1 5684 187 SHOULD WE EMBRACE THE INCORPORATION OF GENETICALLY GUIDED "DOPAMINE HOMEOSTASIS" IN THE TREATMENT OF REWARD DEFICIENCY SYNDROME (RSD) AS A FRONTLINE THERAPEUTIC MODALITY? IN 2019, THE US CENTER FOR DISEASE CONTROL AND PREVENTION PROVIDED VITAL STATISTICS RELATED TO DRUG OVERDOSES IN THE UNITED STATE1. THEY CONCLUDED THAT IN THE USA THE NUMBER OF DEATHS AT ALMOST 72,000 WAS DUE TO 66.6% OF OPIOID OVERDOSES. IN FACT, THE RATE IS ALARMING AND INCREASING YEARLY. TO MAKE 2021 EVEN MORE SCARY IS THE DAUNTING EFFECT ON INCREASED DRUG USAGE DUE TO COVID 19 AS A PANDEMIC, ALBEIT THE NEW VACCINES. SPECIFICALLY, IN 2020, THE DEATH RATE FROM OPIOID OVERDOSES ROSE TO 13% NATIONALLY AND IN SOME SATES 30%. THE COMMON NEUROMODULATING ASPECTS OF NEUROTRANSMISSION, AND ITS DISRUPTION VIA CHRONIC EXPOSURE OF DRUGS AND BEHAVIORAL ADDICTIONS, REQUIRES FURTHER INTENSE RESEARCH FOCUS ON DEVELOPING NOVEL STRATEGIES TO COMBAT THESE UNWANTED GENETIC AND EPIGENIC INFRACTIONS AS ACCOMPLISHED WITH HEROIN ADDICTION BY OUR GROUP. THE TAKE HOME MESSAGE IS THE PLAUSIBLE ACCEPTANCE OF THE WELL-ESTABLISHED EVIDENCE FOR HYPODOPAMINERGIA, A BLUNTED REWARD PROCESSING SYSTEM, REDUCED RESTING STATE FUNCTIONAL CONNECTIVITY, GENETIC ANTECEDENTS, ANTI- REWARD SYMPTOMATOLOGY, POOR COMPLIANCE WITH MAT, AND GENERALIZED RDS. WITH THIS EVIDENCE IT IS CONCEIVABLE THAT PURSUIT THROUGH INTENSIVE FUTURE RESEARCH SHOULD INVOLVE AN APPROACH THAT INCORPORATES "DOPAMINE HOMEOSTASIS". THIS REQUIRED PARADIGM SHIFT MAY CONSIST OF MANY BENEFICIAL MODALITIES INCLUDING BUT NOT LIMITED TO: EXERCISE, PRO-DOPAMINE REGULATION, NUTRIGENOMICS, COGNITIVE BEHAVIORAL THERAPY, HEDONIC HOT SPOT TARGETS BRAIN, RTMRS, DEEP BRAIN STIMULATION, DIET, GENETIC EDITS, GENETIC GUIDED THERAPEUTICS, EPIGENETIC REPAIR, AMONGST OTHERS. IT IS OUR OPINION THAT NUTRIGENOMICS MAY ASSIST THE MILLIONS OF PEOPLE OF GETTING OUT OF A" HYPODOPAMINERGIC DITCH" WC 250. 2021 2 5230 60 PRO-DOPAMINE REGULATOR (KB220) A FIFTY YEAR SOJOURN TO COMBAT REWARD DEFICIENCY SYNDROME (RDS): EVIDENCE BASED BIBLIOGRAPHY (ANNOTATED). BACKGROUND: WE ARE FACING A SIGNIFICANT CHALLENGE IN COMBATTING THE CURRENT OPIOID AND DRUG EPIDEMIC WORLDWIDE. IN THE USA, ALTHOUGH THERE HAS BEEN NOTABLE PROGRESS, IN 2017 ALONE 72,000 PEOPLE DIED FROM A NARCOTIC OVERDOSE. THE NIAAA & NIDA CONTINUE TO STRUGGLE WITH INNOVATION TO CURB OR ELIMINATE THIS UNWANTED EPIDEMIC. THE CURRENT FDA LIST OF APPROVED MEDICATION ASSISTANCE TREATMENTS (MATS) WORK BY PRIMARILY BLOCKING DOPAMINE FUNCTION AND RELEASE AT THE PRE-NEURON IN THE NUCLEUS ACCUMBENS. WE OPPOSE THIS OPTION IN THE LONG TERM TERTIARY TREATMENT BUT AGREE FOR SHORT TERM HARM REDUCTION POTENTIAL. BIBLIOGRAPHY PRESENTATION: AS AN ALTERNATIVE MOTIF, THE UTILIZATION OF A WELL-RESEARCHED NEURO-NUTRIENT CALLED KB220 HAS BEEN INTENSELY INVESTIGATED IN AT LEAST 38 STUDIES SHOWING EVIDENT EFFECTS RELATED TO EVERYTHING FROM AMA RATE, ATTENUATION OF CRAVING BEHAVIOR, REWARD SYSTEM ACTIVATION INCLUDING BOLD DOPAMINE SIGNALING, RELAPSE PREVENTION, AS WELL AS REDUCTION IN STRESS, ANGER, AND AGGRESSIVE BEHAVIORS. WE ARE CONTINUING RESEARCH ESPECIALLY AS IT RELATES TO GENETIC RISK, INCLUDING THE NOW PATENTED GENETIC ADDICTION RISK SCORE (GARS((R))) AND THE DEVELOPMENT OF "PRECISION ADDICTION MANAGEMENT (PAM)" TO POTENTIALLY COMBAT THE OPIOID/PSYCHOSTIMULANT EPIDEMIC. CONCLUSION: BASED ON ANIMAL RESEARCH AND CLINICAL TRIALS AS PRESENTED HEREIN, THE PRO-DOPAMINE REGULATOR KNOWN AS KB220 SHOWS PROMISE IN THE ADDICTION AND PAIN SPACE. OTHER NEUROBIOLOGICAL AND GENETIC STUDIES ARE REQUIRED TO HELP UNDERSTAND THE MECHANISM OF ACTION OF THIS NEURO-NUTRIENT. HOWEVER, THE EVIDENCE TO DATE POINTS TO INDUCTION OF "DOPAMINE