1、KEY CONCEPTS IN ACUTE PAIN MANAGEMENT - SURGERY RESIDENTS Feb. 7, 2006John Penning MD FRCPC Director Acute Pain ServiceObjectivesGeneral Key ConceptsThe “real cost” of acute painMulti-modal analgesiaDiscuss key concepts of each modalityAlways a COX-inhibitor before opioidTylenol # 3 has its limitati

2、ons Review principles discussed by case presentationOpioid tolerance, conversion from IV to POWhen, how to use naloxoneAssessing the hypotensive epidural patientConsequences of poorly managed acute post-operative painThe Patient suffersCVS: MI, dysrhythmiasResp: atelectasis, pneumoniaGI: ileus, anas

3、tamosis failureEndocrine: “stress hormones”Hypercoagulable state: DVT, PEImpaired immunological stateInfection, cancer, wound healingPsychological:Anxiety, Depression, FatigueChronic Post-surgery/trauma PainConsequences of poorly managed acute post-operative painThe HospitalIncreased costs $Poor sta

4、ff moraleReputation/Standing in the Community, NationallyAccreditationLitigationThe Healthcare professionalMoraleComplaints to CollegeLitigationBenefits of Optimal Acute Post-Operative Pain ManagementThe HospitalIncreased patient satisfactionIncreased staff moraleCompliance with national guidelines,

5、 accreditation criteriaCost SavingsEarlier ambulation and enteral feedingDecreased complications/ICU expendituresDecreased Length of StayThe New Challenges in Managing Acute Pain after Surgery and TraumaPatients/Society more “aware” of their rights to have good pain controlWe are being held accounta

6、blePressure from hospital to minimize length of stayControl pain, limit S/E and complicationsThe New Challenges in Managing Acute Pain after Surgery and TraumaThe Opioid Tolerant PatientThe greatest change in practice/attitudes in the last 10 years is the now wide spread acceptance of the use of opi

7、oids for CHRONIC NON-MALIGNANT PAINRenders the “usual” standard “box” orders totally inadequate in these patientsGet an accurate Drug HistoryWhat is the “Best Way” to manage acute post-operative pain?FIRST, DO NO HARMTherefore, the “best way” is a BALANCEPatient SafetyEffective AnalgesicModalitiesKE

8、Y POINTS“Emphasis is placed on the utilization of a multimodal analgesic approach to maximize analgesia while minimizing side-effects.” TransductionTransmissionModulationPerceptionThere is as of yet no single silver bullet!Pain PathwaysAcute Pain Management Modalities Cyclo-oxygenase inhibitorsNon-s

9、pecific COX inhibitors(classical NSAIDs)Selective COX-2 inhibitors, the “coxibs”Acetaminophen is probably COX-3OpioidsNMDA antagonistsKetamine, dextromethorphanAnti-convulsantsGabapentin, PregabalinLocal anesthetics Cell Membrane PhospholipidsArachidonic AcidEndoperoxidesThromboxaneProstaglandinsPro

10、stacyclinToxic Oxygen RadicalsCyclo-oxygenaseCOXPhospholipaseTissue TraumaCase Problem: Inadequate Analgesia with IV PCA after Open Cholecystectomy45 yr. female c/o severe pain at rest and difficulty breathing due to incisional pain- 4 hrs. post-opIV PCA morphine: 1mg bolus, 5 min. lock-out, no cont

11、inuous infusion 150 demands : 28 goodhas stopped using PCA because, “it is making me sick(N/V) and its not working”received 25 mg gravol X 2 one hour ago which helped just a little with the N/V, but did make her quite groggySolution! Continuous infusion? Increase bolus dose? Case Problem: Inadequate

12、 Analgesia with IV PCA after Open CholecystectomyProblem: Patient unable to attain required morphine blood level due to intolerable side-effects (N/V, sedation)Solution:Administer NSAIDToradol IV/IM, Naprosyn 500 mg PR Q12H and this may be changed to 250 mg PO TID with meals once eatingControl N/VMa

13、xeran/Stemetil, Ondansetron, DecadronMay need to consider changing opioid i.e. DemerolMortality From NSAID-Induced GI Complications vs Other Diseases in USWolfe MM: NEJM 1999; 340: 1888-99Pennings Pessimistic Policy on Pain PillsPick your “Poison” Pursuant to Patient ProfileCOX-inhibitors are potent

14、ial killers “in the long run”Opioids are potential killers “in the short run”Analgesia with Opioids aloneThe harder we “push” with single mode analgesia, the greater the degree of side-effects AnalgesiaSide-effectsMulti-modal Analgesia“With the multimodal analgesic approach there is additive or even

15、 synergistic analgesia, while the side-effects profiles are different and of small degree.” AnalgesiaSide-effectsCase Problem: Severe Respiratory Depression after Toradol?Healthy 34 yr. patient c/o severe incisional pain in PACU after ovarian cystecomyReceived 200 g fentanyl with induction and 10 mg

16、 morphine during casePCA morphine started in PACU, plus nurse supplements totaled 26 mg in 90 minutesStill c/o pain, 30 mg Toradol IM given with some relief after 15 minutes, so patient sent to ward60 minutes later found unresponsive, cyanotic, RR 4/min.Case Problem: Severe Respiratory Depression af

17、ter Toradol?Pharmacodynamic drug interaction between morphine and NSAIDmorphines respiratory depressant effect opposed by the stimulatory effects of pain, busy PACU environmentNSAID decreases pain, morphines effect unappossedGain control of acute pain with fast onset, short acting opioid(fentanyl)Ad

18、d NSAID adjunct earlyMonitor closely for sedation and respiratory depression after pain is alleviated by any meansThe problem with the “Little Pain Little Gun”, “Big Pain Big Gun” ApproachWith opioids analgesic efficacy is limited by side-effects “Optimal” analgesia is often difficult to titrate10 f

19、old variability in opioid dose:response for analgesiaA dose of opioid that is inadequate for patient A can lead to significant S/E or even death in patient B.Many patient factors add to the difficultyOpioid tolerance, anxiety, obstructive sleep apnea, sleep deprivation, concomitantly administered se

20、dative drugs The rationale for COX-Inhibitors in acute pain managementThe problem with the “Little Pain Little Gun, Big Pain Big Gun Approach”Patient Safety! If the “Big Gun” is failing due to dose limiting sedation/respiratory depression, the addition at that time of the “Little Gun” may kill the p

21、atient.NSAID and AcetaminophenCONCEPT # 1The foundation of all acute pain Rx protocols. ”First on last off” sole agent in mild /moderate pain Analgesic efficacy is limited inherentlyIn contrast, with opioids efficacy is limited by S/Eadjunctive analgesic for patients requiring opioidsopioid sparing

22、effect 30-60 %The rationale for pre-operative administrationThe benefits of “Pre-emptive Analgesia”Goal: prevent the establishment of peripheral and central sensitization (“wind-up”), conditions that lead to an augmented response to pain stimulii.e. prevention of “hyper-algesic” stateRequirements: t

23、he analgesic must be pharmacologically active at the time of surgical incision and its activity must be maintained peri-operatively. ( 1 hr. pre-op for PO/PR NSAIDs)The rationale for pre-operative administrationPre-emptive Analgesic effect of Rofecoxib after Ambulatory Arthroscopic Knee Surgery. Sco

24、tt S. Reuben et al. Anesth Analg 2002;94: 55-9.Showed that 50 mg of rofecoxib PO one hour before surgery is better than 50 mg PO upon completion of surgery. VAS at 24 hoursCyclo-oxygenase inhibitorsAcetaminophenNaproxenCelecoxibKetorolacRofecoxibCell Membrane PhospholipidsArachidonic AcidPhospholipa

25、seProstaglandinsProstaglandinsGastric ProtectionPlatelet HemostasisRenal FunctionAcute PainInflammationFeverCOX-2 COX-1Why a COX-2 inhibitor?Equivalent analgesic efficacy with non-selective COX-inhibitorsNo effects on platelets! Better GI tolerabilityLess dyspepsia, less N/VCyclo-oxygenase inhibitor

