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dividing the total daily dose and administering every 6 to 8 hours. Non-opioid medications dosed
continuouslyor“asneeded”canalsobeaddedtotheregimen.
Currently there are no established perioperative or postoperative guidelines for patients on
buprenorphine.Limitedliteratureofferssuggestionsontreatmentmethods,butoftendecisionsaremade
based on patient- and institution-specific factors. For patients on buprenorphine in need of inpatient
analgesictreatment,thereareafewoptions(Alfordetal.,2006):
1. Continue buprenorphine once-daily maintenance and titrate a short-acting opioid to effect. Due to
increasedpainsensitivityandthemechanismofactionofbuprenorphine,higherdosesoftheopioid
willneedtobeadministeredtotreatpain.Anopioidwithahighaffinitytothemureceptor,suchas
hydromorphone or fentanyl, would be needed to overcome the strong receptor binding of
buprenorphine.
2.Dividetotaldailydoseofbuprenorphineandadministerevery6to8hours.Low-dosebuprenorphine
canbeconsideredasneededforadditionalacutepaincontrol.
3.Foranticipatedacutepainfromscheduledsurgery,buprenorphinecanbediscontinuedordosagecanbe
reducedwhilefullopioidagonistsareinitiated(includingmethadone)forthetreatmentofanticipated
postoperativepain.Initially,higherdosesofopioidswillbeneededtoovercomethehighaffinityof
buprenorphinetothemureceptor.Patients shouldbe monitoredforpossible respiratorydepression
thatmayoccuroncethebuprenorphineisnolongerinthesystem,thatis,ifbuprenorphineisstopped
whenacutepaintreatmentsareinitiated.
4. Whenacutepainis resolved andopioids discontinued,thebuprenorphinecanberestartedafterthe
patientisinconfirmedwithdrawal.
Noconsensus existsonthepropermethodofswitchingtobuprenorphinefroma full opioidagonist.
Levelofdependence,typeofopioidused(longactingvs.shortacting),andtimesincelastdoseofopioid
takenshouldbe determinedpriortoswitchingtobuprenorphine.Onemethodoftransitionrecommends
discontinuingtheopioid(bytapering,ifhighdose-opioiduse)andwaitingforthepatienttoexperience
objective symptomsofwithdrawal.Oncethepatientisinwithdrawal,low-dose buprenorphine(2 mg)
with available redosing every 1 to 2 hours as needed for signs of withdrawal and cravings can be
prescribed. Each subsequent day, the dose can be adjusted to the previous day’s total dose with
breakthrough doses accessible until effective dose is established. The buprenorphine/naloxone
(Suboxone®) package insert recommends that when switching from short-acting opioids or heroin,
buprenorphineshouldbegivenatleast6to12hoursafterlastuseofashort-actingopioid,atleast24to
96hoursafterlong-actingopioid,and/orpreferablywhenmoderateobjectivesignsofopioidwithdrawal
areobserved.Therapyshouldbetitratedtoclinicaleffectivenessasquicklyaspossible.
Inductioninthepackageinsertisasfollows(Indivior,Inc.,2019):
OnDay1,aninductiondosageofupto8mg/2mgSUBOXONEsublingualfilmis recommended.
Cliniciansshouldstartwithaninitialdoseof2mg/0.5mgor4mg/1mgbuprenorphine/naloxoneand
maytitrateupwards in2 or 4 mgincrementsofbuprenorphine,at approximately2-hourintervals,
undersupervision,to8mg/2mgbuprenorphine/naloxonebasedonthecontrolofacutewithdrawal
symptoms. On Day 2, a single daily dose of up to 16 mg/4 mg SUBOXONE sublingual film is
recommended.
Whenswitchingfromlong-actingopioids(suchasmethadone)tobuprenorphine/naloxone,withdrawal
symptoms may be more likely to occur. Also, the naloxone component may be minimally absorbed,
potentiallyworseningwithdrawal.Forthisreason,buprenorphinemonotherapyisrecommendedwithan
eventualswitchtocombinationformulationwhenconvertingfromlong-actingformulations.