HOMEOSTASIS"ENABLING AN ASYMPTOTIC APPROACH FOR EPIGENETIC INDUCED "NORMALIZATION" OF BRAIN NEUROTRANSMITTER SIGNALING AND ASSOCIATED IMPROVED FUNCTION IN THE FACE OF EITHER GENETIC OR EPIGENETIC IMPAIRMENT OF THE BRAIN REWARD CASCADE (BRC).WITH THAT SAID, WE ARE ENCOURAGED ABOUT THESE RESULTS AS PUBLISHED OVER THE LAST 50 YEARS AND LOOK FORWARD TO CONTINUED ADVANCEMENTS RELATED TO APPROPRIATE NUTRIGENOMIC SOLUTIONS TO THE MILLIONS OF VICTIMS OF ALL ADDICTIONS (FROM DRUGS TO FOOD TO SMOKING TO GAMBLING AND GAMING ESPECIALLY IN OUR NEXT GENERATION) CALLED REWARD SURFEIT SYNDROME (RSS) IN ADOLESCENTS AND REWARD DEFICIENCY SYNDROME (RDS) IN ADULTHOOD. 2018 3 29 37 A BIOPSYCHOSOCIAL OVERVIEW OF THE OPIOID CRISIS: CONSIDERING NUTRITION AND GASTROINTESTINAL HEALTH. THE OPIOID CRISIS HAS REACHED EPIDEMIC PROPORTIONS IN THE UNITED STATES WITH RISING OVERDOSE DEATH RATES. IDENTIFYING THE UNDERLYING FACTORS THAT CONTRIBUTE TO ADDICTION VULNERABILITY MAY LEAD TO MORE EFFECTIVE PREVENTION STRATEGIES. SUPPLY SIDE ENVIRONMENTAL FACTORS ARE A MAJOR CONTRIBUTING COMPONENT. PSYCHOSOCIAL FACTORS SUCH AS STRESS, TRAUMA, AND ADVERSE CHILDHOOD EXPERIENCES HAVE BEEN LINKED TO EMOTIONAL PAIN LEADING TO SELF-MEDICATION. GENETIC AND EPIGENETIC FACTORS ASSOCIATED WITH BRAIN REWARD PATHWAYS AND IMPULSIVITY ARE KNOWN PREDICTORS OF ADDICTION VULNERABILITY. THIS REVIEW ATTEMPTS TO PRESENT A BIOPSYCHOSOCIAL APPROACH THAT CONNECTS VARIOUS SOCIAL AND BIOLOGICAL THEORIES RELATED TO THE ADDICTION CRISIS. THE EMERGING ROLE OF NUTRITION THERAPY WITH AN EMPHASIS ON GASTROINTESTINAL HEALTH IN THE TREATMENT OF OPIOID USE DISORDER IS PRESENTED. THE BIOPSYCHOSOCIAL MODEL INTEGRATES CONCEPTS FROM SEVERAL DISCIPLINES, EMPHASIZING MULTICAUSALITY RATHER THAN A REDUCTIONIST APPROACH. POTENTIAL SOLUTIONS AT MULTIPLE LEVELS ARE PRESENTED, CONSIDERING INDIVIDUAL AS WELL AS POPULATION HEALTH. THIS SINGLE COHESIVE FRAMEWORK IS BASED ON THE INTERDEPENDENCY OF THE ENTIRE SYSTEM, IDENTIFYING RISK AND PROTECTIVE FACTORS THAT MAY INFLUENCE SUBSTANCE-SEEKING BEHAVIOR. NUTRITION SHOULD BE INCLUDED AS ONE FACET OF A MULTIDISCIPLINARY APPROACH TOWARD IMPROVED RECOVERY OUTCOMES. CROSS-DISCIPLINARY COLLABORATIVE EFFORTS, NEW IDEAS, AND FISCAL RESOURCES WILL BE CRITICAL TO ADDRESS THE EPIDEMIC. 2019 4 2934 41 GENETIC ADDICTION RISK SCORE (GARS) , A PREDICTOR OF VULNERABILITY TO OPIOID DEPENDENCE. THE INTERACTION OF NEUROTRANSMITTERS AND GENES THAT CONTROL THE RELEASE OF DOPAMINE IS THE BRAIN REWARD CASCADE (BRC). VARIATIONS WITHIN THE BRC, WHETHER GENETIC OR EPIGENETIC, MAY PREDISPOSE INDIVIDUALS TO ADDICTIVE BEHAVIORS AND ALTERED PAIN TOLERANCE. THIS DISCUSSION AUTHORED BY A GROUP OF CONCERNED SCIENTISTS AND CLINICIANS EXAMINES THE GENETIC ADDICTION RISK SCORE (GARS), THE FIRST TEST TO ACCURATELY PREDICT VULNERABILITY TO PAIN, ADDICTION, AND OTHER COMPULSIVE BEHAVIORS, DEFINED AS REWARD DEFICIENCY SYNDROME (RDS). INNOVATIVE STRATEGIES TO COMBAT EPIDEMIC OPIOID, IATROGENIC PRESCRIPTION DRUG ABUSE AND DEATH, BASED ON THE ROLE OF DOPAMINERGIC TONE IN PAIN PATHWAYS, ARE PROPOSED. SENSITIVITY TO PAIN MAY RESIDE IN THE MESOLIMBIC PROJECTION SYSTEM, WHERE GENETIC POLYMORPHISMS ASSOCIATE WITH A PREDISPOSITION TO PAIN VULNERABILITY OR TOLERANCE. THEY PROVIDE UNIQUE THERAPEUTIC TARGETS THAT COULD ASSIST IN THE TREATMENT OF PAIN, AND IDENTIFY RISK FOR SUBSEQUENT ADDICTION. PHARMACOGENOMIC TESTING OF CANDIDATE GENES LIKE CB1, MU RECEPTORS, AND PENK MIGHT RESULT IN PHARMACOGENOMIC, PERSONALIZED SOLUTIONS, AND IMPROVED CLINICAL OUTCOMES. GENETICALLY IDENTIFYING RISK FOR ALL RDS BEHAVIORS, ESPECIALLY IN COMPROMISED POPULATIONS, MAY BE A FRONTLINE TOOL TO ASSIST MUNICIPALITIES TO PROVIDE BETTER RESOURCE ALLOCATION. 2018 5 6617 34 UNDERPINNING THE NEUROBIOLOGICAL INTRICACIES ASSOCIATED WITH OPIOID TOLERANCE. THE OPIOID CRISIS IS A MAJOR THREAT OF THE 21ST CENTURY, WITH A REMARKABLE JUXTAPOSITION OF USE AND ABUSE. OPIOIDS ARE THE MOST POTENT AND EFFICACIOUS CLASS OF ANALGESICS, BUT DESPITE THEIR PROVEN THERAPEUTIC EFFICACY, THEY HAVE RECENTLY BEEN DEGRADED TO THIRD-LINE THERAPY FOR THE MANAGEMENT OF CHRONIC PAIN IN CLINICS. THE REASON BEHIND THIS IS THE DEVELOPMENT OF POTENTIAL SIDE EFFECTS AND TOLERANCE AFTER REPEATED DOSING. OPIOID TOLERANCE IS THE MAJOR LIMITING FACTOR LEADING TO THE WITHDRAWAL OF TREATMENT, SEVERE SIDE EFFECTS DUE TO DOSE ESCALATION, AND SOMETIMES EVEN DEATH OF THE PATIENTS. EVERY DAY MORE THAN 90 PEOPLE DIE DUE TO OPIOIDS OVERDOSE IN AMERICA, AND A SIMILAR TREND HAS BEEN SEEN ACROSS THE GLOBE. OVER THE PAST TWO DECADES, RESEARCHERS HAVE BEEN TRYING TO DISSECT THE NEUROBIOLOGICAL MECHANISM OF OPIOID TOLERANCE. RESEARCH ON OPIOID TOLERANCE SHIFTED TOWARD CENTRAL NERVOUS SYSTEM-BASED ADAPTATIONS BECAUSE TOLERANCE IS MUCH MORE THAN JUST A CELLULAR PHENOMENON. THUS, NEUROBIOLOGICAL ADAPTATIONS ASSOCIATED WITH OPIOID TOLERANCE ARE IMPORTANT TO UNDERSTAND IN ORDER TO FIND NEWER PAIN THERAPEUTICS. THESE ADAPTATIONS ARE ASSOCIATED WITH ALTERATIONS IN ASCENDING AND DESCENDING PAIN PATHWAYS, REWARD CIRCUITRY MODULATIONS, RECEPTOR DESENSITIZATION AND DOWN-REGULATION, RECEPTOR INTERNALIZATION, HETERODIMERIZATION, AND ALTERED EPIGENETIC REGULATION. THE PRESENT REVIEW IS FOCUSED ON NOVEL CIRCUITRIES ASSOCIATED WITH OPIOID TOLERANCE IN DIFFERENT AREAS OF THE BRAIN, SUCH AS PERIAQUEDUCTAL GRAY, ROSTRAL VENTROMEDIAL MEDULLA, DORSAL RAPHE NUCLEUS, VENTRAL TEGMENTAL AREA, AND NUCLEUS ACCUMBENS. UNDERSTANDING THE NEUROBIOLOGICAL MODULATIONS ASSOCIATED WITH CHRONIC OPIOID EXPOSURE AND TOLERANCE WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL PHARMACOLOGICAL TOOLS FOR SAFER AND BETTER MANAGEMENT OF CHRONIC PAIN IN PATIENTS. 2020 6 1984 32 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 7 4440 34 MOLECULAR GENETIC TESTING IN PAIN AND ADDICTION: FACTS, FICTION AND CLINICAL UTILITY. THE BRAIN REWARD CASCADE (BRC) IS AN INTERACTION OF NEUROTRANSMITTERS AND THEIR RESPECTIVE GENES TO CONTROL THE AMOUNT OF DOPAMINE RELEASED WITHIN THE BRAIN. ANY VARIATIONS WITHIN THIS PATHWAY, WHETHER GENETIC OR ENVIRONMENTAL (EPIGENETIC), MAY RESULT IN ADDICTIVE BEHAVIORS AS WELL AS ALTERED PAIN TOLERANCE. WHILE THERE ARE MANY STUDIES CLAIMING A GENETIC ASSOCIATION WITH ADDICTION AND OTHER BEHAVIORAL INFRACTIONS, DEFINED AS REWARD DEFICIENCY SYNDROME (RDS), NOT ALL ARE SCIENTIFICALLY ACCURATE AND IN SOME CASE JUST WRONG. ALBEIT OUR BIAS, WE DISCUSS HEREIN THE FACTS AND FICTIONS BEHIND MOLECULAR GENETIC TESTING IN RDS (INCLUDING PAIN AND ADDICTION) AND THE SIGNIFICANCE BEHIND THE DEVELOPMENT OF THE GENETIC ADDICTION RISK SCORE (GARSPREDX), THE FIRST TEST TO ACCURATELY PREDICT ONE'S GENETIC RISK FOR RDS. 2015 8 2841 42 FREQUENCY OF THE DOPAMINE RECEPTOR D3 (RS6280) VS. OPIOID RECEPTOR MICRO1 (RS1799971) POLYMORPHIC RISK ALLELES IN PATIENTS WITH OPIOID USE DISORDER: A PREPONDERANCE OF DOPAMINERGIC MECHANISMS? WHILE OPIOIDS ARE A POWERFUL CLASS OF DRUGS THAT INHIBIT TRANSMISSION OF PAIN SIGNALS, THEIR USE IS TARNISHED BY THE CURRENT EPIDEMIC OF OPIOID USE DISORDER (OUD) AND OVERDOSE DEATHS. NOTWITHSTANDING PUBLISHED REPORTS, THERE REMAIN GAPS IN OUR KNOWLEDGE OF OPIOID RECEPTOR MECHANISMS AND THEIR ROLE IN OPIOID SEEKING BEHAVIOR. THUS, NOVEL INSIGHTS INTO MOLECULAR, NEUROGENETIC AND NEUROPHARMACOLOGICAL BASES OF OUD ARE NEEDED. WE PROPOSE THAT AN ADDICTIVE ENDOPHENOTYPE MAY NOT BE ENTIRELY SPECIFIC TO THE DRUG OF CHOICE BUT RATHER MAY BE GENERALIZABLE TO