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European Journal of Endocrinology -18-0270 synthesized fromitaredescribedas‘opiates’,whilst naturally occurringalkaloidsofopiumandthedrugs cultivated bytheSumeriansataround4000BC.The pod oftheopiumpoppy( Opium isacquiredinthedriedlatexformfromseed Introduction (particularly whenrelevantclinicalmanifestationsarepresent)andevaluationofthebonehealthstatusadvised. safe andcost-effective clinicalguidelinesbecomeavailable,periodicalassessmentofthegonadalandadrenalfunction address reliablythelong-termbenefitsandrisksofhormonaltreatmentinpatientsonopioids.Untilevidence-based, clearly establishtheprevalenceofhormonalabnormalitieswithvariousregimes,dosesandroutesopioids to especially whentheabovemeasuresarenotpracticallyfeasible,needstobeconsidered.Furtherstudiesneeded to consideration ofalternativetherapiesforpainreliefarepotentialmanagementoptions.Hormonalreplacement, in otherhormonesremainstobeclarified.Discontinuationorreductionoftheopioidand,caseschronic pain, and increasedfracturerisk)occasionallyhyperprolactinaemia,whereastheclinicalsignificanceofalterations can alsobefound.Furthermore,thereisanegativeimpactonbonehealth(withreducedmineraldensity may remainundiagnosedwithpotentialadverseoutcomesforthepatients.Althoughlessfrequent,cortisoldeficiency them. Hypogonadismisthemostwell-recognisedconsequenceofopioiduse(prevalence21–86%)which,however, elucidated, andawarenessoftheirendocrinesequelaeisvitalforallspecialistsprescribingormanagingpatients on These drugshaveeffects onmultiplelevelsoftheendocrinesystemthroughmechanismswhicharestillnotfully The useofopioidshasgrownsubstantiallyoverthepasttwodecadesreachingdimensionsaglobalepidemic. Abstract Trust, Birmingham,UK UK, and Birmingham, UK, 1 Athanasios Fountas Endocrinology ofopioids MECHANISMS OFENDOCRINOLOGY Institute ofMetabolismandSystemsResearch,CollegeMedicalDentalSciences,UniversityBirmingham, https://doi.org/ www.eje-online.org Review Review and hypopituitarism. tumours research disease with particular focus on pituitary interest is on hypothalamo–pituitary Consultant Endocrinologist at the QueenElizabethHospital,Birmingham,UK.Her andHonorary and SystemsResearch, CollegeofMedicalandDental SciencesattheUniversityofBirmingham Niki Karavitaki Invited Author’s prof 3 Department ofEndocrinology, QueenElizabethHospital,UniversityHospitalsBirminghamNHSFoundation 10.1530/EJE 2 Centre forEndocrinology, DiabetesandMetabolism,BirminghamHealthPartners,Birmingham, -18-0270 , MSc, PhD, FRCP 1 , 2 , 3 ile , Shu Teng Chai 4 Papaver somniferum © 2018EuropeanSociety ofEndocrinology A Fountasandothers isSeniorClinicalLecturerintheInstituteofMetabolism 1 , 2 Printed inGreatBritain , 3 , Chrysoula Kourkouti ), initially codeine andthebaine),estersofmorphine(e.g. in theresinofopiumpoppy, mainly morphine, classes ofopioidsincludenaturalopiates(alkaloids receptors areincludedintheterm‘opioids’.Themain all naturalorsyntheticchemicalsthatbindtoopioid endocrine system Effects ofopioidson Published byBioscientifica Ltd. 2 , 3 and Niki Karavitaki Downloaded fromBioscientifica.com at10/02/202108:57:18AM 1 , 2 , 3 (2018) Endocrinology European Journal of [email protected] Email to NKaravitaki should beaddressed Correspondence 179 179 :4 , R183–R196

R183 –R196 via freeaccess European Journal of Endocrinology www.eje-online.org underdiagnosed withpotential adversesequelaeforthe endocrine system,which, nonetheless,mayremain low-dose tricyclicantidepressants ( mortality, compared with analgesic anticonvulsants or elevated riskofall-causeandcardiovascular-specific non-cancer painhasbeenassociatedwithasignificantly prescription oflong-actingopioidsinpatientswithchronic from 9479to53 666 duringthestudyperiod.Inaddition, this report,thenumberofstrongopioidusersincreased the majorityadministeredfornon-cancerpatients( morphine andoxycodone)between20002010,with strong opioidprescriptions(buprenorphine, fentanyl, Practice Research Datalinkconfirmasignificantrisein rehabilitation specialists( anaesthesiologists, psychiatrists,physicalmedicineand pain physicians,familyorthopaedicsurgeons, involve awiderangeofhealthprofessionalsincluding around 69%oftheworld’s supplyofopioids;prescribers a realglobalepidemic( USA and210%globallymakingopioidconsumption decades; between2000and2014,itincreased216%in κ μ whilst buprenorphinehaspartialagonistactivityon δ antagonists ( buprenorphine andpentazocinearemixedagonists/ pethidine) are primarily their derivatives,aswellmethadone,tramadoland available opioids (morphine, codeine, fentanyl, and its euphoriceffects(illicituse).Themostcommonly whereas heroinisusedasarecreationaldrugdueto and aremainlyofferedasanalgesicagents( opioids usedinclinicalpracticehavevariousindications reversed by naloxone, was discovered in 1994 ( whereas thenociceptinreceptor, witheffectsnot three mainbeing ( and theiractivationproducesarangeofdifferenteffects which belongtothefamilyofG-protein-coupledones, endorphins, enkephalins)( endogenous opioidpeptidesproducedinthebody(e.g. (e.g. fentanyl,pethidine,methadone,tramadol)and