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OPIOID OBJECTIVESTHE ROLE OF OPIOID IN PAIN MANAGEMENTPHARMACODYNAMIC OF OPIOIDSPHARMACOKINETIC OF OPIOIDSCLINICAL APLICATION OF OPIOIDSIntroductionOpioid most commonly used analgesic in clinical practiceEffectiveness Easy availabilityLow costOpium ( juice ) papaver somniferum contains 20 distinct alkaloidsMorphine , first isolated in 1803Opioid : all substances, natural and synthetic that have morphine like properties

WHO ANALGESIC LADDER

By the mouth By the clock By the ladderIndividualized for the patientAttention to detail Analgesic Ladder of WFSAPain IntensityOpiate And NSAID and ParacetamolOral route available give orallyOral route unavailable Rectal paracetamol & NSAID, Opiate: IV, PCA, IM algorithm, Epidural infusion analgesiaNSAID and ParacetamolParacetamolPain decreases as time passesDoctors problem OPIOPHOBIALimited information about OPIOID drug availableDrugs doses and interval Regular assessment Common mis-interpretations about opioid

MYTHS OF USE OPIOID !!!!!!!ADDICTION & DEPENDENCE TOLERANCE DOSE INCREMENT ISCONSERVATIVENARCOTIC IN OLDER BE AVOIDEDADEQUATE PAIN CONTROLPARENTERAL MORE EFFECTIVE AS NEEDED BASISHEAVY SEDATIONOPIOID EFFECTIVE FOR ALLPAIN CANNOT BE RELIEVED M Y T H SWe are a DOCTOR LOGICAL APPROACH TO PAIN CONTROL

SpinothalamictractPeripheralnerveDorsal HornDorsal root ganglionPainModulation

TransductionAscendinginputDescendingmodulationPeripheralnociceptorsAdapted from Gottschalk A et al. Am Fam Physician. 2001;63:1981, and Kehlet H et al. Anesth Analg. 1993;77:1049. Perception

TransmissionAnalgesia Mechanism 9

(Casy AF, Parfitt RT. Opioid Analgesic Chemistry and receptors. New York; Plenum Press;1996)Opioid Receptors in modulationOpioid ReceptorMOR or OP3 ( opioid receptor )Cortex, amygdala,hippocampus,thalamus, mesenchepalon, pons, medulla and spinal cordKOR or OP2 ( opioid receptor )Similar distributed but also in hypothalamusDOR or OP1 ( opioid receptor )Not widely distributed Telencephalon and spinal cordORs also identified in peripheral administrationOP4/ ORL-1 : Nociceptin / Orphanin-FQMechanism Action of OpioidsBinding to specific membrane receptor ( ORs )

Pharmacology effect as analgesia

Endogenous opioid peptide ( EOPs ) endorphins, dynorphins, enkhepalins, binding also to ORs Endogenous Opioid System (EOS) modulate nociceptive transmission Central and Peripheral NS, CV, GI and Immune Cell.

Opioid Mechanisms of ActionBasic and Clinical Pharmacology. 8th ed. 2001.Primary afferentPresynapticterminalPostsynaptic neuronSpinal pain-transmission neuron, d, k receptors gCa++ Transmitter release receptors gK+{{Opioid mechanismsSubstance PetcSpinal cord neuroneC-fibreDescending controlsTo the brainGlutamateOpioid mechanismsSubstance PetcSpinal cord neuroneC-fibreDescending controlsTo the brainOpioidGlutamateIf pain is not adequately controlled with NSAID or is expected to be moderate to severe, an appropriate opioid should be added to the NSAID

Patients with absolute or strong relative contraindications to NSAIDs an opioid for mild to moderate pain should be considered.

Opioid analgesicsHow to give OPIOID ?Routes of administrationIntravenousIntramuscularOralTransdermalSubcutaneousSpinal route : Epidural and IntratechalBuccalIntranasalRectal Opioid drugs

Opioid in Indonesia Morphine considered to be the standard opioid analgesic, oral sustained release and IV prep. availableFentanyl fast onset, more potent than morphine, less side effect, transdermal sustained and IV prep. availableMeperidine is not considered a first-line opioid analgesic medication, just IV preparation availableCodein, a weak opioid, is pro-drug of morphine, just oral Tramadol, a weak opioid that acts on mu-receptors, is another reasonable alternative, oral and IV preparations