For treatmentof acutepainfor patients onmethadonethathavefailednon-opioidadjuncts,thetotal
dailydoseofmethadonecanbedividedevery6to8hours.Ifunabletopartitionmethadonedosing(only
somemethadoneclinicswilloffersplitdosing),opioids(notincludingmixedagonist/antagonistopioids)
mayneedtobeprescribedunderclosemonitoring.
WhenapatientisdiagnosedwithOUDandnotreceivingmedicationand/ortherapyforOUD,referral
shouldbemadefortreatment.Ifthepatientiscurrentlyonprescribedorrecreationalopioids,considera
switchtomethadoneor buprenorphine.Buprenorphinewithnaloxonemaybeconsidered asaferoption
duetoitsceilingeffectandpresenceofanopioidreversalagentthatminimizesabusepotential.
SpecialConsiderations
Pediatric
ThesafetyofbuprenorphinewhenusedforOUDhasnotbeenestablishedinpatientslessthan16years
old,andthesafetyandeffectivenessofmethadonehavenotbeenestablishedinpatientslessthan18years
old.
The American Academy of Pediatrics recommends the consideration of MAT in adolescents with
severe OUD (“Medication-Assisted Treatment,” 2016). Generally,at leasttwo documentedattempts at
psychosocial treatment within 12 months before being considered for methadone maintenance are
recommended(Federetal.,2017).
Geriatric
Methadoneandbuprenorphineneedtobe usedcautiouslyinolderpatientsduetodecreasesinhepatic,
renal, and cardiac function; and alterations in absorption, distribution, metabolism, and excretion of
medications.Recommendationsaretostartatlowerdosesandgraduallytitrateuptoefficacy.Thispatient
populationmayalso be on multiple medications,thereby increasingtheriskofdrug-druginteractions.
Monitorcloselyforsignsandsymptomsofoverdoseortoxicity.
Women
MethadonehistoricallyhasbeenconsideredthestandardofcarefortreatingpregnantpatientswithOUD;
however,bothmethadoneandbuprenorphine(withoutnaloxone)areconsideredsafeandeffectiveforuse
in pregnancy. Dataonbuprenorphine with naloxone are currentlylimitedandtherefore buprenorphine
monotherapy is preferred. Prolonged exposure to opioids in utero can result in neonatal abstinence
syndrome(NAS).Buprenorphineandmethadonebothcrosstheplacentaandcanresultinwithdrawalofa
neonateinthefirstweekafterbirth.NAScanoccurwitheithertreatmentoptionalthoughsomestudies
have shownthatbuprenorphinemaybe associatedwithreducedseverityofNASas well as improved
fetal growth outcomes when compared to methadone (Krsak et al., 2017). However, there is also
evidence that methadone maintenance in opioid-dependent women may also improve maternal and
newbornoutcomes(Kumar,2020).Itisundeterminedwhetherornotintrauterineexposuretomethadone
orbuprenorphineleadstodevelopmentalissuesininfants,butthereisalsonocurrentevidenceshowing
that either resultsinbirthdefects (Kumar, 2020). Overall, the risk ofusing MATduring pregnancy is
commonly preferred to the risk of overdose or withdrawal. Pregnant women who are on MAT are
generally encouraged to continue on buprenorphine or methadone throughout pregnancy. Transmucosal
buprenorphineisthepreferredformulationforpregnantwomen(Lexicomp,2019).Thepharmacokinetics
ofbuprenorphineandmethadonechangeas pregnancyprogresses, andtherefore, higher dosesormore
frequent dosing may be needed. After childbirth, the doses can be gradually tapered back down to
prepregnancydoses.