oxymorphone, buprenorphine),fullysyntheticopioids esters, e.g.hydromorphone,hydrocodone,oxycodone, opioids (producedfromthenaturalopiatesormorphine diacetate ordiamorphine(heroin)),semi-synthetic 1 -receptors ( - and - andnociceptinreceptorsantagonistactivityon ). Therearemanytypesofopioidreceptorswiththe Review The useofopioidshasgrownoverthepasttwo Opioids exerttheiractionsbybindingtoreceptors Exogenous opioidscanhave variouseffectsonthe κ -receptors andasanantagonistonthe 4 3 ). ). Pentazocineactsasapartialagoniston μ , κ and 5 ). Notably, in2014,USAused 5 δ 1 ). DatafromtheUKClinical (that are naloxone sensitive), μ ). -receptors agonists, whilst A Fountasandothers 5 , 7 ). μ -receptor, al 1 Table 2 ). The 6 ); in ), Hyperprolactinaemia that can be occasionally caused by dose-dependent effectonthe testosteronelevelsofheroin of drugabstinence( of testosteronetonormaloccurred afterabout1 month ( wasshorter similar results,albeittheduration ofrecovery values 48 after the drug administration and returning to baseline of thedrug,withlevelsremaining low around24 significant reductionoftestosterone4 on acetylmethadolforopioiddependence,therewas hours ofopioidadministration;inastudy13males 22 hypogonadism rangesbetween21%and86%( decades and thereportedprevalence of opioid-induced status havebeenstudiedextensivelyinthepastfour and intra-testiculartestosterone( decreased production of sperm, testicular interstitial fluid have alsodirecteffectsonthegonads:theseinclude (HPG)axis( hypothalamo–pituitary–gonadal opioids maycontributetotheirsuppressiveeffectsonthe directly inhibit the pituitary release of gonadotropins ( directly inhibit the pituitary gonads ( gland,andoftestosteroneoroestradiolfromthe pituitary stimulating hormone(FSH–toalesserextent)fromthe of thereleaseluteinisinghormone(LH)andfollicle- releasing hormone(GnRH)secretionandreduction or disruptionofthenormalpulsatilitygonadotropin- in the hypothalamus ( gonadal functionprimarilybyactingonopioid Opioids, bothendogenousandexogenous,modulate Hypothalamo-pituitary-gonadal axis identify areasrequiringfurtherresearch inthisfield. discuss theirclinicalsignificanceandmanagementto of theseeffectsandtheirunderlyingmechanisms,to patients. Theaimofthismanuscriptistoprovideareview with anassociatedreductioninLHand/orFSH( demonstrated reductionoftestosteronelevelsinmales, and patientsonmethadoneformaintenancehad possibly differencesintheageofpatientsincluded). other comorbiditiesandofconcurrentmedications of opioidadministration,potentialimpactpain, assessed, variationsinthetype,dose,routeandduration heterogeneity ofthestudies(differencesinpopulations 13 endocrine system Effects ofopioidson 11 ). Thedecreaseintestosteroneoccurswithinafew , ). In another study with male heroin addicts, recovery ). In another study with male heroin addicts, recovery 14 The effectsoflong-termopioiduseonthegonadal The initialstudiesinvolvedmainlyheroinaddicts , 15 9 h post acetylmethadol use ( , , 10 16 , , 11 19 , ). Thiswiderangeisattributedtothe 12

21 , 13 ). Furthermore, methadone hasa 8 Downloaded fromBioscientifica.com at10/02/202108:57:18AM ). This leads toreduced release , 14 , 15 18 , 16 ). 23 179 ). Opioidsmayalso h aftertheingestion ). Woody :4 9 ε 10 ). Opioids -receptors et al. , 20 R184 11 , , had 17 21 12 via freeaccess h ). , , European Journal of Endocrinology Tramadol Tapentadol Sufentanil Remifentanil Pethidine (meperidine) Pentazocine Papaveretum Oxycodone Morphine Methadone Meptazinol Hydromorphone Fentanyl Dipipanone Dihydrocodeine Diamorphine (heroin) Codeine Buprenorphine Alfentanil Opioid Formulary, (Online).Available: Table 1 Review Types, administrationroutesandindicationsofopioidsaccordingtoBritishNationalFormulary(British https://bnf.nice.org.uk Intravenous Intramuscular Oral Oral Sublingual Intravenous Intravenous Intramuscular Subcutaneous Oral Intravenous Intramuscular Subcutaneous Oral Intravenous Intramuscular Subcutaneous Intravenous Subcutaneous Oral Rectal Intravenous Intramuscular Subcutaneous Oral Intramuscular Subcutaneous Oral Intravenous Intramuscular Oral Oral Transdermal Intranasal Intravenous Buccal Sublingual Oral Intramuscular Subcutaneous Oral Rectal Intravenous Intramuscular Subcutaneous Intramuscular Oral Transdermal Intravenous Intramuscular Sublingual Oral Intravenous Administration route A Fountasandothers . (Accessed:24-Mar-2018). Breakthrough paininpatientsreceivingopioidtherapyfor Chronic pain Acute pain Acute orchronicpain Pulmonary oedema Myocardial infarction Acute orchronicpain Acute diarrhoea Unproductive cough Acute pain Opioid dependence Intra-operative analgesia Premedication beforesurgery Acute orchronicpain Analgesia andsuppressionofrespiratoryactivityinventilated Analgesia andenhancementofanaesthesiaduringoperation Indications Acute orchronicpain Acute orchronicpain Acute pain Analgesia andsedationinventilatedpatients Analgesia andenhancementofanaesthesiaduringoperation Premedication Obstetric analgesia Acute pain Acute orchronicpain Postoperative analgesia Premedication beforesurgery Chronic pain Acute orchronicpain Pulmonary oedema Myocardial infarction Cough interminaldisease Premedication beforesurgery Acute orchronicpain Cough interminaldisease Opioid dependence Chronic pain Obstetric analgesia Acute pain Acute orchronicpain Analgesia andsuppressionofrespiratoryactivityinventilated Analgesia andenhancementofanaesthesiaduringoperation patients patients chronic cancerpain endocrine system Effects ofopioidson

