVE BEEN IDENTIFIED AS BEING SIGNIFICANT. 2012 13 1736 26 EARLY DETECTION AND PREVENTION OF SCHIZOPHRENIC PSYCHOSIS-A REVIEW. PSYCHOTIC DISORDERS OFTEN RUN A CHRONIC COURSE AND ARE ASSOCIATED WITH A CONSIDERABLE EMOTIONAL AND SOCIAL IMPACT FOR PATIENTS AND THEIR RELATIVES. THEREFORE, EARLY RECOGNITION, COMBINED WITH THE POSSIBILITY OF PREVENTIVE INTERVENTION, IS URGENTLY WARRANTED SINCE THE DURATION OF UNTREATED PSYCHOSIS (DUP) SIGNIFICANTLY DETERMINES THE FURTHER COURSE OF THE DISEASE. IN ADDITION TO ESTABLISHED DIAGNOSTIC TOOLS, NEUROBIOLOGICAL FACTORS IN THE DEVELOPMENT OF SCHIZOPHRENIC PSYCHOSES ARE INCREASINGLY BEING INVESTIGATED. IT IS SHOWN THAT NUMEROUS MOLECULAR ALTERATIONS ALREADY EXIST BEFORE THE CLINICAL ONSET OF THE DISEASE. AS SCHIZOPHRENIC PSYCHOSES ARE NOT ELICITED BY A SINGLE MUTATION IN THE DEOXYRIBONUCLEIC ACID (DNA) SEQUENCE, EPIGENETICS LIKELY CONSTITUTE THE MISSING LINK BETWEEN ENVIRONMENTAL INFLUENCES AND DISEASE DEVELOPMENT AND COULD POTENTIALLY SERVE AS A BIOMARKER. THE RESULTS FROM TRANSCRIPTOMIC AND PROTEOMIC STUDIES POINT TO A DYSREGULATED IMMUNE SYSTEM, LIKELY EVOKED BY EPIGENETIC ALTERATIONS. DESPITE THE INCREASING KNOWLEDGE OF THE NEUROBIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF PSYCHOTIC DISORDERS, FURTHER RESEARCH EFFORTS WITH LARGE POPULATION-BASED STUDY DESIGNS ARE NEEDED TO IDENTIFY SUITABLE BIOMARKERS. IN CONCLUSION, A COMBINATION OF BLOOD EXAMINATIONS, FUNCTIONAL IMAGING TECHNIQUES, ELECTROENCEPHALOGRAPHY (EEG) INVESTIGATIONS AND POLYGENIC RISK SCORES SHOULD BE CONSIDERED AS THE BASIS FOR PREDICTING HOW SUBJECTS WILL TRANSITION INTO MANIFEST PSYCHOSIS. 2021 14 6159 48 THE GENETICS AND EPIGENETICS OF FATIGUE. FATIGUE IS A COMMON SYMPTOM AND INCLUDES BOTH PHYSICAL AND MENTAL COMPONENTS. IT CAN BE ASSOCIATED WITH A VARIETY OF DIFFERENT SYNDROMES AND DISEASES, BUT IN MANY CASES IS NOT ASSOCIATED WITH OTHER COMORBID CONDITIONS. MOST HUMANS HAVE EXPERIENCED ACUTE FATIGUE IN RELATION TO DIFFERENT STRESSORS. ACUTE FATIGUE TYPICALLY DECREASES AS THE EFFECT OF THE TRIGGERING FACTOR IS REDUCED AND A NORMAL HOMEOSTATIC BALANCE IS RESTORED. FATIGUE THAT PERSISTS FOR 6 MONTHS OR MORE IS TERMED CHRONIC FATIGUE. CHRONIC FATIGUE (CF) IN COMBINATION WITH A MINIMUM OF 4 OF 8 SYMPTOMS AND THE ABSENCE OF DISEASES THAT COULD EXPLAIN THESE SYMPTOMS, CONSTITUTE THE CASE DEFINITION FOR CHRONIC FATIGUE SYNDROME. IN SPITE OF ITS PREVALENCE, THE BIOLOGY OF FATIGUE IS RELATIVELY POORLY UNDERSTOOD AND BIOLOGICAL MARKERS HAVE NOT YET BEEN IDENTIFIED. THIS LITERATURE SEARCH WAS PERFORMED IN PUBMED TO IDENTIFY RESEARCH ON THE GENETICS AND EPIGENETICS OF FATIGUE. PUBLICATIONS WERE INCLUDED IF FATIGUE WAS A MAJOR TOPIC AND THE TOPIC WAS COMBINED WITH GENETIC