Buprenorphineandits metabolitenorbuprenorphinehavebeendetectedinlow levels inbreastmilk
althoughavailabledatahavenotyetshownadverseeventsininfantswhowerebreastfed(possiblydueto
low oral bioavailability). Methadone is also excreted into breast milk with incidences of infant
respiratorydepressionandsedation.Weaningbreast-fedinfantsgraduallytopreventwithdrawalmaybe
necessary(Bostwicket al., 2019).Infants ofpatientsreceivingbuprenorphineor methadoneshould be
monitoredforbreathingdifficultiesandrespiratorydepression.
Nonpharmacologic
NonpharmacologictreatmentsarerecommendedforthetreatmentofpaininconjunctionwithbothnonopioidmedicationsandMAT(seeBox10.2).
Cognitive behavioral therapy (CBT) is a psychotherapy that helps patients change negative and
maladaptivethoughtsaboutpainwiththegoalofreducingandgainingbetterfunctioningandcopingskills.
Itinvolvesmultipleintensivesessionsandhasbeenfoundtobeefficaciousinpatientswithchronicpain.
DuringCBT,patientsareabletolearntechniquestotransitiontheirthoughtsawayfrompainandlessen
the exacerbation of symptoms that they may be experiencing through pain-related coping mechanisms
(Lemmon&Hampton,2018).
OtherNonpharmacologicTreatmentOptionsforPain
Box10.2 NonpharmacologicTreatmentOptionsforPain
OtherNonpharmacologicTreatmentOptionsforPain
•Acupuncture
•Hypnosis
•MassageTherapy
•Meditation
•TranscutaneousElectricalNerveStimulation
•Mindfulness
Examples of exercise-based therapy include tai chi, yoga, and therapeutic exercise. Each of these
therapieshasevidencetosupportthetreatmentofcommoncausationsofpainsuchaskneeosteoarthritis,
chroniclower backpain,andfibromyalgia.As with medications,differentnonpharmacologic treatment
options have greater efficacy for different conditions. For example, tai chi, with its low impact and
flowing movements, was found to be an effective treatment of knee osteoarthritis, but lower-quality
evidence of improvement in the chronic low back pain and fibromyalgia (Lemmon, 2018).
Complementary modalities include treatment options such as spinal manipulative therapy, massage
therapy, and acupuncture. One of the most important things to remember when considering
nonpharmacologicoptionsistouseacombinationofalternativetreatments.
MONITORINGPATIENTRESPONSE
Self-reported painandutilizationof“asneeded”medicationsfor treatmentshouldbereassessedatall
subsequentvisits. Discuss and manageany sideeffects thatthepatient may be experiencing. Patient’s
qualityoflifeshouldalsobeconsidered.The5A’sofanalgesiacanbeappliedtoassesspainaswellas
responsetotreatment(seeBox10.3).InpatientswithOUD,itisimportanttoevaluateforcravingsand/or
fortheneedtousemoremedicationthanprescribed.Verifyingpharmacyfills throughaPDMPmaybe
helpful inmonitoringadherenceinsomecases,althoughmethadoneobtainedfroma clinicwill notbe
documented in this system. Random urine drug screens can be conducted using immunoassays.
Confirmatorytestingwillneedtobecompletedforunexpectedresults.
Box10.3 The5A’sofAnalgesia
•Analgesia
○Howwellistherapyworking?Howmuchpainreliefisachievedwithcurrentdosing?
•AdverseReactions
○Constipation,nausea,dizziness,drowsiness,confusion
•AberrantBehaviors
○Aremedicationsbeingtakenasprescribed?Havetherebeenlostprescriptionsandearlyrefills
requested?
•ActivityofDailyLiving
○Hasthepatient’sfunctionimprovedontherapy?
•Affect
○Ispainimpactingmood?Isthereconcurrentdepression/anxiety?
PATIENTEDUCATION
Patientsmustbeeducatedonproperadministrationoftheirpainmedication.Commonsideeffectsshould
be discussed with patients and follow-up appointments established. Encourage patients to report
increasedorrecurringpainattheirfollow-upappointments.Patientscanalsobeeducatedondrugtakeback programs (DEA, 2020). These programs help reduce the quantity of circulating opioids by
promotingandmakingaccessiblethereturnofunusedprescriptions.Resourcesonpainmanagementand
OUDshouldbeprovidedtopatient.Instructpatientstokeepanopioidreversalagentsuchasnaloxone
(Narcan®)inthehousehold.Educateontheproper administrationofthis medicationtothepatientand
theirfamilymembers.