Morphine Least lipid solubleMetabolites M6G and M3G ( longer half lifes )M6G more potent than morphineM3G ( no analgesic effect ) role in toleranceSlow release ( controlled release or sustained release ) use for chronic and cancer pain Slow onset, prolonged duration fast titration its impossible

FentanylHighly lipid soluble synthetic opioidRapid onset and short durationMetabolite inactive ( safe for renal impairment )Available in IV preparation for rapid onset and Transdermal preparation as sustained release ( slow onset and long duration )

Pethidine Synthetized as a potential substitute for atropine ( atropine like effect )Weak affinity for NMDA receptorPethidine superior in renal and biliary colic but evidenced show that all opioids are equally effectiveMetabolite is norphetidine ( normeperidine ) with long half-life ( 15-20 hrs ) analgesia ( receptors ) but neurotoxicity ( CNS excitation : anxiety, mood changes, tremors, twitching, myoclonic , convulsion )Available in IV preparation

CodeineNaturally alkaloid like morphineMetabolized in liver by CYP 2D6 converted to morphine (2-10%) analgesic effect of Codeine ( ineffective prodrug of morphine )Usually for mild to moderate pain Adverse effect more pronounced

Tramadol Centrally acting synthetic analgesiaMechanism : receptors activityInhibit reuptake NE and serotonine (5HT )Act as NMDA antagonistConsidered to have a lower risk of addiction and safety profile when compared to other opioidsAvailable in IV preparation and Oral ( single and combined )Advantages of equianalgesic dose opioidLess sedation Less repiratory depressionLess constipation Nausea and vomiting similarNot a controlled drug

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SEROTONINNEOREPINEPHRINE

Think about the issue of efficacyNeuropathic / nociceptive / unknown (use cautiously) Think about how to initiating therapy Think about side effects Think about the issue of tolerance and addiction Think about increase in function ( for chronic pain )Thinks when prescribing Opioids

Opioid principles of using Opioid titrationOpioid rescue doseOpioid rotationOpioid side-effect managementOpioid sparing strategies

Opioid Titration GuidelinesTitrate with shortacting hydrophilic opioid; can be given at interval based on the time to peak serum level as needed; oral ~ 1 hour , sc ~ 30 min, iv ~ 10 min.Calculate 24 hrs requirements and convert to long-acting opioidAlways increase by a percentage of the present dose based upon patients pain rating and current assessment Mild pain 1-3/10Moderate pain4-6/10 25-50% increaseSevere pain7-10/10 50-100% increaseOpioid Dose Escalation29Opioid Rescue DoseUsed for breakthrough pain.Dose:Approximately 10% of daily dose equivalent.Frequency :Oralevery 1 - 2 hoursParenteralevery 15 - 30 minutes22Opioid RotationOral dose ( mg )Opioid Parenteral iv/sc/im( mg )150Meperidine 50150Tramadol100150Codeine5015Morphine5-Fentanyl 0.050Morphine 50 mg PO in 24 hrs = Fentanyl patch 25 mcg/hr Equianalgesic doses OpioidsOpioid-induced adverse effectRespiratory depressionPruritusGastrointestinal effectUrinary effectsNausea and Vomiting

Develop tolerance Prophylaxis Opioid-sparing strategiesAnalgesic adjuvantse.g. Antiemetics, Laxatives, Antidepressant, Anticonvulsant, Corticosteroid, Anxiolytics, NMDA antagonistAlternate route (e.g. intraspinal)Anaesthetic/Neurolytic proceduresPM&R approachesCognitive therapyComplementary therapiese.g., acupuncture, massage, music therapy

ToleranceA change in the dose-response relationship induced by exposure to the drug and manifest as a need for a higher dose to maintain an effect.Develops at different rates to these varying effects:respiratory depression, somnolence, nausea >> analgesia > constipation.Analgesic tolerance is rarely a problem26DependenceThe development of a withdrawal syndrome following dose reduction or administration of an antagonist.Often develops after only a few days of opioid therapy.Not a clinical problem if drug is tapered before discontinuation.Taper by no more than 50% of the dose/day2936AddictionAddiction is a psychological / behavioural syndrome characterized by loss of control and the compulsive use of a substance despite harm.CONCLUSSIONOpioid still a main analgesic to manage pain The prescriber of an opioid agent should have current opioid pharmacotherapy knowledge, judgment, and wisdom to use opioid One of strategies to give good analgesia and low side effect is a Combination of opioid with non-opioidWe are not an Opiophobia Doctor !!!

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