ALTERED BRAIN REWARD CIRCUITS IMPACTING NET MESOCORTICOLIMBIC DOPAMINE RELEASE. WE SUGGEST THAT GENETIC OR EPIGENETIC ALTERATIONS ACROSS DOPAMINERGIC REWARD SYSTEMS LEAD TO UNCONTROLLABLE SELF-ADMINISTRATION OF OPIOIDS AND OTHER DRUGS. FOR INSTANCE, DIMINISHED AVAILABILITY VIA KNOCKOUT OF DOPAMINE D3 RECEPTOR (DRD3) INCREASES VULNERABILITY TO OPIOIDS. BUILDING UPON THIS CONCEPT VIA THE USE OF A SOPHISTICATED POLYMORPHIC RISK ANALYSIS IN A HUMAN COHORT OF CHRONIC OPIOID USERS, WE FOUND EVIDENCE FOR A HIGHER FREQUENCY OF POLYMORPHIC DRD3 RISK ALLELE (RS6280) THAN OPIOID RECEPTOR MICRO1 (RS1799971). IN CONCLUSION, WHILE OPIOIDERGIC MECHANISMS ARE INVOLVED IN OUD, DOPAMINE-RELATED RECEPTORS MAY HAVE PRIMARY INFLUENCE ON OPIOID-SEEKING BEHAVIOR IN AFRICAN AMERICANS. THESE FINDINGS SUGGEST OUD-TARGETED NOVEL AND IMPROVED NEUROPHARMACOLOGICAL THERAPIES MAY REQUIRE FOCUS ON DRD3-MEDIATED REGULATION OF DOPAMINERGIC HOMEOSTASIS. 2022 9 5786 26 SPORT AND MALE SEXUALITY. THE RELATIONSHIPS BETWEEN SPORT AND SEXUALITY IN MALES ARE OF GREAT SOCIAL AND CLINICAL INTEREST, BECAUSE OF SPORTS AND MOTOR ACTIVITIES THAT HIGHLY PROMOTE SOCIAL AND SEXUAL RELATIONSHIPS. EVEN IF FEW LITERATURE EXIST, TWO MAIN QUESTIONS SHOULD BE TAKEN INTO ACCOUNT: WHETHER AND HOW PHYSICAL EXERCISE AND SPORT POSITIVELY OR NEGATIVELY INFLUENCE SEXUAL HEALTH AND BEHAVIOR AND/OR WHETHER AND HOW SEXUAL BEHAVIOR MAY AFFECT A SUB-SEQUENT SPORT PERFORMANCE. PHYSICAL EXERCISE AND SPORT PER SE CAN INFLUENCE, POSITIVELY OR NEGATIVELY, THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS FUNCTION AND, CONSEQUENTLY, THE INDIVIDUAL'S REPRODUCTIVE AND/OR SEXUAL HEALTH. THIS DEPENDS ON INDIVIDUAL FACTORS SUCH AS GENETIC AND EPIGENETIC ONES AND ON DIFFERENT VARIABLES INVOLVED IN THE PRACTICE OF SPORT ACTIVITIES (TYPE OF SPORT, INTENSITY AND DURATION OF TRAINING, DOPING AND DRUG USE AND ABUSE, NUTRITION, SUPPLEMENTS, PSYCHOLOGICAL STRESS, ALLOSTATIC LOAD, ETC.). IF WELL CONDUCTED, MOTOR AND SPORT ACTIVITIES COULD HAVE BENEFICIAL EFFECTS ON SEXUAL HEALTH IN MALES. AMONG DIFFERENT LIFESTYLE CHANGES, INFLUENCING SEXUAL HEALTH, REGULAR PHYSICAL ACTIVITY IS FUNDAMENTAL TO ANTAGONIZE THE ONSET OF ERECTILE DYSFUNCTION (ED). HOWEVER, COMPETITIVE SPORT CAN LEAD BOTH REPRODUCTIVE AND/OR SEXUAL TRACT DAMAGES AND DYSFUNCTIONS, TRANSIENT (GENITAL PAIN, HYPOESTHESIA OF THE GENITALIA, HYPOGONADISM, DE, ALTERED SEXUAL DRIVE, ETC.) OR PERMANENT (HYPOGONADISM, DE, ETC.), BY ACTING DIRECTLY (TRAUMAS OF THE EXTERNAL GENITALIA, SADDLE-RELATED DISORDERS IN CYCLISTS, ETC.) OR INDIRECTLY (EXERCISE-RELATED HYPOGONADISM, DRUG ABUSE, DOPING, STRESS, ETC.). SEXUAL ACTIVITIES SHORTLY PERFORMED BEFORE A SPORT COMPETITION COULD DIFFERENTLY INFLUENCE SPORT PERFORMANCE. DUE TO THE FEW EXISTING DATA, IT IS ADVISABLE TO AVOID AN ABSOLUTE PRE-COMPETITION SEXUAL ABSTINENCE. 2017 10 4418 33 MOLECULAR AND EPIGENETIC ASPECTS OF OPIOID RECEPTORS IN DRUG ADDICTION AND PAIN MANAGEMENT IN SPORT. OPIOIDS ARE SUBSTANCES DERIVED FROM OPIUM (NATURAL OPIOIDS). IN ITS RAW STATE, OPIUM IS A GUMMY LATEX EXTRACTED FROM PAPAVER SOMNIFERUM. THE USE OF OPIOIDS AND THEIR NEGATIVE HEALTH CONSEQUENCES AMONG PEOPLE WHO USE DRUGS HAVE BEEN STUDIED. TODAY, OPIOIDS ARE STILL THE MOST COMMONLY USED AND EFFECTIVE ANALGESIC TREATMENTS FOR SEVERE PAIN, BUT THEIR USE AND ABUSE CAUSES DETRIMENTAL SIDE EFFECTS FOR HEALTH, INCLUDING ADDICTION, THUS IMPACTING THE USER'S QUALITY OF LIFE AND CAUSING OVERDOSE. THE MESOCORTICOLIMBIC DOPAMINERGIC CIRCUITRY REPRESENTS THE BRAIN CIRCUIT MEDIATING BOTH NATURAL REWARDS AND THE REWARDING ASPECTS OF NEARLY ALL DRUGS OF ABUSE, INCLUDING OPIOIDS. HENCE, UNDERSTANDING HOW OPIOIDS AFFECT THE FUNCTION OF DOPAMINERGIC CIRCUITRY MAY BE USEFUL FOR BETTER KNOWLEDGE OF THE PROCESS AND TO DEVELOP EFFECTIVE THERAPEUTIC STRATEGIES IN ADDICTION. THE AIM OF THIS REVIEW WAS TO SUMMARIZE THE MAIN FEATURES OF OPIOIDS AND OPIOID RECEPTORS AND FOCUS ON THE MOLECULAR AND UPCOMING EPIGENETIC MECHANISMS LEADING TO OPIOID ADDICTION. SINCE SYNTHETIC OPIOIDS CAN BE EFFECTIVE FOR PAIN MANAGEMENT, THEIR ABILITY TO INDUCE ADDICTION IN ATHLETES, WITH THE RISK OF INCURRING DOPING, IS ALSO DISCUSSED. 