APPENDIX10-1
CASESTUDY1
Elizabethis a 55-year-oldfemale data analyst witha pastmedical historyofhypertension,bipolar
disorder, fibromyalgia, spinal stenosis, andopioid usedisorder (OUD). Patientcomes to the clinic
reportingofworseningpain"allovermybody."Patientisdisabledfromwork.Patientstatesthather
painiscausingherseveredistress anddepression.PatientstatesthatduetoherOUDhistory,sheis
havingdifficultyfindingaprescribertoadequatelytreatherpain(LearningObjective1).
1.Whatassessmentsshouldbedoneonthispatient?
Answer:BothpainassessmentsandOUDassessmentsshouldbecompletedforthispatient.Type
andclassofpainshouldbeidentified.Anup-to-datemedicationlistshouldbe obtainedfromthe
patienttoassessforpotentialdruginteractions.Pastmedicationsusedtotreatthepatient'spainwill
needtobeobtainedandpatient'sresponsestothesetreatmentswill needtobeevaluated.Assess
patientforcurrentmedication-assisted treatment.Patientshouldbe assessed for active substance
misuse. Urine drug screens and referencing Prescription Drug Monitoring Program can also be
utilized.
2.Whatarethegoalsofmedicationtherapyforthispatient?
Answer:ThegoalsoftreatingpaininpatientswithOUDinclude(1)reducingoreliminatingpain
andtreatingunderlyinginjury/disease,(2)reducingoreliminatingcravings,(3)preventingrelapse,
(4)minimizingormanagingsideeffects,and(5)improvingqualityoflife.
3.Patientreportsthatsheisonquetiapineforherbipolardisorder.Howcanthispotentiallyaffecther
urinedrugscreenimmunoassay.
Answer:Quetiapinecansometimesproduceafalsepositiveforopioidssuchasfentanyl,inwhich
case, if this patient's urine drug screen was positive for fentanyl, a gas chromatography-mass
spectrometryisadvised.While immunoassays are moreaffordable andyield rapid results,false
positive rates are high. Gas chromatography-mass spectrometry is more sensitive and tests for
specificmedications.
CASESTUDY2
Jamesisa41-year-oldmalelandscaper withapastmedicalhistoryofdepression,gastroesophageal
refluxdisease,andopioidusedisorder(OUD).Twoweeksago,patientstartedtoexperiencelower
lumbarpainafteranincidentatwork.HevisitedhisPCPaweekagoandwasprescribedibuprofen
600mgevery6hourasneeded.Patienthasbeentakingthismedicationaroundtheclock.Patientcomes
totheclinicreportingcontinuedlowerlumbarpain.Patientstatesthatwhileinthemorninghispainis
controlledwiththeibuprofen,intheeveningafteralongdayofwork,hispainismoresevereandthe
ibuprofen"barelytouchesthepain."Patientiscompliantwithhiscurrentmedicationregimen.
CurrentMedications:
BupropionXL150mgtablet:1tabletorallydaily
Ranitidine150mgtablet:1tabletorallyatbedtime
StJohn'sWort300mgcapsule:2capsulesorallytwicedaily
Buprenorphine/Naloxone 8 mg/2 mg sublingual films: 2 films sublingually once daily in the
morning
Ibuprofen600mgtablet:1tabletorallyevery6hoursasneededforpain(LearningObjective2)
1.Whatmedicationadjustmentcanbemadetothispatient'sregimenthatmayhelpmanagehisevening
pain?
Answer:Buprenorphine's analgesic effectis relativelyshortincomparisonto its effect inOUD
maintenance,lastingabout6to8hours.Dividingthetotaldailydoseofthispatient'sbuprenorphine
(16mg)every6to8hoursmayhelptomanagepatient'seveningpain(i.e.,buprenorphine/naloxone
4mg/1mgevery6hours).The"as-needed"ibuprofencanalsobe continuedandreassessedwith
thebuprenorphineatfollow-up.