26、s The CAMPAIGNCOX-2 FOR UCOX-2 for U?COX-2 blockers, like Celebrex may not be suitable for patients at risk for thrombotic complications peri-operativelyWe need an other campaign slogan?Cyclo-oxygenase inhibitors The CAMPAIGNBlock the COXTwo hours before surgery associated with post-op painCelecoxib

27、 400 mg PO Healthy patients Naproxen 500 mg POPatients at risk for thrombotic complicationsAcetaminophen 1000 mg POContra-indications to NSAID36 yr. Open Cholecystectomy patient experiencing difficulty weaning from IV PCAEndometriosis, fibromyalgia and chronic low back pain- has been on Tylenol #3 f

28、or several years- functions well and stable usage of 8-10/dayDay 3 post-op Tylenol #3, 2 tabs Q4h started and IV PCA D/CPatient c/o severe pain, not able to go home36 yr. Open Cholecystectomy patient experiencing difficulty weaning from IV PCAA better way?Celecoxib 400 mg PO 2 hours pre-op, after Na

29、proxen 500 mg PR Q12H to 250 mg PO TIDOn day 2, when patient is tolerating diet, review the 24 hour consumption of IV PCA morphineMultiply the total by 2(for conservative IV to PO conversion) and divide by 6 to derive the Q4H PO morphine dose90 mg IV X 2 = 180 mg, 180 mg/6 = 30 mg PO Q4HOrder the PO

30、 morphine straight, plus an additional half dose for breakthrough pain, prnPermit 6 hours overlap between IV PCA and POThe OpioidsWe have to stop trying to put every patient in the “analgesic dose box”Meperidine 75 mg IM Q4HprnTylenol #31 2 PO Q4H prnOpioidsConcept # 2The dose of opioid administered

31、 is dependant upon multiple factorsPharmacological tolerance to opioids?Route of administrationPO, IM/SC, IV bolus, intrathecalAgeWeightSeverity of painOpioidsCONCEPT # 3Pharmacokinetic + Pharmacodynamic patient to patient variability results in1000 % variability in opioid dose requirements (standar

32、dized procedure, opioid nave patient)opioid dosage must be individualized therefore, if parenteral therapy indicated, IV PCA much better suited to individual patient needs than IM/SC Opioids *Cancer Pain Monograph (H&W, 1984)CONCEPT # 4Under utilization of high efficacy PO opioidsPO opioid equivalen

33、ce of 10 mg morphine IM/SC *Morphine 20 mg meperidine 200 mg Hydromorphone 4 mg codeine 200 mg oxycodone 10 mgTrue or False?One opioid is just like any other, in terms of analgesic efficacy and side-effects.The is considerable variability between patients in response to different opioidsMeperidine s

34、hould be eliminated from the hospital formularyOpioids Do they all act the same?Opioids work as analgesics by activating endogenous pain modulating systems Opioid receptorsMu, Delta and KappaLarge genetic variability in expressionGood choice in one patient may be poor choice in anotherAnalgesic effi

35、cacy Side-effect profileOpioids Are they all the same?MorphineHydromorphone (dilaudid)OxycodoneMeperidine (demerol)MorphineMeperidineFentanylAtropineBupivacaineMeperidine PharmacologyOpioid agonist Mu and some kappaNMDA antagonist (weak)Local anesthetic action equipotent to lidocaineSSRI (weak)Musca

36、ric blockade “atropine-like”Central anti-cholinergic effects often causes confusion in the elderly Meperidines major problemNormeperidineThe “ugly” metaboliteNeuroexcitatory: twitches, dilated pupils, hallucinations, hyperactive DTR, seizuresNon-opioid receptor mediated, no toleranceHalf-life is 15

37、20 hours N-demethylationMeperidine and MAO InhibitorsMeperidine blocks the neuronal re-uptake of serotonin, may result in serotonergic crisis in patients being treated with MAO inhibitorsExcitatory reaction with delirium, hyper or hypo tension, hyperthermia, rigidity, seizures, coma, deathSupportive