2023 11 3606 34 IMPROVING TREATMENT OF NEURODEVELOPMENTAL DISORDERS: RECOMMENDATIONS BASED ON PRECLINICAL STUDIES. INTRODUCTION: NEURODEVELOPMENTAL DISORDERS (NDDS) ARE COMMON AND SEVERELY DEBILITATING. THEIR CHRONIC NATURE AND RELIANCE ON BOTH GENETIC AND ENVIRONMENTAL FACTORS MAKES STUDYING NDDS AND THEIR TREATMENT A CHALLENGING TASK. AREAS COVERED: HEREIN, THE AUTHORS DISCUSS THE NEUROBIOLOGICAL MECHANISMS OF NDDS, AND PRESENT RECOMMENDATIONS ON THEIR TRANSLATIONAL RESEARCH AND THERAPY, OUTLINED BY THE INTERNATIONAL STRESS AND BEHAVIOR SOCIETY. VARIOUS DRUGS CURRENTLY PRESCRIBED TO TREAT NDDS ALSO REPRESENT A HIGHLY DIVERSE GROUP. ACTING ON VARIOUS NEUROTRANSMITTER AND PHYSIOLOGICAL SYSTEMS, THESE DRUGS OFTEN LACK SPECIFICITY OF ACTION, AND ARE COMMONLY USED TO TREAT MULTIPLE OTHER PSYCHIATRIC CONDITIONS. THERE HAS ALSO BEEN RELATIVELY LITTLE PROGRESS IN THE DEVELOPMENT OF NOVEL MEDICATIONS TO TREAT NDDS. BASED ON CLINICAL, PRECLINICAL AND TRANSLATIONAL MODELS OF NDDS, OUR RECOMMENDATIONS COVER A WIDE RANGE OF METHODOLOGICAL APPROACHES AND CONCEPTUAL STRATEGIES. EXPERT OPINION: TO IMPROVE PHARMACOTHERAPY AND DRUG DISCOVERY FOR NDDS, WE NEED A STRONGER EMPHASIS ON TARGETING MULTIPLE ENDOPHENOTYPES, A BETTER DISSECTION OF GENETIC/EPIGENETIC FACTORS OR "HIDDEN HERITABILITY," AND A CAREFUL CONSIDERATION OF POTENTIAL DEVELOPMENTAL/TROPHIC ROLES OF BRAIN NEUROTRANSMITTERS. THE VALIDITY OF ANIMAL NDD MODELS CAN BE IMPROVED THROUGH DISCOVERY OF NOVEL (BEHAVIORAL, PHYSIOLOGICAL AND NEUROIMAGING) BIOMARKERS, APPLYING PROPER ENVIRONMENTAL ENRICHMENT, WIDENING THE SPECTRUM OF MODEL ORGANISMS, TARGETING DEVELOPMENTAL TRAJECTORIES OF NDD-RELATED BEHAVIORS AND COMORBID CONDITIONS BEYOND TRADITIONAL NDDS. WHILE THESE RECOMMENDATIONS CANNOT BE ADDRESSED ALL IN ONCE, OUR INCREASED UNDERSTANDING OF NDD PATHOBIOLOGY MAY TRIGGER INNOVATIVE CROSS-DISCIPLINARY RESEARCH EXPANDING BEYOND TRADITIONAL METHODS AND CONCEPTS. 2016 12 747 36 CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA AND COGNITIVE DECLINE IN HUMANS: EMBRACING PUTATIVE INDUCTION OF DOPAMINE HOMEOSTASIS. OVER YEARS, THE REGULAR USE OF CANNABIS HAS SUBSTANTIALLY INCREASED AMONG YOUNG ADULTS, AS INDICATED BY THE RISE IN CANNABIS USE DISORDER (CUD), WITH AN ESTIMATED PREVALENCE OF 8. 3% IN THE UNITED STATES. RESEARCH SHOWS THAT EXPOSURE TO CANNABIS IS ASSOCIATED WITH HYPODOPAMINERGIC ANHEDONIA (DEPRESSION), COGNITIVE DECLINE, POOR MEMORY, INATTENTION, IMPAIRED LEARNING PERFORMANCE, REDUCED DOPAMINE BRAIN RESPONSE-ASSOCIATED EMOTIONALITY, AND INCREASED ADDICTION SEVERITY IN YOUNG ADULTS. THE ADDICTION MEDICINE COMMUNITY IS INCREASING CONCERN BECAUSE OF THE HIGH CONTENT OF DELTA-9-TETRAHYDROCANNABINOL (THC) CURRENTLY FOUND IN ORAL AND VAPING CANNABIS PRODUCTS, THE COGNITIVE EFFECTS OF CANNABIS MAY BECOME MORE PRONOUNCED IN YOUNG ADULTS WHO USE THESE CANNABIS PRODUCTS. PRELIMINARY RESEARCH SUGGESTS THAT IT IS POSSIBLE TO INDUCE 'DOPAMINE HOMEOSTASIS,' THAT IS, RESTORE DOPAMINE FUNCTION WITH DOPAMINE UPREGULATION WITH THE PROPOSED COMPOUND AND NORMALIZE BEHAVIOR IN CHRONIC CANNABIS USERS WITH CANNABIS-INDUCED HYPODOPAMINERGIC ANHEDONIA (DEPRESSION) AND COGNITIVE DECLINE. THIS PSYCHOLOGICAL, NEUROBIOLOGICAL, ANATOMICAL, GENETIC, AND EPIGENETIC