2.Wastheprescribingofibuprofenanappropriateinitialtreatmentinthispatient?
Answer:Nonsteroidalanti-inflammatorydrugshavebothanalgesicandanti-inflammatoryactivity
andareanappropriatefirst-linetreatmentoptionforacutepaininpatientswithOUD.
3. Which medication that the patient is currently taking may also be decreasing the effect of the
buprenorphine/naloxone?
Answer:BuprenorphineismetabolizedbyCYP3A4.StJohn'sWortisaCYP3A4inducertherefore
when St. John's Wort is taken with buprenorphine, it will metabolize the buprenorphine more
rapidlydecreasingitsconcentrationandeffect.
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11
CannabisandPainManagement
AndrewM.PetersonandMilyShah
LearningObjectives
1.Identifythevariouscomponentsofcannabis.
2.Describehowtheendocannabinoidsystemmodulatespain.
3.Describetherelationshipbetweentetrahydrocannabinol(THC)andcannabidiol(CBD)andtheendo-
cannabinoidsystem.
4.Identifypotentialdrug-druginteractionsandsideeffectsofTHCandCBD.
INTRODUCTION
Cannabis, more commonlyknownasmarijuana, hasahistorythatdates backmore than12,000 years.
Throughoutmankind’shistory,humanshavecultivatedcannabisforlongerthananyotherplant.Thereisa
commonmisconceptionofcannabisasaharmfulsubstanceofabuse,butinreality,itcanbebothgoodand
bad. Cannabis canbe used medicinallybutcanalso cause harm ifnotused with theright knowledge.
There are hundreds of chemicals in the cannabis plant, many of whichact in the bodybymimicking
regulatory molecules that contribute to physiologic processes. Cannabis acts on the endocannabinoid
system(ECS), a complex regulatorysystem witha broad functionin thehumanbody, whichregulates
pain, appetite, immunity, and other physiologic processes (Backes, 2014). This chapter reviews the
basicsofcannabispharmacologyanddiscussesthecurrentlyapproveddrugsderivedfromormimicking
chemicalsinthecannabisplant.
CANNABIS
CannabisasaPlant
Thecannabisplantiscomprisedofmanydifferentstructures(seeFigure11.1).Cannabis plantscanbe
male,female,orbothdependingonthereproductiveorgans,butfemaleplantsproducethepotentflowers
thatpatientsconsume.Cannabisplantsstemoffalongbranchcalledthenode,andthemaleandthefemale
bothcontainacola.Thecolaisaclusterofbudsthatgrowcloselytogether,andthemaincolagrowsat
thetopoftheplant.Thepistiloftheplantcontainsthereproductivepartsoftheflower,andthehair-like
strandsthatstemofffromthepistilareknownasthestigmas.Stigmasarefoundonlyonfemaleplantsand
areusedtocollectthepollenfromthemaleplants.Thebractofthefemaleplantisessentialbecauseitis
coveredintheresinglands.Theresinglandsproducethehighestconcentrationofcannabinoids.Onthe
cannabisbud,thereisalayerofcrystalresin;whenitisdry,theresinisknownaskief.Thecalyxisthe
layerovertheovuleattheflower’sbase.Thelastpartofthecannabisplantisthetrichome.Trichomes
weredeveloped to protecttheplantagainsttheenvironment andpredators;this resincreatesan ooze,
whichisknownasterpenes.Theoozealsocontainscannabinoidssuchastetrahy-drocannabinol(THC)
andcannabidiol(CBD).
There are over 100 cannabinoids in the cannabis plant, and THC and CBD are currently the most
studiedcompoundsinhealthcare.THCisthecompoundthatproducesthepsychoactiveeffects,whereas
CBD contains no psychoactive effects. There are currently three species identified: Cannabis sativa,
Cannabisindica,andCannabisruderalis.C.sativacontainshigherlevelsofTHCthanCBD,whereas
C.indicacontainsmoreCBDthanTHC.
