Pharmacotherapy of Pain: Opioid Analgesics. Evolving Role of Opioid Therapy From the 1980s to the presentFrom the 1980s to the present More pharmacologic

Pharmacotherapy of Pain: Pharmacotherapy of Pain: Opioid AnalgesicsOpioid Analgesics

Pharmacotherapy of Pain: Pharmacotherapy of Pain: Opioid AnalgesicsOpioid Analgesics

Evolving Role of Opioid TherapyEvolving Role of Opioid Therapy

• From the 1980s to the presentFrom the 1980s to the present• More pharmacologic interventions for acute More pharmacologic interventions for acute

and chronic painand chronic pain

• Changing perspectives on the use of opioid Changing perspectives on the use of opioid drugs for chronic paindrugs for chronic pain

Evolving Role of Opioid TherapyEvolving Role of Opioid TherapyEvolving Role of Opioid TherapyEvolving Role of Opioid Therapy

• Historically, opioids have been emphasized Historically, opioids have been emphasized in medical illness and de-emphasized in in medical illness and de-emphasized in nonmalignant painnonmalignant pain

Opioid Therapy in Pain Related to Opioid Therapy in Pain Related to Medical IllnessMedical Illness

Opioid Therapy in Pain Related to Opioid Therapy in Pain Related to Medical IllnessMedical Illness

Opioid therapy is the mainstay approach for Opioid therapy is the mainstay approach for • Acute painAcute pain

• Cancer painCancer pain

• AIDS painAIDS pain

• Pain in advanced illnessesPain in advanced illnesses

But undertreatment is a major problemBut undertreatment is a major problem

Barriers to Opioid TherapyBarriers to Opioid TherapyBarriers to Opioid TherapyBarriers to Opioid Therapy

• Patient-related factorsPatient-related factors– Stoicism, fear of addictionStoicism, fear of addiction

• System factorsSystem factors– Fragmented care, lack of reimbursementFragmented care, lack of reimbursement

• Clinician-related factorsClinician-related factors– Poor knowledge of pain management, opioid Poor knowledge of pain management, opioid

pharmacology, and chemical dependency pharmacology, and chemical dependency – Fear of regulatory oversightFear of regulatory oversight

Opioid Therapy in Chronic Opioid Therapy in Chronic Nonmalignant PainNonmalignant Pain

Undertreatment is likely because of Undertreatment is likely because of • Barriers (patient, clinician, and system)Barriers (patient, clinician, and system)• Published experience of multidisciplinary Published experience of multidisciplinary

pain programs pain programs • Opioids associated with poor functionOpioids associated with poor function

• Opioids associated with substance use disorders and other Opioids associated with substance use disorders and other psychiatric disorderspsychiatric disorders

• Opioids associated with poor outcomeOpioids associated with poor outcome

Opioid Therapy in Chronic Opioid Therapy in Chronic Nonmalignant PainNonmalignant Pain

• Use of long-term opioid therapy for Use of long-term opioid therapy for diverse pain syndromes is increasingdiverse pain syndromes is increasing– Slowly growing evidence baseSlowly growing evidence base– Acceptance by pain specialistsAcceptance by pain specialists– Reassurance from the regulatory and law enforcement Reassurance from the regulatory and law enforcement

communitiescommunities

Opioid Therapy in ChronicOpioid Therapy in ChronicNonmalignant PainNonmalignant Pain

Opioid Therapy in ChronicOpioid Therapy in ChronicNonmalignant PainNonmalignant Pain

• Supporting evidenceSupporting evidence– >1000 patients reported in case series and >1000 patients reported in case series and

surveyssurveys

• Small number of RCTsSmall number of RCTs

Positioning Opioid TherapyPositioning Opioid TherapyPositioning Opioid TherapyPositioning Opioid Therapy

• Consider as first-line for patients with moderate-Consider as first-line for patients with moderate-to-severe pain related to cancer, AIDS, or to-severe pain related to cancer, AIDS, or another life-threatening illnessanother life-threatening illness

• Consider for all patients with moderate-to-Consider for all patients with moderate-to-severe noncancer pain, but weigh the influencessevere noncancer pain, but weigh the influences

• What is conventional practice?What is conventional practice?• Are opioids likely to work well? Are opioids likely to work well? • Are thereAre there reasonable reasonable alternatives?alternatives?• Are drug-related behaviors likely to be responsible, or problematic Are drug-related behaviors likely to be responsible, or problematic

so as to require intensive monitoring?so as to require intensive monitoring?

Opioid Therapy: Needs and ObligationsOpioid Therapy: Needs and Obligations

• Learn how to assess patients with pain Learn how to assess patients with pain and make reasoned decisions about a trial and make reasoned decisions about a trial of opioid therapyof opioid therapy

• Learn prescribing principlesLearn prescribing principles

• Learn principles of addiction medicine Learn principles of addiction medicine sufficient to monitor drug-related behavior sufficient to monitor drug-related behavior and address aberrant behaviorsand address aberrant behaviors

Opioid Therapy: Prescribing PrinciplesOpioid Therapy: Prescribing PrinciplesOpioid Therapy: Prescribing PrinciplesOpioid Therapy: Prescribing Principles

• Prescribing principlesPrescribing principles– Drug selectionDrug selection– Dosing to optimize effectsDosing to optimize effects– Treating side effectsTreating side effects– Managing the poorly responsive patientManaging the poorly responsive patient

Opioid Therapy: Drug SelectionOpioid Therapy: Drug SelectionOpioid Therapy: Drug SelectionOpioid Therapy: Drug Selection

• Immediate-release preparations Immediate-release preparations – Used mainly Used mainly

• For acute painFor acute pain

• For dose finding during initial treatment of chronic painFor dose finding during initial treatment of chronic pain

• For “rescue” dosingFor “rescue” dosing

– Can be used for long-term management in select Can be used for long-term management in select patientspatients


• Immediate-release preparationsImmediate-release preparations– Combination products Combination products

• Acetaminophen, aspirin, or ibuprofen combined with Acetaminophen, aspirin, or ibuprofen combined with codeine, hydrocodone, dihydrocodeinecodeine, hydrocodone, dihydrocodeine

– Single-entity drugs, eg, morphineSingle-entity drugs, eg, morphine– TramadolTramadol


• Extended-release preparations Extended-release preparations – Preferred because of improved treatment Preferred because of improved treatment

adherence and the likelihood of reduced risk in adherence and the likelihood of reduced risk in those with addictive diseasethose with addictive disease

– Morphine, oxycodone, fentanyl, Morphine, oxycodone, fentanyl, hydromorphone, codeine, tramadol, hydromorphone, codeine, tramadol, buprenorphinebuprenorphine

– Adjust dose q 2–3 dAdjust dose q 2–3 d


• Role of methadoneRole of methadone– Another useful long-acting drugAnother useful long-acting drug– Unique pharmacology when commercially Unique pharmacology when commercially

available as the racemic mixtureavailable as the racemic mixture– Potency greater than expected based on Potency greater than expected based on

single-dose studiessingle-dose studies– When used for pain: multiple daily doses, When used for pain: multiple daily doses,

steady-state in 1 to several weeks steady-state in 1 to several weeks

Opioid Selection:Opioid Selection:Poor Choices for Chronic Pain Poor Choices for Chronic Pain

Opioid Selection:Opioid Selection:Poor Choices for Chronic Pain Poor Choices for Chronic Pain

• MeperidineMeperidine– Poor absorption and toxic metabolitePoor absorption and toxic metabolite

• Propoxyphene Propoxyphene – Poor efficacy and toxic metabolite Poor efficacy and toxic metabolite

• Mixed agonist-antagonists (pentazocine, Mixed agonist-antagonists (pentazocine, butorphanol, nalbuphine, dezocine)butorphanol, nalbuphine, dezocine)– Compete with agonists Compete with agonists withdrawal withdrawal– Analgesic ceiling effectAnalgesic ceiling effect

Opioid Therapy: Routes of AdministrationOpioid Therapy: Routes of AdministrationOpioid Therapy: Routes of AdministrationOpioid Therapy: Routes of Administration

• Oral and transdermal—preferred Oral and transdermal—preferred

• Oral transmucosal—available for fentanyl Oral transmucosal—available for fentanyl and used for breakthrough pain and used for breakthrough pain

• Rectal route—limited use Rectal route—limited use

• Parenteral—SQ and IV preferred and feasible Parenteral—SQ and IV preferred and feasible for long-term therapy for long-term therapy

• Intraspinal—intrathecal generally preferred Intraspinal—intrathecal generally preferred for long-term usefor long-term use

Opioid Therapy: GuidelinesOpioid Therapy: GuidelinesOpioid Therapy: GuidelinesOpioid Therapy: Guidelines

• Consider use of a long-acting drug and a Consider use of a long-acting drug and a “rescue” drug—usually 5%–15% of the total “rescue” drug—usually 5%–15% of the total daily dosedaily dose

• Baseline dose increases: 25%–100% orBaseline dose increases: 25%–100% orequal to “rescue” dose useequal to “rescue” dose use

• Increase “rescue” dose as baseline dose Increase “rescue” dose as baseline dose increasesincreases

• Treat side effectsTreat side effects

Opioid Therapy: Side EffectsOpioid Therapy: Side EffectsOpioid Therapy: Side EffectsOpioid Therapy: Side Effects

• CommonCommon– ConstipationConstipation– Somnolence, mental cloudingSomnolence, mental clouding

• Less commonLess common– NauseaNausea –– Sweating Sweating– MyoclonusMyoclonus –– Amenorrhea Amenorrhea– ItchItch –– Sexual dysfunction Sexual dysfunction– Urinary retentionUrinary retention –– Headache Headache

Opioid ResponsivenessOpioid Responsiveness

• Opioid dose titration over time is critical to Opioid dose titration over time is critical to successful opioid therapy successful opioid therapy

• Goal: Increase dose until pain relief is adequate Goal: Increase dose until pain relief is adequate or intolerable and unmanageable side effects or intolerable and unmanageable side effects occuroccur

• No maximal or “correct” doseNo maximal or “correct” dose

• Responsiveness of an Responsiveness of an individualindividual patient to a patient to a specificspecific drug cannot be determined unless dose drug cannot be determined unless dose was increased to treatment-limiting toxicitywas increased to treatment-limiting toxicity

Poor Opioid ResponsivenessPoor Opioid ResponsivenessPoor Opioid ResponsivenessPoor Opioid Responsiveness

• If dose escalation If dose escalation adverse effects adverse effects– Better side-effect managementBetter side-effect management– Pharmacologic strategy to lower opioid Pharmacologic strategy to lower opioid

requirementrequirement• Spinal route of administrationSpinal route of administration

• Add nonopioid or adjuvant analgesicAdd nonopioid or adjuvant analgesic

– ““Opioid rotation”Opioid rotation”– Nonpharmacologic strategy to lower opioid Nonpharmacologic strategy to lower opioid

requirementrequirement

Opioid RotationOpioid RotationOpioid RotationOpioid Rotation

• Based on large intraindividual variation in Based on large intraindividual variation in response to different opioidsresponse to different opioids

• Reduce equianalgesic dose by 25%–50% Reduce equianalgesic dose by 25%–50% with provisos:with provisos:– Reduce less if pain severeReduce less if pain severe– Reduce more if medically frailReduce more if medically frail– Reduce less if same drug by different routeReduce less if same drug by different route– Reduce fentanyl lessReduce fentanyl less– Reduce methadone more: 75%–90%Reduce methadone more: 75%–90%

Equianalgesic TableEquianalgesic TableEquianalgesic TableEquianalgesic Table

PO/PR PO/PR (mg)(mg) AnalgesicAnalgesic SC/IV/IM SC/IV/IM (mg)(mg)

3030 MorphineMorphine 1010

4–84–8 HydromorphoneHydromorphone 1.51.5

2020 OxycodoneOxycodone --

2020 MethadoneMethadone 1010

Opioid Therapy and Chemical DependencyOpioid Therapy and Chemical DependencyOpioid Therapy and Chemical DependencyOpioid Therapy and Chemical Dependency