Downloaded fromBioscientifica.com at10/02/202108:57:18AM 179 www.eje-online.org :4 R185 via freeaccess European Journal of Endocrinology www.eje-online.org and managementofopioid-induced hypogonadism. is noconsensusorclinical guidelinesforthediagnosis common problem amongst the clinicians. Currently, there patients combinedwiththe underappreciationofthis this may relate with lack of symptoms reporting by the condition remainsunderdiagnosedindailypractice; opioids leadtohypogonadotropichypogonadism,this systematically studied. 30 or cessationoftherapyreversesthehypogonadism( compared tomethadone( persistent pain results in less severe hypogonadism when for opioiddependenceorthemanagementofacute/ the variousstudies.Buprenorphineusedasmaintenance at the doses used for different opioids in observations be pointedout,however, thatthesefindingsreflectthe deficiency whencomparedtohydrocodone( combined) areassociatedwithhigheroddsofandrogen and oxycodone(long-short-actingformulations ( deficiency comparedtochronicuseofshort-actingones acting opioids isassociated with greater odds of androgen the intrathecalroute( are administeredorally/transdermallycomparedwith suppression ofLHmaybelessprofoundwhenopioids pain ( in womentakingoralopioidsforchronicnon-cancer prevalence ofhypogonadismishigherinmenthan women, LHandFSHlevelscanbedecreased( in premenopausalfemales( libido, ameno- or oligomenorrhoea with anovulation night sweats in males ( libido, infertility, fatigue,depression,hotflushesand manifestations includeerectiledysfunction,decreased changes aredoserelated( as theopioid is taken( 27 when interpretingtheirresults( patients’ age,andtheseneedtobetakenintoaccount including painpathophysiology, paincomorbiditiesand other factorsmayalsocontributetothehypogonadism sectional studies;itshouldbenoted,however, that for cancerousornon-cancerouspainincohortcross- patients onopioids(oral,transdermalorintrathecal) this groupofpatientsarenotavailable. present ( heroin addicts, amenorrhoea and galactorrhoea may be addicts on methadone detoxification ( 31 Review , , , 28 Despite theabundanceofevidenceindicatingthat Hypogonadism isalsopresentinbothmaleandfemale 36 32 15 , , ). Furthermore,transdermalfentanyl,methadone 29 37 ). In premenopausal chronic pain patients, the 24 ). TheeffectsontheHPGaxisbeginassoon ) butthetimecourseofthishasnotbeen ); nonetheless,seriessystematicallyassessing 9 12 13 ). Notably, chronicuseoflong- , 34 , 13 13 16 , , , 35 , 31 16 16 27 ). Reductioninthedose A Fountasandothers ). Theresultantclinical , 12 ). Inpostmenopausal 30 , , 28 ) andthe hormonal 13 , , 29 22 14 ) and reduced 33 ). In female , 16 ). Itshould , 16 25 ). The , 26 26 , , the abovemeasuresarenotviable,gonadalhormone for patientsonchronicpainrequiringrelief.When the opioid and consideration of alternative therapies includes discontinuationorreductionofthedose also advised. of othercauseshypogonadotropichypogonadismare other medicationsandcomorbidities,aswellexclusion of prolactin(PRL)andtakingintoaccounttheimpact ( (combined withmenstrualhistory) in menandoestradiolgonadotropinswomen (in amorningsamplebefore10 opioid) and include measurementofbloodtestosterone periodically (andalsowhenchangingdoseorregimeof experience any. evaluations need to be taken Laboratory encouraged toreporthypogonadalsymptomsshouldthey should beeducatedonthispotentialsideeffectand before, aswellduringopioidtreatmentandpatients Manifestations of hypogonadism should be enquired seen in two patients, one in each group and erythrocytosis seen intwopatients,oneeach groupanderythrocytosis reduction in fat mass ( and pressurehyperalgesia insexualdesire,aswell arm demonstrated greater improvement in mechanical foundthatmeninthetestosterone placebo for14 weeks, pain, randomisedtoreceivetransdermaltestosterone or induced androgendeficiencyandchronicnon-cancer years)withopioid- males (agedbetween18and64 double-blind, parallelplacebo-controlledtrialof65 and haematocrit( validated questionnaires,aswellofthehaemoglobin psychological wellbeinganddepressedmoodbyusing in androgendeficiencysymptoms,sexualfunction, weeks,foundimprovement transdermal patchesfor24 methadone forpainsyndromes)offeredtestosterone deficiency (onoralsustainedreleaseoxycodoneor with opioid-induced androgen between 34 and 55 years) al. et Scale ratingsshowedsignificantchanges( scores orCentreforEpidemiologicalStudiesDepression normal limits.NoneoftheProfileMoodStatesubscale prostate-specific antigen(PSA)levelsremainedwithin the growthofbodyhairandimproved appetite, andtheir questionnaire ( Symptoms scaleandintheMentalIndexofSF-36 improvement inthesexualdimensionofAgingMales’ months,demonstrated with testosteronegelfor12 morphine fornon-oncologicalchronicpaintreated of ninemales(agedbetween44and75 years) onepidural studies showingbeneficialeffects.Aloisi replacement shouldbeconsideredwithanumberof endocrine system Effects ofopioidson Management oftheopioid-inducedhypogonadism , inanopen-labelpilotstudyon16men(aged 39 ). Thepatientsalsoreportedincreasein 40

). Basaria 41 Downloaded fromBioscientifica.com at10/02/202108:57:18AM ); elevation in PSA t al. et am) andgonadotropins 179 , inarandomised, 38 :4 et al. ). Measurement > gm was 4 ng/mL 39 , inaseries ). Daniell R186 via freeaccess European Journal of Endocrinology also supported by the observation thathumansubjects also supportedbytheobservation through thisreceptor)( diamorphine, fentanylandloperamide actpredominantly (morphine, hydromorphone, methadone, tramadol, subtype intheopioid-induced regulationofHPA axis μ adrenalinsufficiencyinpatients receiving secondary ( predominant type; are notentirelyknownbut release ( on adrenocorticotropichormone(ACTH)andcortisol and vasopressinsecretionbyreducingtheireffect by inhibitingcorticotropin-releasinghormone(CRH) (HPA) level axismainlyatthehypothalamic-pituitary Opioids suppress the hypothalamo–pituitary–adrenal Hypothalamo–pituitary–adrenal axis for opioidusedisorder. ofpatientsonmethadone sensitivity andontherecovery as thepotentialimpactofhormonaltreatmentonpain of hormonereplacementinthisgrouppatients,aswell are neededtoestablishthelong-termbenefitsandrisks considered. Adequatelypoweredwell-designedstudies not possible,gonadalhormonetreatmentneedstobe dose ofopioidcanreversethissequelabutwhenis to hypogonadism. Discontinuation or reduction in the the HPGaxisthroughactionatvariouslevelsleading induced hypogonadisminwomenarenotavailable. looking at gonadal hormone replacement in opioid- patients. In contrast to their male counterparts, series cardiovascular safetyoftestosteronetherapyinthese duration ofthisstudywasnotlongenoughtoevaluate did notdifferbetweenthetwogroups( markers and adipokines also glucose load, inflammatory in bothgroups;glucoseandinsulinresponseto75 protein weresimilarfrombaselinetotheendoftreatment model assessmentforinsulinresistanceandC-reactive in lipidprofile,fastingglucoseandinsulin,homeostatic testosterone gelorplacebodaily, foundthatchanges weeksoftransdermal randomisedto 14 spectrometry), (as measuredbyliquidchromatography-tandemmass cancer painandmorningtotaltestosterone years)onopioidanalgesicsforchronicnon- 18 and64 the samecentreof64non-diabeticmen(agedbetween placebo-controlled, double-blindrandomizedtrialfrom occurred inneithergroup.Notably, Huang 8 -receptor agonistssuggestsapotential role ofthis Review , In summary, effecton opioidusehasaninhibitory 48 , 49 43 ). Nonetheless, the increasing evidence of , 44 , 45 δ , -receptors havealsobeenimplicated 46 36 , , 47 37 κ ). Thereceptorsinvolved , - areconsideredtobethe 50 A Fountasandothers , 51 , 52 42 , ). However, the 53 , < t al. et 54 12 nmol/L ). Thisis , ina g oral ( followed byarebounddecreaseofitsactivity( an exaggeratedresponseoftheHPA axis,whichmaybe cells ( cortisol productioninisolatedhumanadrenocortical saline ( to highercortisol(butnotACTH)levelscomparedwith disconnectionled patients withhypothalamo-pituitary unit;naloxoneadministrationin hypothalamo-pituitary the adrenalglands,independentlyoftheireffecton to naloxone( response tometyraponeandexaggeratedcortisolrelease binding affinityto OPRM1 the A118G SNP of the carrying and chronicpaincanbea majorconfounder(chronic insufficiency in these patients has not been clearly defined 37 few days)mainlyforpainrelief havebeenpublished( administration ofvariableduration (includingevenofa adrenal insufficiency after oral or transdermal opioid morning cortisollevelscomparedwithcontrols( disturbed cortisolcircadian rhythmwithlower ( vasopressin andcortisolcomparedtohealthycontrols diacetylmorphine have reduced serum levels of patients onmaintenancetreatmentwithintravenous on heroin-ssistedtreatment( effect onHPA axisinheroin-dependentaddicts women intheearlyfollicularphase( naltrexone-induced increasesinserumcortisolthan women inthelutealphaseoftheircyclehadgreater cycle mayalsobeimplicatedwithastudyshowingthat the endogenous opioid system ( response comparedtomensuggestingsexdifferencesin antagonists (naloxone and naltrexone) on their cortisol demonstrate agreatersensitivitytoopioidreceptor a roleintheeffectofopioidsonHPA axis.Women stress ( diminished cortisolresponsetopsychosocialorsurgical response to CRH, and secretion, blunted pituitary-adrenal results insuppression of ACTHandglucocorticoid heroin, buprenorphine, remifentanil) in normal subjects release areconflictingshowingactivation( administration ofopioidsonACTHandglucocorticoid Data fromanimalstudiesassessingtheeffectsofchronic endocrine system Effects ofopioidson 59 43 , ) ornoeffect( ). Itisofnotethatinheroinaddicts,therea 50 Acute administrationofopioidsinanimalsresults Several case reports documenting secondary Several casereportsdocumentingsecondary In addition,diamorphinehasanacutesuppressive Single administration of various opioids (morphine, 58 , 57 (whichhasbeenshowntoincreasethereceptor’s 45 51 ). ) and , , 52 46 , 55 , 53 β 63 , -endorphin suppressedACTH-stimulated , 62 56 54 ,

