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Tramadol – interaction with SSRIs and with Morphine

Tramadol – interaction with SSRIs and with Morphine

Tramadol – interaction with SSRIs and with Morphine

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Serotonin Syndrome (SS)• all drugs that directly/indirectly central serotoninneurotransmission at postsynaptic 5-HT(2A)receptors in nervous system, on platelet surfaces,on vascular endothelium, can SS• spectrum serotonergic adverse effects to intrasynapticserotonin concentration-related toxidrome• When serotonergic drugs <strong>with</strong> differentmechanisms of action are mixed together intra-synaptic serotonin• low incidence• dose-related; rapid onset <strong>and</strong> progression (hours)• no formal test for the diagnosis of SS


Diagnosis of SS• diagnostic criteria are confusing• vague, non-specific clinical features• combination of altered mental status,neuromuscular hyperactivity, <strong>and</strong> autonomichyperactivity• exclude common mental status adverse effectsfrom centrally acting pharmaceuticals• Differential - neuroleptic malignant syndrome;anticholinergic delirium; malignant hyperthermia


Neuromuscular hyperactivityClonus,myoclonus,hyper-reflexia,shivering,hypertonia,rigidityAutonomic hyperactivitydiaphoresis, fevertachycardiatachypnoeaflushing,hyperthermiaAltered mental statusAgitation, anxietyhypomaniaconfusionWhytesDistinguishingFeatures


Hunter Serotonin Toxicity CriteriaSerotonergicagent ingestion oroverdoseSpontaneousclonusNoInducible orocular clonusTremorNoPlusPlusYesAgitation ordiaphoresis orhypertonia<strong>and</strong> pyrexia(> 38 C)HyperreflexiaNot clinically significant serotonin toxicityNoYesYesSEROTONINTOXICITY


Drugs associated <strong>with</strong> SerotoninToxicity• <strong>SSRIs</strong> - fluoxetine, fluvoxamine, paroxetine,citalopram, sertraline, escitalopram• SNRIs - venlafaxine, duloxitine, milnacipran,sibutramine• TCAs - clomipramine, imipramine• Opioids - pethidine, fentanyl, methadone,dextromethorphan, dextropropoxyphene, tramadol• Anti-histamines - chlorpheniramine, brompheniramine• Serotonin releasers - fenfluramine, amphetamine,MDMA (ectasy)• Monoamine oxidase inhibitors <strong>–</strong> moclobemide(reversible), linzolid; tranylcypromine, phenelzine• Others - lithium, tryptophan


Pathways by which serotonin acts <strong>with</strong>in the centralnervous system (MJA 2007;187:361-5)


Cyproheptadine (5-HT 2Aantag)to reducepyrexia,agitation,seizures12 mg orallyor crushed vianasogastrictube, then4<strong>–</strong>8 mgevery 6 hBenzodiazepinesChlorpromazine (5-HT 2Aantag)12.5<strong>–</strong>25 mg i.vafter fluidload, then 25mg orally oriv every 6 hSupportivepassive + active coolingsedation, intubation,muscle paralysis + ventilation


<strong>Tramadol</strong>


<strong>Tramadol</strong> <strong>and</strong> <strong>SSRIs</strong>• <strong>Tramadol</strong> - atypical opioid analgesic <strong>with</strong> partialµ agonism; central re-uptake inhibition of 5HT<strong>and</strong> noradrenaline; serotonin release (induced athigh doses)• <strong>Tramadol</strong> partial inhibition of serotonin uptake(especially in drug combinations) cerebralserotonin activity• <strong>SSRIs</strong> can inhibit the CYP2D6 iso-enzymemetabolising tramadol therapeutic overdoseof tramadol idiosyncratic induction of SS (insusceptible individuals)


<strong>Tramadol</strong> <strong>and</strong> <strong>SSRIs</strong>• SS - rare <strong>with</strong> tramadol (less than 20 cases inPUBMED); used over 30 years <strong>with</strong> > 5 billiontreatment days• Most frequent (<strong>and</strong> almost the only) fatalcombination is: - MAOIs <strong>with</strong> <strong>SSRIs</strong>• Safety Practice Points - use no more than twoSRI drugs; use low doses of combinations- e.g. fluoxetine 20 mg plus tramadol SR 100 mgbd- if fluoxetine dose to 40 mg, reduce <strong>and</strong> stoptramadol