AND/OR EPIGENETIC MEASUREMENTS IN ADULT HUMANS. A TOTAL OF 40 PUBLICATIONS WERE IDENTIFIED. ALTHOUGH ALTERED FUNCTIONING IN THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS, THE SEROTONERGIC SYSTEM, AND ASSOCIATIONS WITH INFECTIOUS AGENTS HAVE BEEN IDENTIFIED, THE SEARCH FOR GENETIC OR EPIGENETIC MARKERS OF FATIGUE, EITHER IN THE CONTEXT OF CF OR CHRONIC FATIGUE SYNDROME (CFS) HAS BEEN RELATIVELY UNPRODUCTIVE OR, IN THE CASE OF EPIGENETICS, NONEXISTENT. ALTHOUGH SEVERAL STUDIES, BOTH HYPOTHESIS-TESTING AND HYPOTHESIS-GENERATING, HAVE BEEN PERFORMED TO SEARCH FOR BIOMARKERS, THEY HAVE MOSTLY BEEN UNDERPOWERED, RESTRICTED BY THE HETEROGENEITY OF THE PHENOTYPE, OR LIMITED BY AN UNSYSTEMATIC STUDY DESIGN. TO BE ABLE TO CONFIRM THE HYPOTHESIS THAT RISK FOR, OR LEVELS OF, FATIGUE ARE INFLUENCED BY THE GENETIC OR EPIGENETIC BACKGROUND OF AN INDIVIDUAL, STUDIES NEED TO BE BASED ON LARGER SAMPLE SIZES WITH A MORE CLEARLY DEFINED PHENOTYPE. STUDIES NEED TO FOCUS NOT ONLY ON THE INFLUENCE OF A SINGLE ASPECT SUCH AS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OR DIFFERENTIAL GENE EXPRESSION ON DISEASE RISK OR STATE, BUT ALSO ON THE SYSTEMS BIOLOGY BEHIND THE DISEASE IN COMBINATION WITH INFORMATION ON ENVIRONMENTAL INFLUENCES AND VALIDATION OF FINDINGS IN FUNCTIONAL STUDIES. 2010 15 1314 32 DELINEATING CONDITIONS AND SUBTYPES IN CHRONIC PAIN USING NEUROIMAGING. DIFFERENTIATING SUBTYPES OF CHRONIC PAIN STILL REMAINS A CHALLENGE-BOTH FROM A SUBJECTIVE AND OBJECTIVE POINT OF VIEW. PERSONALIZED MEDICINE IS THE CURRENT GOAL OF MODERN MEDICAL CARE AND IS LIMITED BY THE SUBJECTIVE NATURE OF PATIENT SELF-REPORTING OF SYMPTOMS AND BEHAVIORAL EVALUATION. PHYSIOLOGY-FOCUSED TECHNIQUES SUCH AS GENOME AND EPIGENETIC ANALYSES INFORM THE DELINEATION OF PAIN GROUPS; HOWEVER, EXCEPT UNDER RARE CIRCUMSTANCES, THEY HAVE DILUTED EFFECTS THAT AGAIN, SHARE A COMMON RELIANCE ON BEHAVIORAL EVALUATION. THE APPLICATION OF STRUCTURAL NEUROIMAGING TOWARDS DISTINGUISHING PAIN SUBTYPES IS A GROWING FIELD AND MAY INFORM PAIN-GROUP CLASSIFICATION THROUGH THE ANALYSIS OF BRAIN REGIONS SHOWING HYPERTROPHIC AND ATROPHIC CHANGES IN THE PRESENCE OF PAIN. ANALYTICAL TECHNIQUES SUCH AS MACHINE-LEARNING CLASSIFIERS HAVE THE CAPACITY TO PROCESS LARGE VOLUMES OF DATA AND DELINEATE DIAGNOSTICALLY RELEVANT INFORMATION FROM NEUROIMAGING ANALYSIS. THE ISSUE OF DEFINING A "BRAIN TYPE" IS AN EMERGING FIELD AIMED AT INTERPRETING OBSERVED BRAIN CHANGES AND DELINEATING THEIR CLINICAL IDENTITY/SIGNIFICANCE. IN THIS REVIEW, 2 CHRONIC PAIN CONDITIONS (MIGRAINE AND IRRITABLE BOWEL SYNDROME) WITH SIMILAR CLINICAL PHENOTYPES ARE COMPARED IN TERMS OF THEIR STRUCTURAL NEUROIMAGING FINDINGS. INDEPENDENT INVESTIGATIONS ARE COMPARED