FIGURE11–1Structureofthecannabisplant.
CannabisasMedicine
Cannabis and cannabinoids have been used to alleviate numerous symptoms and treat diseases.
Cannabinoids have been studied in the treatment of chronic pain in patients with neuropathic pain,
fibromyalgia,rheumatoidarthritis, andmixedchronicpain.Currentevidencesuggeststhatcannabinoids
are safe, withminimalside effects,andareeffective inthetreatmentof neuropathicpain,specifically
fibromyalgiaandrheumatoidarthritis.
Cannabinoids havealsobeenstudied asagents inalleviatingchemotherapy-relatednausea. ATHCbased agent such as dronabinol has been approved for use as an antiemetic. Along with alleviating
nausea, cannabis-based medicine has been used for treating epilepsy, multiple sclerosis (MS),
Huntington’s disease, and Tourette’s. Medical cannabis has been used for a variety of conditions,
including Alzheimer’s disease, human immunodeficiency virus (HIV)/acquired immunodeficiency
syndrome (AIDS), amyotrophic lateral sclerosis, cancer, inflammatory bowel disease, glaucoma,
autoimmune disorders, Parkinson’s disease, posttraumatic stress disorder (PTSD), autism, cachexia,
chronicpain,migraineheadaches,nauseaandvomiting,seizuredisorders,andmusclespasticity.
Cannabis’sLegalStatus
Between the 1800s andthe1900s, cannabis was widely usedacross multiple countries, includingthe
UnitedStates.In1850, cannabis wasincludedintheU.S.pharmacopeia andwasusedtotreata wide
variety of conditions ranging from chronic cough to gonorrhea. However, in the later 1800s, attitude
towardthemedicaluseofmarijuanashifted,withthegrowthofopiumandmorphineabuse.Whileitdid
notspecificallyaddressmarijuana,theenactmentofthe1906PureFoodandDrugActtookitstollonall
mind-alteringsubstances.Subsequently,in1914theHarrisonActmadedrugconsumptionacrimeandby
1937, 23 states hadoutlawed theuse ofmarijuana. Followingthis, the federal government passedthe
MarijuanaTaxActof1937, whichmadenonmedicaluseofmarijuanaacrime.AfterWorld WarII,the
Boggs Act (1951) and Narcotics Control Act (1956) were passed, which introduced compulsory
sentencesfordrugoffenders.Whiletherewasageneralrelaxationinmarijuanalawsduringthe1960s,
largely associated with changing public perception, President Nixon introduced the Controlled
SubstancesAct(CSA)in1970,whichclassifiedmarijuanaas a Schedule1 drug,deemingittohavea
highpotentialforabuseandnoacceptedmedicaluse.Today,theU.S.DrugEnforcementAgency(DEA)
stillconsidersmarijuanaaSchedule1drugundertheCSA.
Priorto2018,marijuanaandhempwereoftenconsideredthesame,astheybothareunderthecannabis
umbrella.In2018,CongresspassedtheAgriculturalImprovementAct,alsoknownasthe2018FarmBill,
whichseparated,legally,marijuanaandhemp.Inthisbill,anypartorderivativeoftheC.sativaplantthat
containslessthan0.3%THCisconsideredhemp;anythingoverthisisconsideredmarijuana.Further,this
billamendedtheCSA,legalizinghempandthusremovingitfromtheDEASchedule1classification.
AsofJanuary2020,cannabisislegalforadultusein11statesandtheDistrictofColumbia:Alaska,
California, Colorado, Illinois, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and
Washington.Therearecurrently33stateswheremedicalmarijuanaislegal.Thisrequirespatientstosign
upthroughthestate,whichallowsthemtopurchasemedicalmarijuanaatanapprovedretaillocation.Due
to regulatory implications, physicians are unable to legally prescribe medicinal marijuana due to its
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