RESEARCH ALSO COULD PROVIDE EVIDENCE TO USE FOR THE DEVELOPMENT OF AN APPROPRIATE POLICY REGARDING THE DECRIMINALIZATION OF CANNABIS FOR RECREATIONAL USE. 2021 13 609 43 BEYOND MOR: CAN INDUCTION OF DOPAMINE HOMEOSTASIS ALONG WITH ELECTROTHERAPY ATTENUATE THE OPIOID CRISIS? ONE IMPORTANT AREA FOR CONSIDERATION ESPECIALLY IN TERMS OF COMBATING THE ONGOING NEVER ENDING OPIOID CRISIS, RELATES TO NOVEL NEWER ASSESSMENTS FOR ALL ADDICTIVE BEHAVIORS BOTH SUBSTANCE AND NON-SUBSTANCE BEHAVIORS (RDS). IT IS VERY IMPORTANT TO IDENTIFY EARLY IN ONE'S LIFE THE POSSIBILITY OF, BECAUSE OF KNOWN DNA ANTECEDENTS, THE PRESENCE OF PRE-ADDICTION. THE DEVELOPMENT OF THE GENETIC ADDICTION RISK SEVERITY (GARS) TEST, BLUM'S GROUP BELIEVES THAT THIS TYPE OF TESTING SHOULD BE THE "STANDARD OF CARE" FOLLOWING ADDITIONAL STUDIES. UNDERSTANDABLY THAT WHILE POLYMORPHISMS IN THE MU-OPIOID RECEPTOR (MOR) IS OF REAL CONCERN IN TERMS OF SETTING PEOPLE UP FOR PREDISPOSITION TO OPIOID DEPENDENCE, THE GENETIC AND EPIGENETIC STATUS OF DOPAMINERGIC FUNCTION MUST BE CONSIDERED AS WELL. WHILE THIS SOUNDS BOLD (WHICH IT IS) THE RESULTS SHOULD BE PROTECTED BY THE G.I. N. A. LAW ENACTED IN THE USA IN 2011. ONE AVENUE OF FURTHER INVESTIGATION, INSTEAD OF PROVIDING POWERFUL OPIOIDS FOR OPIOID DEPENDENCE, IS TO SEEK OUT NON-ADDICTIVE ALTERNATIVES. ACCORDINGLY, OTHER NON-ADDICTIVE MODALITIES INCLUDING GENETIC GUIDED KB220 (AMINO-ACID-ENKEPHALINASE-N-ACETYLCYSTEINE-NAD), NON-INVASIVE RTMS FOR PSYCHIATRY AND PAIN, EPIGENETIC REMODELING, GENE EDITS, NON-INVASIVE H-WAVE FOR PAIN MANAGEMENT AND ENHANCED FUNCTIONALITY, BRAIN SPOTTING, COGNITIVE BEHAVIORAL THERAPY AWARENESSS INTEGRATION THERAPY, NUCALM, TRAUMA THERAPY, AWARENESS TOOLS, GENOGRAMS, EXERCISE, SPORTS, FITNESS PROGRAMS (ONE HOUR PER DAY), LIGHT THERAPY AND EVEN LAUGHING THERAPY AS WELL AS ANY OTHER KNOWN MODALITIES THAT CAN INDUCE REWARD SYMMETRY. WHILE THE SHORT TERM USE OF OPIOIDS FOR OPIOID DEPENDENCE TO REDUCE HARM IS CERTAINLY ACCEPTABLE, CLINICIANS SHOULD CONSIDER A BETTER LONG-TERM PLAN. 2023 14 5129 23 POSTOPERATIVE PAIN AND ANALGESIA: IS THERE A GENETIC BASIS TO THE OPIOID CRISIS? BACKGROUND: MULTIPLE FACTORS HAVE BEEN IMPLICATED IN DETERMINING WHY CERTAIN PATIENTS HAVE INCREASED POSTOPERATIVE PAIN, WITH THE POTENTIAL TO DEVELOP CHRONIC PAIN. THE PURPOSE OF THIS STUDY WAS TO: 1) IDENTIFY AND DESCRIBE GENES THAT AFFECT POSTOPERATIVE PAIN PERCEPTION AND CONTROL; 2) ADDRESS MODIFIABLE RISK FACTORS THAT RESULT IN EPIGENETIC ALTERED RESPONSES TO PAIN; AND 3) CHARACTERIZE DIFFERENCES IN PAIN SENSITIVITY AND THRESHOLDS BETWEEN OPIOID-NAIVE AND OPIOID-DEPENDENT PATIENTS. MATERIALS AND METHODS: THREE ELECTRONIC DATABASES WERE USED TO CONDUCT THE LITERATURE SEARCH: PUBMED, EBSCO HOST, AND SCOPUS. A TOTAL OF 372 ABSTRACTS WERE REVIEWED, OF WHICH 46 STUDIES WERE DEEMED RELEVANT AND ARE INCLUDED IN THIS REVIEW. RESULTS: SPECIFIC GENE ALTERATIONS THAT WERE SHOWN TO AFFECT POSTOPERATIVE PAIN CONTROL INCLUDED SINGLE NUCLEOTIDE POLYMORPHISMS IN THE MU, KAPPA, AND DELTA OPIOID RECEPTORS, ION CHANNEL GENES, CYTOTOXIC T-CELLS, GLUTAMATE RECEPTORS AND CYTOKINE GENES, AMONG OTHERS. ALCOHOLISM, OBESITY, AND SMOKING WERE ALL LINKED WITH GENETIC POLYMORPHISMS THAT ALTERED PAIN SENSITIVITY. OPIOID ABUSE WAS FOUND TO BE ASSOCIATED WITH A POORER RESPONSE TO ANALGESICS POSTOPERATIVELY, AS WELL AS A RISK FOR PRESCRIPTION OVERDOSE. CONCLUSION: ALTHOUGH PAIN PERCEPTION HAS MULTIPLE COMPLEX INFLUENCES, THE GREATEST VARIABILITY SEEN IN RESPONSE TO OPIOIDS AMONG POSTOPERATIVE PATIENTS KNOWN TO DATE CAN BE TRACED TO GENETIC DIFFERENCES IN OPIOID METABOLISM. FURTHER STUDY IS NEEDED TO DETERMINE THE CLINICAL SIGNIFICANCE OF THESE GENETIC ASSOCIATIONS. 