). ). Opioidshavealsodirecteffectson 64 ). Theaccurateprevalenceof adrenal β -endorphin) showbluntedACTH , Downloaded fromBioscientifica.com at10/02/202108:57:18AM 65 ). Notably, gendermayplay μ -receptor encoding gene 70 66 ). Opioid-dependent , 69 179 67 ). www.eje-online.org :4 , 61 68 ), suppression ). Menstrual 65 59 R187 , , 71 60 36 ). via freeaccess ). ,

European Journal of Endocrinology www.eje-online.org blind, placebo-controlled crossover study with 17 patients Interestingly, Nenke ofthishasnotbeensystematicallystudied. time interval in thedoseofdrug( or returns to normal after discontinuation or reduction are possiblyatriskofcortisoldeficiency. opioids, itisanticipatedthatalargenumberofpatients as yetestablished.However, giventhewidespreaduseof development of abnormal cortisol stress response are not non-malignant pain( levels duringopioidtherapyinpatientswithchronic there is reduction of the adrenal androgen DHEAS cortisol levelsduringITT day) demonstratedhypoadrenalism(definedasstimulated day) and50%of20patientsonoralmorphine(60–120 chronic pumpintrathecalmorphineinfusion(0.2–10 Furthermore, 33%of20chronicpainpatientsreceiving series developedAddisoniancrisisduringpneumonia. 15% ofthemrespectively( < in basal cortisol levels mean durationoftreatment26.6 non-malignant pain(meandailydose4.8 of morphineorhydromorphinein72patientswith response tosyntheticACTH.Intrathecaladministration 10% ofthoseassessedhadaninitialsuboptimalcortisol (excluding tramadolanddihydrocodeine),approximately focusing onthe33patientshigh-doseopioidanalgesia stimulation (peakcortisol in 8%ofthemandfailuretorespondsyntheticACTH glucocorticoids, found8.00 andnorecentexposuretoexogenous at least6 months determined bymorphinesulphateequivalentdose)for dihydrocodeine –mediandailyopioiddoseof68 morphine sulphate,fentanylorbuprenorphinepatch, with long-termopioidanalgesia(tramadol,oxycodone, painclinicsandtreated patients attendingchronictertiary did notinhibittheHPA axis.Gibb (35 withdrawal ( both sexes;thelevelsroseonDay16,24 levels withanimmediateeffectfromDay1to15in persistent severepainledtoreductioninthebloodcortisol morphine (0.9 Aloisi hyper-reactive ACTHreleasetoCRHstimulation)( freecortisollevelscomparedwithcontrolsand urinary of bloodcortisol,lowermorningcortisoland24-h pain hasbeenassociatedwithlossofthediurnalvariation 18 Review µg/h every 72 µg/h every The alteredHPA axisfunctionofopioidusersimproves μ g/dL duringaninsulintolerancetest(ITT)in9%and t al. et showedthatintrathecaladministrationof 30 ). In contrast, transdermal buprenorphine gdy o 5 daysinpatientswith mg/day) for15 h) foracute/persistentpain6 months et al. 14 < , 5 , inapilot,randomized,double- 36 < 75 μ 16 < 430 h bloodcortisol g/dL and peakcortisol value , 18 , ); oneofthepatientsinthis 37 76 nmol/L) in6%( μ , g/dL) ( ). Factorspredictingthe A Fountasandothers 50 ± 63mnh) resulted 16.3 months) et al. , 51 75 , h aftertheopioid inaseriesof48 53 ). Additionally, , ± < 54 g and 3.2mg 100 nmol/L 74 ), butthe ). When 72 mg as , mg/ mg/ 73 ). ).

outcomes ofthebiochemicalfindings(particularlyifthese clinical significanceandpotentialconsequences/adverse opioids atvariousregimesandroutes,toestablishthe define theprevalenceofhypoadrenalismwithdifferent is ofclinicalsignificance.Furtherstudiesareneededto 54 description ofAddisoniancriseswhilstontheseagents( after glucocorticoidadministration( manifestations resemblingthoseofcortisoldeficiency to opioids, the reported cases of improvement of clinical be arguedthathypocortisolismisanadaptiveresponse HPA axisbyactingatvariouslevels.Althoughitcould compared toplacebo( day) ledtoimprovementinvitalityandpaintolerance test), foundthathydrocortisonetherapy(10 response and mildhypocortisolism(definedbyaplasmacortisol on long-termopioidtherapyforchronicnon-cancerpain ( responsetodifferenttypesofopiates the GHstimulatory growth hormone-releasing hormone (GHRH)inhibited mechanism ( generator viaopioidreceptor stimulationisalsoapossible reports ( δ release showthatvarioustypesofopioidreceptors( mechanisms involvedontheeffectsofopioidsGH effect ( to stimulatory hand, chronic administration hasledtono( growth hormone(GH)secretion( In animalmodels,acuteopioidadministrationstimulates Somatotroph axis investigations towardsthisdirection. of symptoms/signscortisoldeficiencyshouldprompt axis assessmentisnotknownbutcertainlythepresence results ofthebasalcortisol.ThefrequencyHPA dynamic assessmentoftheHPA axiswilldependonthe clinical manifestations)isasensibleapproach.Further plasma cortisol(particularlyinthepresenceofrelevant risk of hypoadrenalism and checking an early morning guidelines, patientsonopioidsshouldbeconsideredat provide robust evidence for safe and cost-effective clinical of opioiddose.Althoughtheexistingliteraturecannot the hormonalchangesfollowingwithdrawalorreduction clear guidanceonthereversibilityandtimecourseof reflect modestchangesintheHPA axis)andtoprovide endocrine system Effects ofopioidson 86 ) are implicated, but their activation effects vary between ) are implicated, but their activation effects vary ) suggestthat,atleastinsomepatients,hypocortisolism , In summary, actionsonthe opioidsexertinhibitory 87 ). In addition, opioids exert inhibitory effect on ). In addition, opioids exert inhibitory 82 ≤ , 350 83 85 , nmol/L at60 ). Treatment ofratswithantiserumagainst 84 ). AresetofthehypothalamicGHpulse

77 81 Downloaded fromBioscientifica.com at10/02/202108:57:18AM ). ). Studies on the pathways and min followingacoldpressor 78 52 179 , , 79 53 :4 ). Ontheother , 74 , 77 61 ) andthe , mg/m R188 80 μ ) or , 16 via freeaccess κ 2 / , , European Journal of Endocrinology GH secretionbuttheimpact ofchronicusevaries axis. Overall,acuteadministration ofopioidsincreases effects andrelevantmechanisms ofopioidsontheGH attributed toobesity. suboptimal GHresponsefoundintwocaseswasfinally control groupreceivingnon-opioidanalgesia( to theglucagonstimulationtestwhencompared a abnormal IGF-1 levels or a difference in GH response Finally, chronicpainpatientsonoralopioids hadno 5% and6%ofmethadoneheroinusers,respectively. < as criteriaofanormalresponse;usingthecut-off of or an increment over the baseline addicts ( of methadone-treated patients and in 31% of heroin Abnormal GH response on ITT was also detected in 26% of themshowedpeakGH standard deviationsbelowthemean,whilst15% subjects hadIGF-1concentrationsmorethantwo 1 (IGF-1)levelscomparedwithcontrols;17%ofthe significantly lowerseruminsulin-likegrowthfactor and hydromorphine)fornon-malignantpainhad in healthymalevolunteers( naloxone significantlybluntedtheGHresponsetoGHRH in normalmen( induced GHreleaseinhealthywomenbuthadnoeffect are contradictory. NaloxoneinfusiondecreasedGHRH- are also implicated ( induced GH release, suggestingthatothermechanisms analogue resulted to an enhancing effect of the GHRH- doseofaGHRH combined withamaximallystimulatory a Met-enkephalin analogue G-DAMME, in healthy men dose of15 5 offered ( of opioidsonGHsecretionwhichrelatewiththedose on otherparametersofGHsecretion( marked reduction in thepulse amplitude, had little effect of pulseamplitude;infemales,morphine,apartfroma in amodestincreaseoftheGHpulsefrequencybutnot increased basal and mean GHconcentrations, as well Continuous morphineexposureofmaleratsresultedin dynamics. effects ofthesedrugsontheGHsecretory inhibited this ( andconcomitantadministrationofnaloxone rat pituitary treatment withmorphinedecreasedGHmRNAlevelsin somatostatin release( 3 mg and10 Review μ Humans treated with intrathecal opioids (morphine effects In humansubjects,thereareacutestimulatory The abovedatademonstrate thecomplexityof g/L, acompromisedGHresponsewouldbefoundin 92 98 mg did( , ). In this study, a maximal level of GH mg didnotpromoteGHsecretionbutahigher 93 ). Thus,intravenousmorphineatdosesof 90 96 ). Notably, gender may influence the ). Ontheotherhand,inanotherstudy, 92 93 , 88 94 ). Data on possible sex differences ) andaction( , 95 97 ). Notably, administrationof < ). 3 A Fountasandothers μ g/L duringITT( > 10 89 91 μ ). Finally, chronic ). g/L were defined > 99 9 μ 16 ); a g/L ). ). ( mainlywithpharmacologicaldoses and thisisobserved effect onthyroid-stimulating hormone(TSH)secretion, Based onmostanimalstudies, opioidshaveinhibitory Hypothalamo-pituitary-thyroid axis axis). and itsclinicalsequelae(particularlyonthegonadotroph clinician needs to be aware of thispotential consequence type ofdrughavenotbeenclearlyestablished, but the hyperprolactinaemia andtheimpactofdose,route needs tobetakenintoaccount.Thefrequency of opioids, althoughtheeffectofpainonthisfinding hyperprolactinaemia duetoopioiduse( ( painful gynaecomastia,galactorrhoeaandhypogonadism to highPRL( maintenance therapyforopioiddependencedidnotlead on PRL( intrathecally forchronicnon-cancerpainhadnoeffect PRL ( Furthermore, oralopioidsforchronicpainincrease cycle, whenadministeredfor7 days inthelutealphase,it as women in the early follicular phase of the menstrual in postmenopausal and hypogonadal women, as well thus, whilst naloxone had no effect on PRL secretion may altertheopioid-inducedeffectsonPRLsecretion; postmenopausal women( morphine increasesPRLinhealthymen( hypothalamus ( mediated by effectonPRLsecretion Opioids canhaveastimulatory Prolactin long-term opioidsremainstobeelucidated. The clinicalsignificanceofthesefindingsinpatientsusing factors thatinfluencetheactionofopioidsonGHrelease. considerably. Gender, opioidtype,routeanddoseare addicted subjectsandinopiumsmokers( PRL levelshavebeenfoundtobehighinopioid induced PRLrelease( endocrine system Effects ofopioidson 108 104 Acute administration(oralorintravenous)of Overall, highPRLcanbedetectedinpatientson Bromocriptine hasbeensuccessfullyusedincasesof Opioid-induced hyperprolactinaemia can lead to In chronicuseofopioids,theeffectsarevariable. , ). 109 104 ). , 16 105 34 ). Finally, buprenorphineormethadone ). On the other hand, morphine offered μ , 100 -, 106 ).

κ ). - and 9 ). Downloaded fromBioscientifica.com at10/02/202108:57:18AM 94 δ ). Inwomen,sexsteroids -opioid receptorsinthe 179 www.eje-online.org 107 :4 18 ). , 102 101 R189 , ) and 103 via freeaccess ). European Journal of Endocrinology www.eje-online.org Opioid-induced hypogonadism, as welldirectactionof Exogenous opioidshaveanegative impactonbonehealth. Bone mineraldensity andfracture risk remain challenging. extraction ofrobustconclusionsforclinicalpractice the interpretationofpublisheddataand and nausea,whichcanstimulateAVP release.Therefore, by thesideeffectsofopioids,includinghypotension differences inthefluidstatusofsubjects,aswell as opioids on AVP in humans are confounded by the ( morphine infusionledtoincreaseinserumADHlevels a singledoseofepiduralmorphinepost-induction or orabdominaloperations),foundthatboth genito-urinary al. et patients producedincreaseinplasmaAVP ( extradural injectionofmorphine6 during induction of anaesthesia( significantly higherwithfentanylthansufentanil bypass surgery, artery coronary the levels of AVP were published ( inappropriate antidiuretichormonesecretionhasbeen patient onfentanylpatcheswhodevelopedsyndromeof in adose-dependentmanner( infusions infivehealthyvolunteersincreasedplasma AVP levels. Fentanylofferedintwocontinuousintravenous through Opioids affectargininevasopressin(AVP) secretion Arginine vasopressin this stage,clinicalrecommendationscannotbeprovided. of thesedataremaintobeelucidatedand,therefore,at levels comparedwithhealthyvolunteers( 104 peripheral thyroid hormones compared with controls ( addicts, there was no difference in basal levels of TSH and to thyrotropin-releasinghormonestimulation( increase inserumTSHandenhancedtheresponseof morphine innormalvolunteersledtoasignificant 119 Review , Overall, thestudiesonimpactofexogenous Boulton Acute opioidadministrationcanleadtoariseinAVP The potentialclinicalsignificanceandtheimplications In chronic use of opioids for cancer pain and in opioid In humans,acuteintravenousadministrationof ). , in a series of children undergoing surgery (major , inaseriesofchildrenundergoingsurgery 111 μ , - ( 112 116 113 t al. et ). However, opiumsmokers had lower TSH ). ) andpossibly showedthatinpatientsundergoing κ 115 -opioid receptors( A Fountasandothers 117 ). Notably, acaseof h after surgery insix h aftersurgery ). Administration of 102 118 ). 110 ). Bozkurt 114 ). ). 16 ,

with women( and hadhigherprevalenceofhypogonadismcompared however, maleshadusedopioidsforalongerperiod chronic oralopioidshadosteopenia;inthisreport, another study, 50% of men and 21% of women on lower serumtestosteronethanthecontrols( women; notablyinthisseries,themalepatientshad values throughout the skeleton in men but not in maintenance therapy, BMDwaslowerfromcontrol In across-sectionalstudyofpatientstakingmethadone osteoblast tissuecultures( Furthermore, opioidsinhibitosteocalcinproductionin guidelines aremanagement approaches. of osteoporosisorosteopenia accordingtothecurrent Discontinuing the opioid, if possible, and treatment and particularlyhypogonadism requireassessment. BMD inpatientsonopioids butthosewithriskfactors cannot beexcluded. (due tochronicpain)onthehigherriskoffractures ( cumulative opioidusewasnot,particularlyinwomen initial weeksofadministration,whilstcurrentheavy in adultswithnon-cancerpain,particularlyduringthe of opioids was associated with increased risk of fractures risk offracturewasfound( relationship betweencurrentcumulativeopioiduseand Practice Research Database inwhichacleardose–response nested case–controlstudyusingtheUK-basedGeneral opioids ( systemeffectsof owing totheacutecentralnervous lowdoses,mayberelatedwiththeriskoffalls on very even suggested thatthisincrease,whichwasobserved morphine andotheropioids( in Denmark,therewasincreasedfractureriskusersof anticonvulsants ( were associatedwithsignificantlyreducedBMDbesides Health andNutrition Examination Survey, opioids andolderfromtheThirdNational adults aged17 years osteopenia in50%( in21%and hypogonadism, osteoporosiswasobserved intrathecal opioidsforchronicnon-malignantpainand healthy age-andsex-matchedcontrolsubjects( vertebral bonemineraldensity(BMD)comparedwith this effectwaspreventedbyopioidantagonists( inhibit thegrowthofhumanosteoblasttissuecultures; factors. Osteoblastsexpressopioidreceptorsandopioids these drugsonboneformationarepotentialcontributing endocrine system Effects ofopioidson 125 Male chronicheroinusershavesignificantlylower There is no consensus on the monitoring of the In acase–controlstudyfromnation-wideregister ). Finally, thecontributionoflimitationsin mobility 124 ). Thisviewwasfurthersupportedbya 15 ). Inaddition,inastudyof14maleson 123