• Physical dependencePhysical dependence

• ToleranceTolerance

• Addiction Addiction

• PseudoaddictionPseudoaddiction

Opioid Therapy and Chemical Dependency Opioid Therapy and Chemical Dependency

• Physical dependencePhysical dependence – Abstinence syndrome induced by administration of Abstinence syndrome induced by administration of

an antagonist or by dose reductionan antagonist or by dose reduction– Assumed to exist after dosing for a few days but Assumed to exist after dosing for a few days but

actually highly variableactually highly variable– Usually unimportant if abstinence avoided Usually unimportant if abstinence avoided – Does not independently cause addictionDoes not independently cause addiction


• ToleranceTolerance– Diminished drug effect from drug exposureDiminished drug effect from drug exposure– Varied types: associative vs pharmacologic Varied types: associative vs pharmacologic – Tolerance to side effects is desirable Tolerance to side effects is desirable – Tolerance to analgesia is seldom a problem in the Tolerance to analgesia is seldom a problem in the

clinical settingclinical setting• Tolerance rarely “drives” dose escalation Tolerance rarely “drives” dose escalation • Tolerance does not cause addictionTolerance does not cause addiction


• AddictionAddiction– Disease with pharmacologic, genetic, and Disease with pharmacologic, genetic, and

psychosocial elementspsychosocial elements– Fundamental featuresFundamental features

• Loss of controlLoss of control

• Compulsive useCompulsive use

• Use despite harmUse despite harm

– Diagnosed by observation of aberrant drug-Diagnosed by observation of aberrant drug-related behaviorrelated behavior

Opioid Therapy and Chemical Dependency Opioid Therapy and Chemical Dependency Opioid Therapy and Chemical Dependency Opioid Therapy and Chemical Dependency

• PseudoaddictionPseudoaddiction– Aberrant drug-related behaviors driven by desperation Aberrant drug-related behaviors driven by desperation

over uncontrolled painover uncontrolled pain– Reduced by improved pain controlReduced by improved pain control– ComplexitiesComplexities

• How aberrant can behavior be before it is inconsistent with How aberrant can behavior be before it is inconsistent with pseudoaddiction?pseudoaddiction?

• Can addiction and pseudoaddiction coexist?Can addiction and pseudoaddiction coexist?


• Risk of addiction: Evolving viewRisk of addiction: Evolving view– Acute pain: Very unlikelyAcute pain: Very unlikely– Cancer pain: Very unlikelyCancer pain: Very unlikely– Chronic noncancer pain: Chronic noncancer pain:

• Surveys of patients without abuse or psychopathology show Surveys of patients without abuse or psychopathology show rare addictionrare addiction

• Surveys that include patients with abuse or psychopathology Surveys that include patients with abuse or psychopathology show mixed resultsshow mixed results

Chronic Opioid Therapy in Substance AbusersChronic Opioid Therapy in Substance Abusers

Good outcome Good outcome (N = 11)(N = 11)

• Primarily alcoholPrimarily alcohol

• Good family supportGood family support

• Membership in AA or Membership in AA or similar groupssimilar groups

Bad outcome Bad outcome (N = 9)(N = 9)

• PolysubstancePolysubstance

• Poor family supportPoor family support

• No membership in No membership in support groupssupport groups

Dunbar SA, Katz NP. J Pain Symptom Manage. 1996;11:163-171.

Opioid Therapy: Monitoring OutcomesOpioid Therapy: Monitoring OutcomesOpioid Therapy: Monitoring OutcomesOpioid Therapy: Monitoring Outcomes

• Critical outcomesCritical outcomes– Pain reliefPain relief– Side effectsSide effects– Function—physical and psychosocialFunction—physical and psychosocial– Drug-related behaviorsDrug-related behaviors

Monitoring Drug-Related BehaviorsMonitoring Drug-Related Behaviors

Probably more predictive of Probably more predictive of addictionaddiction

• Selling prescription drugsSelling prescription drugs

• Forging prescriptionsForging prescriptions

• Stealing or “borrowing” drugs Stealing or “borrowing” drugs from another personfrom another person

• Injecting oral formulationInjecting oral formulation

• Obtaining prescription drugs Obtaining prescription drugs from nonmedical sourcefrom nonmedical source

•““Losing” prescriptions repeatedlyLosing” prescriptions repeatedly

Probably less predictive of Probably less predictive of addictionaddiction

• Aggressive complainingAggressive complaining

• Drug hoarding when symptoms Drug hoarding when symptoms are milderare milder

• Requesting specific drugsRequesting specific drugs

• Acquiring drugs from other Acquiring drugs from other medical sourcesmedical sources

• Unsanctioned dose escalation Unsanctioned dose escalation once or twiceonce or twice

Monitoring Drug-Related Behaviors (cont.)Monitoring Drug-Related Behaviors (cont.)Monitoring Drug-Related Behaviors (cont.)Monitoring Drug-Related Behaviors (cont.)

Probably more Probably more predictive of addictionpredictive of addiction

• Concurrent abuse of related Concurrent abuse of related illicit illicit drugsdrugs

• Multiple dose escalations Multiple dose escalations despite despite warningswarnings

• Repeated episodes of gross Repeated episodes of gross impairment or dishevelmentimpairment or dishevelment

Probably less predictive Probably less predictive of addictionof addiction

• Unapproved use of the drug to Unapproved use of the drug to treat another symptomtreat another symptom

• Reporting of psychic effects not Reporting of psychic effects not intended by the clinicianintended by the clinician

• Occasional impairmentOccasional impairment

Monitoring Aberrant Drug-Related Behaviors:Monitoring Aberrant Drug-Related Behaviors:2-Step Approach2-Step Approach

Step 1: Step 1: Are there aberrant drug-related Are there aberrant drug-related behaviors?behaviors?

Step 2:Step 2: If yes, are these behaviors best If yes, are these behaviors best explained by the existence of an explained by the existence of an addiction disorder?addiction disorder?

Opioid Therapy and Chemical Dependency Opioid Therapy and Chemical Dependency Opioid Therapy and Chemical Dependency Opioid Therapy and Chemical Dependency

• Differential diagnoses of aberrant drug- Differential diagnoses of aberrant drug- related behaviorrelated behavior– AddictionAddiction– PseudoaddictionPseudoaddiction– Other psychiatric disorders (eg, borderline Other psychiatric disorders (eg, borderline

personality disorder)personality disorder)– Mild encephalopathy Mild encephalopathy – Family disturbancesFamily disturbances– Criminal intentCriminal intent


• Addressing aberrant drug-related behaviorAddressing aberrant drug-related behavior– Proactive and reactive strategiesProactive and reactive strategies– Management principlesManagement principles

• Know laws and regulationsKnow laws and regulations

• Communicate Communicate

• Structure therapy to match perceived risk Structure therapy to match perceived risk

• Assess behaviors comprehensivelyAssess behaviors comprehensively

• Relate to addiction-medicine communityRelate to addiction-medicine community

• Possess a range of strategies to respond to aberrant Possess a range of strategies to respond to aberrant behaviorsbehaviors


• Addressing aberrant drug-related behaviorAddressing aberrant drug-related behavior– Strategies to respond to aberrant behaviorsStrategies to respond to aberrant behaviors

• Frequent visits and small quantitiesFrequent visits and small quantities

• Long-acting drugs with no rescue dosesLong-acting drugs with no rescue doses

• Use of one pharmacy, pill bottles, no replacements Use of one pharmacy, pill bottles, no replacements or early scriptsor early scripts

• Use of urine toxicologiesUse of urine toxicologies

• Coordination with sponsor, program, addiction Coordination with sponsor, program, addiction medicine specialist, psychotherapist, othersmedicine specialist, psychotherapist, others

Opioid Therapy: ConclusionsOpioid Therapy: ConclusionsOpioid Therapy: ConclusionsOpioid Therapy: Conclusions

• An approach with extraordinary promise An approach with extraordinary promise and substantial risksand substantial risks

• An approach with clear obligations on the An approach with clear obligations on the part of prescriberspart of prescribers– Assessment and reassessmentAssessment and reassessment– Skillful drug administrationSkillful drug administration– Knowledge of addiction-medicine principlesKnowledge of addiction-medicine principles– Documentation and communicationDocumentation and communication

Documents

Pharmacotherapy of Pain: Opioid Analgesics. Evolving Role of Opioid Therapy From the 1980s to the presentFrom the 1980s to the present More pharmacologic