2018 15 1091 33 COGNITIVE ENHANCERS AS A TREATMENT FOR HEROIN RELAPSE AND ADDICTION. HEROIN ADDICTION IS A DISORDER THAT STEMS FROM MALADAPTIVE PLASTICITY WITHIN NEURAL CIRCUITS AND PRODUCES BROAD COGNITIVE DEFICITS. DESPITE CONSIDERABLE ADVANCES IN PSYCHOTHERAPY AND PHARMACOTHERAPY FOR HEROIN RELAPSE AND ADDICTION, EFFECTIVE TREATMENTS FOR HEROIN USE DISORDER ARE STILL LACKING. INCREASING PRECLINICAL EVIDENCE INDICATES THAT HEROIN SEEKING BEHAVIOR IS PERSISTENT AFTER WITHDRAWAL, WHILE COGNITIVE DYSFUNCTIONS ASSOCIATED WITH CHRONIC HEROIN USE ARE AN IMPORTANT CONTRIBUTING FACTOR TO RISK OF HEROIN RELAPSE AND ADDICTION. COGNITIVE ENHANCERS MAY BE USED TO STIMULATE TREATMENT SUCCESS AND ENHANCE TREATMENT EFFICACY. THE PURPOSE OF THIS REVIEW IS TO OUTLINE THE LITERATURE THAT DEMONSTRATES THE COGNITIVE DEFICITS DURING THE DEVELOPMENT OF HEROIN ADDICTION AND WITHDRAWAL PROCESS, AND SEVERAL FACTORS THAT UNDERLINE THE EFFICACY OF COGNITIVE ENHANCERS FOR HEROIN USE DISORDERS. THE REVIEW, THEN, EXAMINES THE POTENTIAL USE AND PHARMACOLOGICAL MECHANISMS OF COGNITIVE ENHANCERS THAT ACT ON CHOLINERGIC, GLUTAMATERGIC, DOPAMINERGIC OR ADRENERGIC PATHWAYS. IT ALSO EXAMINES THE EFFECTS OF COMPOUNDS THAT ALTER CREB SIGNALING AND EPIGENETIC MECHANISMS IN ANIMAL MODEL OF HEROIN RELAPSE. THE CURRENT BODY OF RESEARCH REVEALS THE NEW INSIGHTS INTO THE PHARMACOLOGICAL MECHANISMS UNDERLYING HEROIN ADDICTION AND HOLDS A SIGNIFICANT PROMISE FOR COGNITIVE ENHANCERS AS AN IMPROVED APPROACH TO TREAT HEROIN USE DISORDER IN A MORE EFFICIENT AND PERSISTENT WAY. 2019 16 1747 27 EARLY LIFE ADVERSITY: EPIGENETIC REGULATION UNDERLYING DRUG ADDICTION SUSCEPTIBILITY. DRUG ADDICTION IS A LEADING CAUSE OF DISABILITY WORLDWIDE, WITH MORE THAN 70,000 AMERICANS DYING FROM DRUG OVERDOSE IN 2019 ALONE. WHILE ONLY A SMALL PERCENTAGE OF CHRONIC DRUG USERS ESCALATE TO DRUG ADDICTION, LITTLE IS UNDERSTOOD ON THE PRECISE MECHANISMS OF THIS SUSCEPTIBILITY. EARLY LIFE ADVERSITY IS CAUSALLY RELEVANT TO ADULT PSYCHIATRIC DISEASE AND MAY CONTRIBUTE TO THE RISK OF ADDICTION. HERE WE REVIEW RECENT PRE-CLINICAL EVIDENCE SHOWING THAT EARLY LIFE EXPOSURE TO STRESS AND/OR DRUGS REGULATES CHANGES IN BEHAVIOR, GENE EXPRESSION, AND THE EPIGENOME THAT PERSIST INTO ADULTHOOD. WE SUMMARIZE THE MAJOR FINDINGS AND GAPS IN THE PRECLINICAL LITERATURE, HIGHLIGHTING STUDIES THAT DEMONSTRATE THE OFTEN PROFOUND DIFFERENCES BETWEEN FEMALE AND MALE SUBJECTS. 2023 17 5855 43 SUBSTANCE USE DISORDER A BIO-DIRECTIONAL SUBSET OF REWARD DEFICIENCY SYNDROME. THIS COMMENTARY IS TO INFORM CLINICIANS CHALLENGED WITH AN INCREASE IN PEOPLE SEEKING TREATMENT FOR SUBSTANCE USE DISORDER (SUD), THAT THE NINETY PERCENT REVOLVING DOOR, IS, IN PART, DUE TO POST-WITHDRAWAL, UNTREATED NEUROTOXICITY. THIS IMPAIRMENT ATTENUATES NEUROTRANSMITTER SIGNALING AND COMPROMISES RESTING STATE FUNCTIONAL CONNECTIVITY, LEADING TO UNWANTED SEQUELAE INCLUDING DEPRESSION, SLEEP DISTURBANCES, SENSATION SEEKING, LACK OF SATISFACTION AND IMPULSIVITY. NEUROIMAGING STUDIES INDICATE THAT NEUROBIOLOGICAL RECOVERY CAN TAKE YEARS. LIKE A "DOUBLE EDGE SWORD" SUD HAS A BIOLOGICAL BI -DIRECTIONAL (BIO-DIRECTIONAL) EFFECT ON THE BRAIN REWARD CIRCUITRY. THE ACUTE INTAKE OF PSYCHOACTIVE DRUGS RESULTS IN HEIGHTENED DOPAMINERGIC ACTIVITY, WHILE, THE OPPOSITE, HYPODOPAMINERGIA OCCURS FOLLOWING CHRONIC ABUSE. INDIVIDUALS WITH SUD CAN HAVE A GENETIC PREDISPOSITION, COMPOUNDED BY STRESS AND NEUROTOXICALLY INDUCED, EPIGENETIC INSULTS THAT IMPACT RECOVERY FROM PROTRACTED ABSTINENCE. FOLLOW-UP POST -SHORT-TERM RECOVERY USUALLY INCLUDES SUPPORTIVE THERAPIES AND PROGRAMS LIKE 12 -STEPS AND OTHER FELLOWSHIPS. HOWEVER, RELAPSE WILL USUALLY OCCUR IF POST -SHORT-TERM RECOVERY HYPODOPAMINERGIA IS NOT TREATED WITH ATTEMPTS AT EPIGENETIC MANIPULATION OF COMPROMISED BRAIN NEUROCHEMISTRY USING SOME MANNER OF PRO-DOPAMINE REGULATION. 