38、 management, ? Benzos, dopaminergics?When to use Meperidine?As a third line opioid when other choices have failedEspecially if patient has Hx of suchLess than 600 mg per dayShort duration of 2 days or lessAvoid in elderly or renal failure patientsMay be useful in small IV doses to supplement other o

39、pioids25 mg IV Q1H prnTrue or False?Codeine is a “weak” opioid?Codeine is inherently safer than the more potent opioids?CODEINE A drug whose time has come and gone? N Engl J Med 351; 27 Dec. 30, 2004Problems with Codeine62 yr. male with CLL, presents with bilateral pneumonia. Broncho-lavage revealed

40、 yeastAnti-biotics: Ceftriaxone, clarithromycin, voriconazoleCodeine 25 mg PO TID for coughProblems with CodeineDay 4 became markedly sedated, pin-point pupils and ABG reveals PaCO2 of 80 mmHg. Marked improvement with Naloxone.Whats the expected morphine blood level?Answer: 1 to 4 mcg/LThis patients

41、 morphine blood level?80 mcg/LCodeine Metabolism in Normal CircumstancesThe major pathways convert codeine to inactive metabolitesCYP3A4 pathway yields norcodeineGlucuronidationThe minor pathway, about 10%, yields morphineCYP2D6, essential for analgesic effect 60 mg Codeine PO approx. 4 mg morphine

42、SCVariability! 60 mg PO Codeine yields potentially 0 to 60 mg parenteral morphinePotential Codeine Drug InteractionsMajor pathway CYP3A4Inducers decrease codeine effectInhibitors increase codeine effectMinor pathway - CYP2D6Inducers increase codeine effectInhibitors decrease codeine effectInhibitors

43、 of CYP2D6SSRIs (potent) especially PAXIL Cimetidine, RanitidineDesipraminePropranololQuinidine (potent)ViagraMany anti-biotics and chemoInstead of Tylenol # 3 ?Acetaminophen 650 mg PO Q4HMorphine 10 20 mg PO Q4H prnORDilaudid 2 4 mg PO Q4H prnWhy combination analgesics are not a great ideaAcetamino

44、phen-Induced Acute Liver Failure: Results of a USA Multicenter, Prospective Study. Hepatology, Vol. 42, No. 6, 2005. Larson et al.22 centers, 662 cases 98 03.50% cases due to acetaminophen50% of acetaminophen cases inadvertentThe Limitations of Tylenol # 3The problem with combination drugsThe codein

45、e dose is limited by the maximum allowed dose for acetaminophen4 grams/day = 12 tabs/day 12 X 30 mg = 360 mg codeine = 60 mg morphine60 mg PO = 15 30 parenteral morphineEquals about 1 mg/hr IV/s.c.Adequate for moderate pain in average patient?Net result is limited efficacyThe Limitations of Tylenol

46、# 3The problem with combination drugsAcetaminophen therapy may be limited by intolerance to codeinePatient sensitive to codeine may only want to take 1 T#3 or even 1/2. If all they can tolerate is 15 mg of codeine Q4H, the patient is not receiving the benefit of optimum dose of acetaminophenThe Limi

47、tations of Tylenol # 3The constipation problemCodeine may be more constipating than other opioids The codeine “allergy” problemTrue immunological allergy is extremely rare99.9% of “allergy” are sensitivitiesN/V, excessive sedation, confusionNeed to perform adequate drug history, otherwise problems m

48、ay arise when an even more potent opioid, such as Percocet is substituted for T#3.The Limitations of Tylenol # 31/ Codeine is a “pro-drug”2/ The problem with combination drugsa. The codeine dose is limited by the maximum allowed dose for acetaminophen b. Acetaminophen therapy may be limited by intol

49、erance to codeine c. Acetaminophen toxicity3/ The constipation problem4/ The codeine “allergy” problem Solution to the T #3 limitations Provided codeine works in your PatientThe oral analgesic ladderTTT#3TT#3T#3T#3T#3Oxy5 mgSolution to the T #3 limitationsEvery 12 hoursCox-inhLong ActingLong ActingO