25 ). ). In across-sectional analysis of Downloaded fromBioscientifica.com at10/02/202108:57:18AM 120 125 ). 124 ); thus,currentlightuse ). Notably, theauthors 179 :4 122 R190 121 120 ). In via freeaccess ). ). ). European Journal of Endocrinology FSH, follicle-stimulatinghormone;LH, luteinisinghormone. *Other causesofhypogonadotrophic hypogonadismneedtobeexcluded( • • Hypothalamo-pituitary-thyroid axis • Prolactin • • • Somatotroph axis • • • • Hypothalamo-pituitary-adrenal axis • • Hypothalamo-pituitary-gonadal axis Key findings management. Table 2 sequelae forthepatients.Althoughlessfrequent,cortisol however, mayremainundiagnosedwithpotentialadverse most well-recognisedconsequenceofopioidusewhich, still not fully elucidated ( the endocrine system through mechanisms which are Exogenous opioidshaveeffectsonmultiplelevelsof Conclusions andfuture perspectives Review unknown with healthyvolunteers:clinical significance Lower TSHlevelsinopiumsmokers compared purposes orinopioidaddicts No effect afteradministrationfortherapeutic Stimulatory ornoeffect not beenestablished offering growthhormonereplacementhave assessment ofthesomatotrophaxisand not clearand,atpresent,thebenefitsof Clinical significanceofthesefindings heroin addicts administration fortherapeuticpurposesin dynamic testing)ornoeffect after Inhibitory (compromisedresponseon in normalhumansubjects Stimulatory effect afteracuteadministration reported after glucocorticoidadministrationhavebeen insufficiency showingclinicalimprovement symptomatology resemblingadrenal Cases ofAddisoniancrisesorwith true cortisoldeficiency? established: adaptiveresponsetoopioids?– Clinical significanceofthesefindingsnot response ofcortisolondynamictesting Low basalbloodcortisollevels/inadequate Inhibitory effect Hypogonadotrophic hypogonadism Inhibitory effect Key findingsonimpactofexogenousopioidsanteriorpituitaryhormoneaxes,proposedinvestigationsand Table 2 A Fountasandothers ). Hypogonadism is the 08:00–09:00 Blood oestradiol,FSH,LH(combinedwith Females* Blood testosterone(08:00–10:00 Males* Proposed investigations Blood prolactin** consultation withendocrinologist) relevant clinicalmanifestationsand adrenal axis(followingconfirmationof assessment ofthehypothalamo-pituitary- menstrual history) LH h bloodcortisol 36 ); **impactofpainorothermedications needtobetakenintoaccount. overlooked duringthecareofthesepatients. negative impactofopioids on bonehealth,whichmaybe conclusions to bedrawn. Of particular importance is the a numberofconfoundingfactorsdonotallowclear levels maybeincreasedinpatientsonthesedrugsbut hyperprolactinaemia canbeoccasionallydetected.AVP on GHandTSHarelessclearoftencomplex,whereas deficiency canbefound.Thedataontheimpactofopioids endocrine system Effects ofopioidson ± dynamic h sample),FSH,

Downloaded fromBioscientifica.com at10/02/202108:57:18AM Discontinuation orreduction If abovenotviable,consider Discontinuation orreduction Management Consider discontinuation, Assess impactongonadal Glucocorticoid replacement replacement gonadal hormone of doseopioid needed alternative opioidif reduction indose,or gynaecomastia galactorrhoea, axis andpresenceof has takenplace reduction indoseofopioid discontinuation or reassessment oftheaxisif insufficiency with confirmed adrenal in casesofbiochemically of doseopioid 179 www.eje-online.org :4 R191 via freeaccess European Journal of Endocrinology www.eje-online.org References the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagencyin Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest present) andevaluationofbonehealthstatusareadvised. (particularly whenrelevantclinicalmanifestationsare periodical assessmentofthegonadalandadrenalfunction clinical guidelines,butuntilthesebecomeavailable, disorder. Thesewillfinallyleadtosafeandcost-effective ofpatientsonmethadoneforopioiduse and recovery sensitivity and potential reduction in opioiddose, treatment anditseffectsonotherareas,includingpain to clarifythelong-termbenefitsandrisksofhormonal factors (likeothercomorbidities,drugsorpain)areneeded studies takingintoaccounttheeffectofconfounding well-designed prospectiveratherthancross-sectional of thebiochemicalfindingsfromHPA axis.Finally, agonists (likebuprenorphine)andtheclinicalsignificance regimes, dosesandroutesofopioids,theimpactpartial prevalence ofhormonalabnormalitieswithvarious dimensions ofthisproblemasaglobalepidemic. on thesedrugsisvital,particularlygiventheexpanding opioids byallspecialistsprescribingormanagingpatients considered ( above measuresarenotpracticallyfeasible,needstobe options. Hormonalreplacement,especiallywhenthe therapies forpainreliefarepotentialmanagement in casesofchronicpain,considerationalternative 6 5 4 3 2 1 Review Zin CS, Chen LC&Knaggs RD.Changes intrendsandpattern Manchikanti L, Kaye AM,Knezevic NN,McAnally H,Slavin K, McDonald J &Lambert DG.Opioidreceptors. Stein C. Opioidreceptors. Dietis N, Rowbotham DJ&Lambert DG.Opioidreceptorsubtypes: Pathan H &Williams J. Basicopioidpharmacology:an of strong opioid prescribing in primary care. of strongopioidprescribinginprimary guidelines. PainPhysicians(ASIPP) pain: AmericanSocietyofInterventional safe, andeffectiveprescriptionofopioids forchronicnon-cancer Trescot AM, Blank S,Pampati V, Abdi S,Grider JS 219–224. 433–451. doi.org/10.1093/bja/aer115) fact orartifact? org/10.1177/2049463712438493) update. Further research isneededtoclearlyestablishthe Discontinuation or reductionoftheopioidand, British Journal ofPain British Journal (https://doi.org/10.1093/bjaceaccp/mku041) (https://doi.org/10.1146/annurev-med-062613-093100) Table 2 Pain Physician British Journal ofAnaesthesia British Journal ). Awareness oftheendocrineeffects 2017 Annual ReviewofMedicine 2012 20 S3–S92. 6 11–16. A Fountasandothers 2011 (https://doi. European Journal European Journal BJA Education et al. 107 2016 8–18. Responsible, 67 2015 (https://

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