2017 18 4469 49 MOLECULAR NEUROLOGICAL CORRELATES OF ENDORPHINERGIC/DOPAMINERGIC MECHANISMS IN REWARD CIRCUITRY LINKED TO ENDORPHINERGIC DEFICIENCY SYNDROME (EDS). THE CONSENSUS OF THE CURRENT LITERATURE STRONGLY SUPPORTS THE CONCEPT THAT BRAIN NEUROTRANSMITTERS, AND SECOND MESSENGERS INVOLVED IN THE NET RELEASE OF DOPAMINE IN THE MESOLIMBIC REGION, ESPECIALLY THE NUCLEUS ACCUMBENS (NAC), IS DIRECTLY LINKED TO MOTIVATION, ANTI-STRESS, INCENTIVE SALIENCE (WANTING), AND WELL-BEING. THE ROLE OF DOPAMINE IN TERMS OF ALCOHOL WITHDRAWAL SYMPTOMOLOGY, COCAINE CRAVING BEHAVIOR, DOPAMINE -CONDENSATION PRODUCTS (TIQS), AND MORE RECENTLY, THE GENETIC ASPECTS OF DRUG-SEEKING AND PRO-DOPAMINE REGULATION, PROVIDE COMPELLING EVIDENCE OF THE RELEVANT MOLECULAR NEUROLOGICAL CORRELATES OF DOPAMINERGIC /ENDORPHINERGIC MECHANISMS IN REWARD CIRCUITRY DUE TO GENETIC POLYMORPHISMS AND EPIGENETIC INSULTS. IN THE FACE OF AN AMERICANS OPIOID EPIDEMIC, THE CLINICAL CONSENSUS IS TO TREAT OPIOID USE DISORDER (OUD) WITH LIFE-LONG OPIOID SUBSTITUTION THERAPY. HOWEVER, THE AUTHORS SUGGEST A PARADIGM SHIFT INVOLVING NOVEL MODALITIES LIKE TARGETING THE ENDORPHINERGIC SYSTEM LINKED TO DOPAMINE RELEASE AT THE NAC, IN TERMS OF THE INDUCTION OF REQUIRED "DOPAMINE HOMEOSTASIS." UTILIZING THE KNOWN GENETIC - ENVIRONMENTAL INTERACTION THEOREM P = G +E, THE AUTHORS PROVIDE A CLEAR RATIONALE FOR THE ADOPTION OF GENETIC RISK TESTING COUPLED WITH ENDORPHINERGIC/DOPAMINE REGULATION TO ADDRESS DYSFUNCTION ACROSS THE BRAIN REWARD CIRCUITRY. THE GOAL OF ALTERING RESTING-STATE, FUNCTIONAL CONNECTIVITY MAY REQUIRE A GENTLE "NEUROTRANSMITTER FIX" VIS ENKEPHALINASE INHIBITION TO OVERCOME OR COMBAT - SELF-INDUCTION OF ACUTE DOPAMINE RELEASE VIA PSYCHOACTIVE SUBSTANCE MISUSE RESULTING IN CHRONIC DOPAMINE DOWN-REGULATION. AS SUBSETS OF REWARD DEFICIENCY, WE ARE POISED TO PROVIDE NOVEL, GENETICALLY GUIDED THERAPY FOR ENDORPHINERGIC, OPIOIDERGIC, AND DOPAMINERGIC DEFICIENCIES AND RELATED SYNDROMES, UTILIZING "PRECISION ADDICTION MANAGEMENT. 2020 19 4631 46 NEUROGENETICS OF ACUTE AND CHRONIC OPIATE/OPIOID ABSTINENCE: TREATING SYMPTOMS AND THE CAUSE. THIS REVIEW BEGINS WITH A COMPREHENSIVE HISTORY OF OPIOID DEPENDENCE AND TREATMENT IN THE UNITED STATES. THE FOCUS IS AN EVIDENCE-BASED TREATMENT MODEL FOR OPIOID/OPIATE DEPENDENT INDIVIDUALS. THE ROLE OF REWARD GENETIC POLYMORPHISMS AND THE EPIGENETIC MODIFICATIONS THAT LEAD TO VULNERABILITY TO USE AND MISUSE OF OPIATES/OPIOID TO TREAT PAIN ARE REVIEWED. THE NEUROCHEMICAL MECHANISMS OF ACUTE OPIATE WITHDRAWAL AND OPIATE/OPIOID REWARD MECHANISMS ARE EXPLORED WITH A GOAL OF IDENTIFYING SPECIFIC TREATMENT TARGETS. ALTERATIONS IN FUNCTIONAL BRAIN CONNECTIVITY BASED ON NEUROBIOLOGICAL MECHANISMS IN HEROIN DEPENDENCE AND ABSTINENCE ARE ALSO REVIEWED. A NEW CLINICAL MODEL AN ALTERNATIVE TO MERELY BLOCKING ACUTE WITHDRAWAL SYMPTOMS AS IDENTIFIED IN THE DSM -5 IS PROPOSED. GENETIC DIAGNOSIS AT THE ONSET OF DETOXIFICATION, TO DETERMINE RISK STRATIFICATION, AND IDENTIFY POLYMORPHIC GENE TARGETS FOR PHARMACEUTICAL AND NUTRACEUTICAL INTERVENTIONS, FOLLOWED BY THE SIMULTANEOUS INITIATION OF MEDICATION ASSISTED THERAPY (MAT), TO ENABLE PSYCHOLOGICAL EXTINCTION, AND STEADY PRO-DOPAMINERGIC THERAPY WITH THE GOAL OF DEVELOPING "DOPAMINE HOMEOSTASIS" IS RECOMMENDED. THE OBJECTIVE OF THESE INTERVENTIONS IS TO PREVENT FUTURE RELAPSE BY TREATING ALL "REWARD DEFICIENCY SYNDROME" (RDS) BEHAVIORS AND EVENTUALLY MAKE AN ADDICTION-FREE LIFE POSSIBLE. 2017 20 1160 19 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