50、pioidFor breakthough painRegular opioid PO Q4h prnAcetaminophen 650 mg PO Q4h prnOpioidsHydromorphine 1 4 mg PO/IM/IV Q4H prnNOT!This represents up to 30 fold range in peak effect in any given patient1 mg PO - 4 mg IV bolushomeopathic dose - potentially lethalSTOPOpioids: Rational multi-route orders

51、?Foundation of Acetaminophen/NSAIDMorphine 5 - 10 mg PO Q4h prnMorphine 2.5 - 5 mg s.c. Q4h prnMorphine 1-2 mg IV bolus Q1h prnHydromorphone 1 - 2 mg PO Q4h prnHydromorphone 0.5 1 mg s.c Q4h prnHydromorphone 0.25 0.5 mg IV Q1h prnWhen a fast onset/short duration opioid is required!Fentanyl 25 - 50 u

52、g IV bolus Q 2 - 3 minutesonset in 30 secondspeak effect in 5 min. (30 min. with morphine)“short duration of action due to lipid solubility, redistribution half-life is 15 minutesvery potent respiratory depressant, give supplemental Oxygen, monitor SaO2be very careful when benzodiazepines are also a

53、dministered ie. VersedAirway management skills/equipment availableNaloxoneCase Problem:32 yr. Male with multiple ribs # Patient previously healthy, MVA with no other injuries. In Trauma Unit, c/o 9/10 pain. Difficultly breathing due to severe splinting.Analgesic orders are: Morphine 2 10 mg PO, SC,

54、IV Q4H prnNurse just gave 5 mg PO one hour ago and now wont give anything for 3 hours!What do you do?Case Problem:32 yr. Male with multiple ribs #Review of PHx reveals no drug use.Patient has received total of 24 mg morphine in the 6 hours since admission.Case Problem:32 yr. Male with multiple ribs

55、#Ketorolac 30 mg IV stat followed by 10 mg IV Q4H. Morphine 10 15 mg s.c. Q4H Morphine 2 - 3 mg IV Q1H prnKetamine 2.5 5 mg IV Q30 min. prnNMDA Antagonists as “analgesics”Really anti-hyperalgesics, anti-pronociceptiveCentral system of facilitatory pain pathways that employ excitatory neurotransmitte

56、rsAspartate, glutamateInvolved with central sensitization, Opioid tolerance and Opioid Induced Hyper-algesiaNMDA antagonists block the facilitatory pain pathways that induce “pathological” acute painHyperalgesia, allodyniaPAINAnalgesiaHyperalgesiaInhibitory Mechanisms OPIOIDSExcitatory Mechanisms NM

57、DA AgonistsNMDA Receptor Antagonists -To prevent or reverse “pathological” acute painKetamine, DextromethorphanKetamine is widely known as a dissociative “general anesthetic” - 3 mg/Kg IV bolusKetamine 2.5 - 5.0 mg IV bolus for analgesia in post-op patient - Ketamine as co-analgesic - combined 1:1 w

58、ith morphine IV PCA. Better analgesia, less S/EDextromethorphan 30 mg PO Q8H available OTC as Benylin DM, 3 mg/ml.Case Problem:32 yr. Male with multiple ribs #IV PCA with morphine / ?ketamineKetorolac changed to naproxen when eating. 250 mg TID Or Celecoxib 200 mg Q12H for 5 days then 100 mg daily u

59、ntil no longer needed.Case Problem:32 yr. Male with multiple ribs #On day three patient is doing well and planning for D/C tomorrow.Convert to PO morphine.Daily IV PCA use is 100 mg per day.Equals about 200 mg per day orally.Order about 50% as long acting.60 mg MS Contin Q12H and 10 20 mg PO Q4H prn

60、.Case Problem:32 yr. Male with multiple ribs #Weaning instructions: As daily “breakthough” morphine requirements decrease, reduce the MS Contin dose by 25% increments.The COX-inhibitor is the last to be D/CAcetaminophen may be used in addition to NSAIDs and CoxibsOpioidsIssueWith parenteral opioids