<strong>Tramadol</strong><strong>and</strong> <strong>Morphine</strong>• Multimodal (or balanced analgesia) is a validatedconcept in the postoperative period- combination of analgesic drugs <strong>with</strong> differentpharmacological properties- supra-additive effects of paracetamol/tramadol onanalgesia (anti-hyperalgesia)• Synergy between opioids reported in animal studies• Remifentanil (0.2 ug kg-1) to tramadol (0.2 mg kg-1), <strong>with</strong>10-min lockout times, for PCA postop analgesia +patient comfort after abdominal surgery, <strong>with</strong>out sedation orrespiratory depression (Unlugenc H. Eur J Anaesthesiol 2008; June 05:1)


<strong>Tramadol</strong> <strong>and</strong>Paracetamol(Filitz J et al, Pain 2008;136:262-70)Double-blind <strong>and</strong> placebo-controlled study <strong>with</strong> across-over in 17 volunteers using high currentintensity TENS(a) Pain ratings <strong>and</strong> (b) Areasof pinprick-hyperalgesia weresignificantly reduced aftercombination of paracetamol<strong>and</strong> tramadol (means ± SE).


<strong>Tramadol</strong>CYP2D6(sparteineoxidase)2500-4000 x less muopioid receptoraffinity vs morphineO-desmethyl tramadolinhibitsneuronalreuptake ofserotonin <strong>and</strong>noradrenaline9-450 x less muopioid receptoraffinity vs morphineactivates descendingmono-aminergic inhibitory paths


<strong>Tramadol</strong><strong>Morphine</strong><strong>Tramadol</strong>Enantiomer - weak mu opioideffectEnantiomer <strong>–</strong> inhibitsnoradrenaline/serotonin uptake+ activates descending monoaminergicinhibitory paths<strong>Morphine</strong>mu opioid agonist - Activatesdescending analgesic pathsInhibits sub P release at spinalcord synapseHyperpolarises post-synapticinter-neuronesPotency (weight for weight)intravenous 1 10epidural 1 13


<strong>Tramadol</strong><strong>Morphine</strong>• Does combination increase efficacy <strong>with</strong> lessadverse effects?Yes!No!• Evidence from studies on post-operative pain fortramadol/morphine combination is mixed


RCT - addition of tramadol to morphine via PCA aftertotal knee arthroplasty(Stiller CO et al, Acta Anaesthesiol Sc<strong>and</strong> 2007;51:322-30)Spinal anaesthesia63 patients r<strong>and</strong>omisedVAS = 40/100<strong>Tramadol</strong> 100mg over 20 miniv every 6 h for 24h(total 400 mg/24 h)PCAmorphine B1mg; LO 6 min(Max 35mg/6h)VAS = 40/100Saline iv every6 h for 24 hVAS of pain, nausea, sedation - every hour for 6 h; priorto infusion of study drugs <strong>and</strong> 1 h after infusion; finalassessment at 24 h


Median (<strong>and</strong> interquartile range) of Average VAS afteradministration of tramadol 100mg 6 hourly for ‘intention to treat’population (Mo <strong>–</strong> morphine)(Stiller CO et al, Acta Anaesthesiol Sc<strong>and</strong> 2007;51:322-30)no significant difference in pain intensity (sedation, nausea)


Median Effective Dose of <strong>Tramadol</strong> <strong>and</strong> <strong>Morphine</strong> forPostoperative Patients: a double-blind, r<strong>and</strong>omised, two-stageprospective study in 90 postoperative patients after slightly ormoderately painful surgery(Marcou TA et al. Anesth Analg 2005;100:469-74)Identical anaesthetic; Three Groups (n = 30) using an up downallocation technique; NPS (0<strong>–</strong>10) at T0 min; at T 20 min if NPS > 3,dose for next patient; at T 20 min if NPS < 3 dose for next patient<strong>Tramadol</strong> groupinitial doses 100mg (increments10 mg)<strong>Morphine</strong> groupinitial doses 5mg (increments1 mgCombined Group40 (6.67) mg: 3 (0.5) mgtramadol:morphinedosing ratio;isobolographic analysis


