Rational Use of Opioids: Intraoperative

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Rational Use of Opioids Intraoperative
Postoperative

• Larry Saidman
• Steve Shafer

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• Actual Orders Written at Stanford June 16, 2005

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Case 1

• 40 y.o. 81 kg ASA PS2 male
• Anterior cervical discectomy
• 3 hour anesthetic with sevoflurane, N2O
• Intraoperative
• Midazolam 4 mg
• Fentanyl 500 mg
• Hydromorphone (Dilaudid) 1 mg
• Post op orders
• Morphine 2-4 mg q 5 min to 30 mg
• Fentanyl 25-50 mg q 5 min to 500mg
• Meperidine 5-10 mg q 5 min to 50mg
• Naloxone 0.1 mg for RRlt6

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Case 2

• 52 y.o. 128 kg ASA PS2 male
• Scalp advancement
• 4 hour anesthetic with isoflurane, N2O
• Intraoperative
• Midazolam 2mg
• Fentanyl 600 mg
• Post op orders
• Morphine 2-4 mg q 5 min to 10mg
• in first 90 minutes patient was drowsy and
  received nothing

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Case 3

• 81 y.o. 80 kg ASA PS2 male
• Lumbar decompression
• 3 hour anesthetic with N20 and propofol infusion
  at 75-100 mg/kg/min
• Intraoperative
• fentanyl 250 mg
• Post op orders
• Morphine 1mg q 5 min to 12 mg
• Fentanyl 25-50 mg q 5 min to 150 mg
• Meperidine 12.5 mg q 5 min to 25mg for shivering

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Summary of Three Cases

• Case 1 40 YO 81 kg
• MS 0.375 mg/kg, fent 7.5 mcg/kg
• Case 2 52 YO 128 kg
• MS 0.08 mg/kg
• Case 3 81 YO 80 kg
• MS 0.15 mg/kg, fent 2 mcg/kg

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Dont tell me what to do!

• Recognizing the variety of practices among the
  large number of anesthesiologists at Stanford and
  not implying that there is/are best practice(s)
  among the anesthesiologists at Stanford I ask Dr
  Shafer to address the following questions

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Questions

• Given the variations in age, weight, and surgical
  procedures, does the variation in postoperative
  opioid prescriptions make clinical or PK/PD
  sense?
• Does the PK/PD of morphine make it the best (or
  even a good) opioid for treatment of acute
  post-op pain?
• Based on known PK/PD of opioids, what opioid
  (including remifentanil) might be better used
  intra-operatively for breakthrough autonomic
  stimulation as well as in anticipation of
  postoperative pain?

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Disclosure

• Ive consulted with Janssen (transdermal
  fentanyl), Cygnus (transdermal fentanyl),
  Anaquest (transdermal fentanyl), Alza
  (transdermal fentanyl), Anesta (oral transmucosal
  fentanyl), Glaxo (remifentanil), Abbott
  (remifentanil), Delex (inhaled liposomal
  fentanyl), and Durect (chronic sufentanil)
• FDA Anesthesia Advisory Panel for Oxycontin
  (oxycodone) and Pallidone (hydromorphone)

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Dont tell me what to do!

• OK, I wont tell you what to do, but you are
  lousy at treating post operative pain.
• You are in good company. We all do poorly here.
• 70-80 of patients have moderate to severe
  postoperative pain
• Svensson et al. Assessment of pain experiences
  after elective surgery. J Pain Symptom Manage
  2000 20 193-201.
• Fundamental problem, we dont have an adequately
  safe and efficacious analgesic
• The dose of opioid in every patient is limited by
  toxicity.

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Dont tell me what to do!
Flood and Daniel Anesthesiology 2004
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Morphine

• