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KEY CONCEPTS IN ACUTE PAIN MANAGEMENT - 2 SURGERY RESIDENTS Jan. 8, 2008 John Penning MD FRCPC Director Acute Pain Service Objectives Review key concepts of each modality – – – – COX-inhibitor before opioid Tylenol # 3 has it’s limitations 3rd dimension of analgesia “anti-pronociception” Role of Pregabalin, Ketamine Review principles discussed by case presentation – Opioid tolerance, conversion from IV to PO – When, how to use naloxone – Assessing the hypotensive epidural patient The problem with the “Little Pain – Little Gun”, “Big Pain – Big Gun” Approach With opioids analgesic efficacy is limited by side-effects “Optimal” analgesia is often difficult to titrate – 10 – fold variability in opioid dose:response for analgesia – A 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 difficulty – Opioid tolerance, anxiety, obstructive sleep apnea, sleep deprivation, concomitantly administered sedative drugs NSAID and Acetaminophen CONCEPT # 1 The foundation of all acute pain Rx protocols. ”First on last off” sole agent in mild /moderate pain Analgesic efficacy is limited inherently In contrast, with opioids efficacy is limited by S/E Opioids added as required opioid sparing effect 30-60 % Acute Pain Management Modalities Cyclo-oxygenase inhibitors – Non-specific COX inhibitors(classical NSAIDs) – Selective COX-2 inhibitors, the “coxibs” – Acetaminophen is probably COX-3 Local anesthetics Opioids NMDA antagonists – Ketamine, dextromethorphan Anti-convulsants Alpha-2 delta sub-unit of VGCC – Gabapentin, Pregabalin Codeine Metabolism in Normal Circumstances The major pathways convert codeine to inactive metabolites – CYP3A4 pathway yields norcodeine – Glucuronidation The minor pathway, about 10%, yields morphine – CYP2D6, essential for analgesic effect 60 mg Codeine PO – approx. 4 mg morphine SC Variability! 60 mg PO Codeine yields potentially 0 to 60 mg parenteral morphine Instead of Tylenol # 3 ? Acetaminophen 650 mg PO Q4H with Morphine 10 – 20 mg PO Q4H prn OR Dilaudid 2 – 4 mg PO Q4H prn Newly available Tramacet 1 – 2 tabs PO Q4H prn Case 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 5 – 10 mg PO / SC Q4H prn Nurse just gave 5 mg PO one hour ago and now won’t 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 # Acetaminophen 650 mg PO Q4H W/A Ketorolac 30 mg IV stat followed by 10 mg IV Q4H. Morphine 10 – 15 mg s.c. Q4H Morphine 2 - 3 mg IV Q1H prn Ketamine 2.5 – 5 mg IV Q30 min. prn NMDA Antagonists as “analgesics” Really anti-hyperalgesics, anti-pronociceptive Central system of facilitatory pain pathways that employ excitatory neurotransmitters – Aspartate, glutamate Involved with central sensitization, Opioid tolerance and Opioid Induced Hyper-algesia NMDA antagonists block the facilitatory pain pathways that induce “pathological” acute pain – Hyperalgesia, allodynia NMDA Receptor Antagonists To prevent or reverse “pathological” acute pain Ketamine, Dextromethorphan – Ketamine is widely known as a dissociative “general anesthetic” - 3 mg/Kg IV bolus – Ketamine 2.5 - 5.0 mg IV bolus for analgesia in post-op patient – Ketamine as co-analgesic - combined 1:1 with morphine IV PCA. Better analgesia, less S/E – Dextromethorphan 30 mg PO Q8H available OTC as Benylin DM, 3 mg/ml. Case Problem: 32 yr. Male with multiple ribs # IV PCA with morphine / ?ketamine Ketorolac changed to naproxen when eating. 250 mg PO TID Or Celecoxib 200 mg PO Q12H for 5 days then 100 mg Q12H until 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. 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 NSAID or coxib is D/C after the opioids D/C Acetaminophen is last to be D/C Hyperalgesia Pro-nociceptive modulation Nociceptive Stimulus Anti-nociceptive modulation Pain Analgesia Analgesic Drugs that act by Nociceptive Modulation Pro-antinociceptive – Augments inhibitory modulation of nociception i.e opioids Anti-pronociceptive – Inhibits the facilitatory modulation of nociception i.e. ketamine, gabapentin and pregabalin Pregabalin for acute pain? Acute pain is “off-label” use Be cautious of Over-sedation – Sleep deprivation – Elderly – Patient already has significant opioids Pregabalin: The Good, The Bad and the Ugly The Good – Chronic pain in region of surgery, when pronociceptive mechanisms play a role such as joint arthroplasty, bowel surgery in IBD patients, chronic limb ischemic pain, opioid tolerant patients The Bad – Mild pain when simple analgesics like acetaminophen, NSAIDs or low dose opioid or Tramacet suffice. The Ugly – Too large a dose in sleep deprived patient already in state of “morphine-failure” Pregabalin dosage This is NOT a one size fits all. – Drugs binding to receptors have considerable patient to patient variability in dose:response Alpha-2 delta sub-unit of Voltage-Gated Calcium Channel 75 mg PO 2 hours pre-op (50 – 150) 50 mg PO Q8H for 3 to 5 days (25 – 75) Naloxone, a two-edged sword! Is there a down side to the administration of naloxone, 0.4 mg IV in the post-op patient where opioid induced respiratory depression is suspected? Severe acute pain, sympathetic response, pulmonary edema, MI, dysrhythmias Case Presentation: Somnolence and hypoxemia while on IV PCA Morphine 65 yr. Female with large ventral hernia repair on IV PCA morphine PMHx: Angioplasty 9 yr. ago, MI, CHF in past – Moderate COPD, NIDDM Doing well day 1, but day 2 found to be somewhat confused, somnolent and SaO2 remains in high 80s despite Oxygen by N/P Is Narcan Indicated? Urgently? Case Presentation: Somnolence and hypoxemia while on IV PCA Morphine Further patient evaluation – Patient arousable, RR 8-16, pupils slightly constricted, BP 130/70, pulse 90 and reg. – Chest: A/E fair bil. And some mild basilar creps – ABG: pH 7.46 pCO2 50 pO2 55 BiCarb 36 FiO2 > .50 – Chest X-ray: Extensive bilateral, diffuse, interstitial infiltrate consistent with ARDS Naloxone would probably have had a serious adverse effect on this patient. Hypoxemia despite supplemental O2 in a breathing patient. Look beyond the Opioids! Case Presentation: Somnolence and hypoxemia while on epidural infusion of hydromorphone/bupivacaine Management of suspected opioid induced respiratory depression – – – – – Support A/W Simulate breathing Supply supplemental oxygen Assess SaO2, BP, Pulse Naloxone titration, IF INDICATED • 0.04 mg Q5 min. X 3 as needed Hypoxemia is a medical emergency Hypercarbia is NOT When a fast onset/short duration opioid is required! Fentanyl 25 - 50 ug IV bolus Q 2 - 3 minutes – onset in 30 seconds – peak effect in 5 min. (30 min. with morphine) – “short duration of action due to lipid solubility, redistribution half-life is 15 minutes – very potent respiratory depressant, give supplemental Oxygen, monitor SaO2 – be very careful when benzodiazepines are also administered ie. Versed – Airway management skills/equipment available – Naloxone Opioids Issue With parenteral opioids the patient may experience intolerable side effects before adequate analgesia is attained Opioids CONCEPT # 3 Targeted regional administration of opioid results in enhancement of the therapeutic index (ratio of analgesia/side effects) Acute Pain Management Modalities: Who Gets What and Why?? Intrathecal morphine – simple technique – potent analgesia for 12 -16 hrs. – highly effective for pain in lower abdomen and lower limbs – risk of delayed onset of respiratory depresson – C/S, Vag. Hyst., Rad. Prostatectomy, Arthroplasty What is an “EPIDURAL”? Anatomical – Location of the catheter, C7 – L5 • Cervical, thoracic and lumbar epidurals • Segmental Blockade Drugs – Opioids (hydrophillic vs. lipophillic) • morphine, hydromorphone, demerol, fentanyl • Hydrophillic drugs migrate rostrally and also yield greater spinal selectivity What is an “EPIDURAL”? Drugs – Local Anesthetics : • Lidocaine, bupivacaine, ropivacaine Varying concentrations/drug mass produces “Differential Blockade” sympathetics > somatosensory > motor – Adjuncts: epinephrine, ketamine Mode of Drug Delivery – Intermittent bolus vs. continuous infusions True or False? Epidural analgesia impairs the resolution of post-operative ileus i.e. it “slows down the gut” delaying return of normal bowel function. Epidural analgesia necessitates a foley catheter until the epidural is removed Epidural Pit-falls for the Surgeon Epidural hematoma – > 50 reported cases in USA in patients treated with LMWH – Epidural insertion and removal of the catheter – Risk factors: Elderly, low body weight, twice daily dosing, anti-coagulation vs. prophylactic dose range The decision to fully anti-coagulate a patient with an epidural in-situ should be made in consultation with anesthesia and thrombosis medicine Epidural Pit-falls for the Surgeon “Masked-Mischief” – The potential high efficacy of the modality could block pain related to complications • Peritonitis; anastomosis dehiscence • Wound infection, wound hematoma • Limb ischemia, compartment syndrome – Delay in appropriate therapy, diagnosis • Neurological problems inappropriately attributed to the epidural i.e. anterior spinal artery syndrome • Hypovolemia The “Hypotensive” Patient with an Epidural 64 yr. female, 48 