Pain Intensity in Three groups by NPS on arrival in Recovery (T0)(Box plot <strong>with</strong> median, 25th<strong>–</strong>75 th , <strong>and</strong> 10th<strong>–</strong>90th percentiles)(Marcou TA et al. Anesth Analg 2005;100:469-74)NPS was similar in the three groups <strong>with</strong> median of 5


Sequence of dosing in groupsmorphine, tramadol, <strong>and</strong> tramadol+ morphine <strong>with</strong> up-<strong>and</strong>-downallocation techniqueED 50is represented by dashed linesno significant in adverse effectsexcept for dry mouth in combinationstars are failures (ineffective analgesia)<strong>and</strong> open circles are success (effectiveanalgesia)


Median Effective Dose of <strong>Tramadol</strong> <strong>and</strong> <strong>Morphine</strong> forPostoperative Patients: a double-blind, r<strong>and</strong>omised, two-stageprospective study in 90 postoperative patients after slightly ormoderately painful surgery(Marcou TA et al. Anesth Analg 2005;100:469-74)ED 50values (95% CI) of<strong>Tramadol</strong> = 86 mg(57<strong>–</strong>115 mg)ED 50values (95% CI) of<strong>Morphine</strong> = 5.7 mg(4.2<strong>–</strong>7.2 mg)ED 50of combinationwas <strong>Tramadol</strong> 72 mg(62<strong>–</strong>82 mg) <strong>and</strong><strong>Morphine</strong> 5.4 mg (4<strong>–</strong>6.2 mg)= infra-additive?


A Double-blind, RCT - addition of a <strong>Tramadol</strong> Infusion to <strong>Morphine</strong>PCA in 69 patients after Abdominal Surgery:(Webb AR et al. Anesth Analg 2002;95:1713-8)end surgery initialloading dose of<strong>Tramadol</strong> (1 mg/kg)end surgery initialloading dose ofSalinepostoperative infusionof <strong>Tramadol</strong> at 0.2 mgkg -1 · h -1postoperative infusionof Salinemorphine B 1mg; LO 5 minvia PCA


Mean (95% CI) Values for analgesic Efficacy four hourly (1 =excellent, 2 = good, 3 = satisfactory, 4 = poor, <strong>and</strong> 5 = very poor)<strong>and</strong> PCA <strong>Morphine</strong> Consumption 48 h after Surgery(Webb AR et al. Anesth Analg 2002;95:1713-8)no evidence of increased adverse effects in patients receiving tramadol


RCT- Effects of a single dose of tramadol prior to extubation onpost-operative pain <strong>and</strong> morphine consumption after coronaryartery bypass surgery(But AK et al, Acta Anaesthesiol Sc<strong>and</strong> 2007;51:601-6)Similar anaesthesia (fentanyl 5 ug/kg;maintenance 30 ug/kg); propofol 1mg/kg/h topre-extubation)60 Patients r<strong>and</strong>omisedinto two groupsGroup T - <strong>Tramadol</strong> 1mg/kg 1 h beforeextubationGroup P - 2 ml ofSaline 0.9% 1 hbefore extubationPCA (for 24h)morphine B1mg; LO 7 minMax 20mg/4h


Mean Post-operative Pain Scores (± SD), group P (Saline) vs.T(<strong>Tramadol</strong>) († p < 0.01 * p < 0.05) (plus morphine PCA)(But AK et al, Acta Anaesthesiol Sc<strong>and</strong> 2007;51:601)pain scores significantly higher 1-4 h in group P[total morphine consumption reduced in group T over 24h (p < 0.01)]


Evidence for tramadol/morphine combinationfrom studies on post-operative painis mixedNeed more prospective double-blind r<strong>and</strong>omisedcontrolled studies in a cross-over design or wherevariables are minimised

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