WITH FINDINGS FROM APPLICATION OF MACHINE-LEARNING ALGORITHMS. FINDINGS ARE DISCUSSED IN TERMS OF DIFFERENTIATING PATIENT SUBGROUPS USING NEUROIMAGING DATA IN PATIENTS WITH CHRONIC PAIN AND HOW THEY MAY BE APPLIED TOWARDS DEFINING A PERSONALIZED PAIN SIGNATURE THAT HELPS SEGREGATE PATIENT SUBGROUPS (EG, MIGRAINE WITH AND WITHOUT AURA, WITH OR WITHOUT NAUSEA; IRRITABLE BOWEL SYNDROME VS OTHER FUNCTIONAL GASTROINTESTINAL DISORDERS). 2019 16 728 35 CAN WE IDENTIFY PATIENTS WITH HIGH RISK OF OSTEOARTHRITIS PROGRESSION WHO WILL RESPOND TO TREATMENT? A FOCUS ON BIOMARKERS AND FRAILTY. OSTEOARTHRITIS (OA), A DISEASE AFFECTING DIFFERENT PATIENT PHENOTYPES, APPEARS AS AN OPTIMAL CANDIDATE FOR PERSONALIZED HEALTHCARE. THE AIM OF THE DISCUSSIONS OF THE EUROPEAN SOCIETY FOR CLINICAL AND ECONOMIC ASPECTS OF OSTEOPOROSIS AND OSTEOARTHRITIS (ESCEO) WORKING GROUP WAS TO EXPLORE THE VALUE OF MARKERS OF DIFFERENT SOURCES IN DEFINING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. THE ESCEO ORGANIZED A SERIES OF MEETINGS TO EXPLORE THE POSSIBILITY OF IDENTIFYING PATIENTS WHO WOULD MOST BENEFIT FROM TREATMENT FOR OA, ON THE BASIS OF RECENT DATA AND EXPERT OPINION. IN THE FIRST MEETING, PATIENT PHENOTYPES WERE IDENTIFIED ACCORDING TO THE NUMBER OF AFFECTED JOINTS, BIOMECHANICAL FACTORS, AND THE PRESENCE OF LESIONS IN THE SUBCHONDRAL BONE. IN THE SECOND MEETING, SUMMARIZED IN THE PRESENT ARTICLE, THE WORKING GROUP EXPLORED OTHER MARKERS INVOLVED IN OA. PROFILES OF PATIENTS MAY BE DEFINED ACCORDING TO THEIR LEVEL OF PAIN, FUNCTIONAL LIMITATION, AND PRESENCE OF COEXISTENT CHRONIC CONDITIONS INCLUDING FRAILTY STATUS. A CONSIDERABLE AMOUNT OF DATA SUGGESTS THAT MAGNETIC RESONANCE IMAGING MAY ALSO ASSIST IN DELINEATING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. AMONG MULTIPLE BIOCHEMICAL BIOMARKERS IDENTIFIED, NONE IS SUFFICIENTLY VALIDATED AND RECOGNIZED TO IDENTIFY PATIENTS WHO SHOULD BE TREATED. CONSIDERABLE EFFORTS ARE ALSO BEING MADE TO IDENTIFY GENETIC AND EPIGENETIC FACTORS INVOLVED IN OA, BUT RESULTS ARE STILL LIMITED. THE MANY POTENTIAL BIOMARKERS THAT COULD BE USED AS POTENTIAL STRATIFIERS ARE PROMISING, BUT MORE RESEARCH IS NEEDED TO CHARACTERIZE AND QUALIFY THE EXISTING BIOMARKERS AND TO IDENTIFY NEW CANDIDATES. 2015 17 4911 26 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 6260 23 THE MOLECULAR NEUROBIOLOGY OF CHRONIC PAIN-INDUCED DEPRESSION. THE INCREASING NUMBER OF INDIVIDUALS WITH COMORBIDITIES POSES AN URGENT NEED TO IMPROVE THE MANAGEMENT OF PATIENTS WITH MULTIPLE CO-EXISTING DISEASES. AMONG THESE COMORBIDITIES, CHRONIC PAIN AND MOOD DISORDERS, TWO LONG-LASTING DISABLING CONDITIONS THAT SIGNIFICANTLY REDUCE THE QUALITY OF LIFE, COULD BE CITED FIRST. THE RECENT