kg, with no Hx of CVS problems, had an esophagectomy for cancer with combined GA/epidural anesthesia. Later that evening you are called because the patient’s BP is 85/50. Epidural at T5/6 and running hydromorphone 10 µg/ml in 0.01% bupivacaine at 8 ml/hr The “Hypotensive” Patient with an Epidural Possibilities? “Normal” for this patient – all is well and confirmed by Hx and absence of postural changes in BP or HR – vascular patients may have marked discrepancy between arms – establish baseline pre-op Surgical complications Medical complications Side-effect of Epidural induced sympathetic block – decreased venous return and decreased SVR Combination of any 4 above Is the Epidural causing the hypotension? What drugs have been administered epidurally? Pure opioids: morphine, hydromorphone, fentanyl – sympathetics not blocked directly so look for another cause Demerol – mild direct sympatholytic effect and some systemic effects in large doses. Rarely cause of significant Hypotension. Be careful to R/O other causes. Local Anesthetics +/- opioids – In a euvolemic patient with normal CVS function hypotension is unlikely if < 8 sensory dermatomes blocked Is the Epidural Local Anesthetic causing the hypotension? Intrathecal catheter migration Inadvertent overdose “Un-masking” of problem with the patient. “Sensitive” patient Is the Epidural Local Anesthetic causing the hypotension? Management ABCs – supplemental O2, fluid bolus, elevate legs – ephedrine 5 mg or phenylephrine 50 µg IV bolus – Hold the epidural infusion Quantify the extent of block – motor block? Thoracic epidural?, that’s a problem! – Sensory block (cold, sharp) • In a euvolemic patient with normal CVS function hypotension is unlikely if < 8 sensory dermatomes blocked Management of Hypotension Cont’d High thoracic epidural blockade may block the compensatory tachycardia response to hypovolemia. – Cardio-accelerator sympathetic nerve fibres arise from T1 - T4 – sympathetic block may extend several dermatomes above the sensory blockade Correct the underlying cause Remove bupicacaine and change to epidural hydromorphone if patient remains hemodynamically unstable 36 yr. Open Cholecystectomy patient experiencing difficulty weaning from IV PCA Endometriosis, fibromyalgia and chronic low back pain- has been on Tylenol #3 for several years- functions well and stable usage of 810/day Day 3 post-op Tylenol #3, 2 tabs Q4h started and IV PCA D/C Patient c/o severe pain, not able to go home 36 yr. Open Cholecystectomy patient experiencing difficulty weaning from IV PCA A better way? Celecoxib 400 mg PO > 2 hours pre-op, after Naproxen 500 mg PR Q12H to 250 mg PO TID On day 2, when patient is tolerating diet, review the 24 hour consumption of IV PCA morphine Multiply the total by 2(for conservative IV to PO conversion) and divide by 6 to derive the Q4H PO morphine dose 90 mg IV X 2 = 180 mg, 180 mg/6 = 30 mg PO Q4H Order the PO morphine straight, plus an additional half dose for breakthrough pain, prn Permit 6 hours overlap between IV PCA and PO Opioid Conversions – Parenteral to Oral and Equivalents (approx.) Morphine 10 mg Morphine 20 mg Hydromorphone 2 mg Hydro…. 4 mg Meperidine 75 mg Meperidine 200 mg Codeine 120 mg Codeine 200 mg Oxycodone (n/a) Oxycodone 10 mg Opioid Conversions – Oral to Parenteral and Equivalents (approx.) Morphine 40 mg Hydromorphone 8 mg Meperidine 300 mg Codeine 300 mg Oxycodone 15 mg Morphine 10 mg Hydro…. 2 mg Meperid.. 75 mg Codeine 120 mg Oxycodone (n/a) Conclusion: Key Concepts The foundation of all acute pain Rx protocols is NSAIDS and acetaminophen. Codeine is a “pro-drug”. Problems may occur with under or over conversion to morphine Under utilization of high efficacy PO opioids Pharmacokinetic + Pharmacodynamic variability Order opioid dosages rationally, especially with patient Hx and route of administration in mind Naloxone can be a dangerous drug, careful titration is almost always possible Conclusion Think! Foundation of COX-inhibitor before opioid – Acetaminophen – NSAID – Celecoxib COX-2 blockers do not increase bleeding risk Conclusions Inadequate analgesia despite cyclooxygenase inhibitors and opioids? – Think “Hyperalgesia” – Consider an anti-hyperalgesic like pregabalin Codeine is a prodrug – Extreme variability in extent of conversion to morphine ACUTE PAIN MANAGEMENT: SCIENTIFIC EVIDENCE 2nd Edition June ‘05 Australian and New Zealand College of Anaesthetists And Faculty of Pain Medicine. http://www.anzca.edu.au/publications/acutepain.pdf The above web site has the entire document and is freely Available to download.