DEVELOPMENT OF ANIMAL MODELS ACCELERATED THE STUDIES FOCUSING ON THE UNDERLYING MECHANISMS OF THE CHRONIC PAIN AND DEPRESSION/ANXIETY COMORBIDITY. THIS REVIEW PROVIDES AN OVERVIEW OF CLINICAL AND PRE-CLINICAL STUDIES PERFORMED OVER THE PAST TWO DECADES ADDRESSING THE MOLECULAR ASPECTS OF THE COMORBID RELATIONSHIP OF CHRONIC PAIN AND DEPRESSION. WE THUS FOCUSED ON THE STUDIES THAT INVESTIGATED THE MOLECULAR CHARACTERISTICS OF THE COMORBID RELATIONSHIP BETWEEN CHRONIC PAIN AND MOOD DISORDERS, ESPECIALLY MAJOR DEPRESSIVE DISORDERS, FROM THE GENETIC AND EPIGENETIC POINT OF VIEW TO KEY NEUROMODULATORS WHICH HAVE BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN THIS COMORBIDITY. 2019 19 638 51 BIOMARKERS ASSOCIATED WITH MIGRAINE AND THEIR POTENTIAL ROLE IN MIGRAINE MANAGEMENT. OBJECTIVE: THE FOCUS OF THIS REVIEW IS TO REVIEW POTENTIAL DIAGNOSTIC AND THERAPEUTIC BIOMARKERS ASSOCIATED WITH MIGRAINE. BACKGROUND: MIGRAINE HEADACHE IS A COMMON DISEASE THAT AFFECTS MILLIONS OF INDIVIDUALS WORLDWIDE. ALTHOUGH WELL-ACCEPTED DIAGNOSTIC CRITERIA EXIST FOR MIGRAINE, IT IS STILL A COMPLEX DISORDER THAT REMAINS BOTH UNDERDIAGNOSED AND MISDIAGNOSED. THE CAUSES OF MIGRAINE ARE LIKELY A MIX OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT, TOGETHER WITH THE INDIVIDUAL'S LIFE HISTORY, TRANSLATE INTO THE OBSERVED CLINICAL HETEROGENEITY. INHERENT CLINICAL HETEROGENEITY IS AN OBSTACLE IN DEVELOPING MORE EFFECTIVE TREATMENTS. THE LACK OF APPROPRIATE BIOMARKERS IS ALSO AN IMPEDIMENT TO DEVELOPING MORE EFFECTIVE THERAPEUTIC/PREVENTIVE APPROACHES. ULTIMATELY, BIOMARKERS MAY FACILITATE THE GOAL OF INDIVIDUALIZED MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER TYPES OF HEADACHE. METHODS: A COMPREHENSIVE REVIEW WAS CONDUCTED OF PUBMED CITATIONS CONTAINING THE KEY WORD "MARKER" OR "BIOMARKER" COMBINED WITH "MIGRAINE" OR "HEADACHE." OTHER KEY WORDS INCLUDED "SERUM," "SALIVA," "CEREBROSPINAL FLUID," "GENES," "BLOOD," AND "INFLAMMATION." THE ONLY RESTRICTION WAS ENGLISH-LANGUAGE PUBLICATION. THE ABSTRACTS OF ALL ARTICLES MEETING THESE CRITERIA WERE REVIEWED, AND FULL TEXT WAS RETRIEVED AND EXAMINED FOR RELEVANT REFERENCES. RESULTS: DATA FROM HUMAN STUDIES HAVE BEGUN TO IDENTIFY GENETIC MUTATIONS/POLYMORPHISMS AND ALTERED LEVELS OF SPECIFIC PROINFLAMMATORY AND NEUROMODULATORY MOLECULES THAT STRONGLY CORRELATE WITH MIGRAINE AS WELL AS SYMPTOM SEVERITY. RESULTS FROM A SMALLER NUMBER OF STUDIES HAVE IDENTIFIED PARAMETERS, SUCH AS THE NEUROPEPTIDE CALCITONIN GENE-RELATED PEPTIDE (CGRP), WHICH ARE SIGNIFICANTLY ASSOCIATED WITH RESPONSE TO SPECIFIC TREATMENTS FOR ACUTE MIGRAINE ATTACKS AND PROPHYLAXIS. EPIGENETIC MECHANISMS MAY ALSO BE INVOLVED IN THE DEVELOPMENT OF MIGRAINE, AND UNDERSTANDING ENVIRONMENTALLY INDUCED GENETIC CHANGES ASSOCIATED WITH THIS DISEASE MAY EVENTUALLY GUIDE THE DEVELOPMENT OF THERAPIES CAPABLE OF REVERSING THESE PATHOPHYSIOLOGICAL CHANGES IN GENE FUNCTION. CONCLUSIONS: THE UNDERSTANDING OF THE ETIOLOGY OF MIGRAINE IS INCOMPLETE. ALTHOUGH THE IDENTIFICATION AND VALIDATION OF BIOMARKERS HAS GREATLY ADVANCED DIAGNOSTIC PRECISION AND MEASURES OF THERAPEUTIC EFFICACY IN OTHER DISEASES, THERE ARE NO CURRENTLY ACCEPTED BIOMARKERS FOR CHRONIC OR EPISODIC MIGRAINE. HOWEVER, THE CONTINUED INVESTIGATION AND IDENTIFICATION OF GENETIC, EPIGENETIC, AND MOLECULAR BIOMARKERS IS LIKELY TO FACILITATE THE GOAL OF INDIVIDUALIZING MEDICINE BY ENABLING CLINICIANS TO MORE ACCURATELY DIAGNOSE AND TREAT MIGRAINE AND OTHER HEADACHE DISORDERS. 2013 20 2816 40 FIBROMYALGIA: PATHOGENESIS, MECHANISMS, DIAGNOSIS AND TREATMENT OPTIONS UPDATE. FIBROMYALGIA IS A SYNDROME CHARACTERIZED BY CHRONIC AND WIDESPREAD MUSCULOSKELETAL PAIN, OFTEN ACCOMPANIED BY OTHER SYMPTOMS, SUCH AS FATIGUE, INTESTINAL DISORDERS AND ALTERATIONS IN SLEEP AND MOOD. IT IS ESTIMATED THAT TWO TO EIGHT PERCENT OF THE WORLD POPULATION IS AFFECTED BY FIBROMYALGIA. FROM A MEDICAL POINT OF VIEW, THIS PATHOLOGY STILL PRESENTS INEXPLICABLE ASPECTS. IT IS KNOWN THAT FIBROMYALGIA IS CAUSED BY A CENTRAL SENSITIZATION PHENOMENON CHARACTERIZED BY THE DYSFUNCTION OF NEURO-CIRCUITS, WHICH INVOLVES THE PERCEPTION, TRANSMISSION AND PROCESSING OF AFFERENT NOCICEPTIVE STIMULI, WITH THE PREVALENT MANIFESTATION OF PAIN AT THE LEVEL OF THE LOCOMOTOR SYSTEM. IN RECENT YEARS, THE PATHOGENESIS OF FIBROMYALGIA HAS ALSO BEEN LINKED TO OTHER FACTORS, SUCH AS INFLAMMATORY, IMMUNE, ENDOCRINE, GENETIC AND PSYCHOSOCIAL FACTORS. A RHEUMATOLOGIST TYPICALLY MAKES A DIAGNOSIS OF FIBROMYALGIA WHEN THE PATIENT DESCRIBES A HISTORY OF PAIN SPREADING IN ALL QUADRANTS OF THE BODY FOR AT LEAST THREE MONTHS AND WHEN PAIN IS CAUSED BY DIGITAL PRESSURE IN AT LEAST 11 OUT OF 18 ALLOGENIC POINTS, CALLED TENDER POINTS. FIBROMYALGIA DOES NOT INVOLVE ORGANIC DAMAGE, AND SEVERAL DIAGNOSTIC APPROACHES HAVE BEEN DEVELOPED IN RECENT YEARS, INCLUDING THE ANALYSIS OF GENETIC, EPIGENETIC AND SEROLOGICAL BIOMARKERS. SYMPTOMS OFTEN BEGIN AFTER PHYSICAL OR EMOTIONAL TRAUMA, BUT IN MANY CASES, THERE APPEARS TO BE NO OBVIOUS TRIGGER. WOMEN ARE MORE PRONE TO DEVELOPING THE DISEASE THAN MEN. UNFORTUNATELY, THE CONVENTIONAL MEDICAL THERAPIES THAT TARGET THIS PATHOLOGY PRODUCE LIMITED BENEFITS. THEY REMAIN LARGELY PHARMACOLOGICAL IN NATURE AND TEND TO TREAT THE SYMPTOMATIC ASPECTS OF VARIOUS DISORDERS REPORTED BY THE PATIENT. THE STATISTICS, HOWEVER, HIGHLIGHT THE FACT THAT 90% OF PEOPLE WITH FIBROMYALGIA ALSO TURN TO COMPLEMENTARY MEDICINE TO MANAGE THEIR SYMPTOMS. 2021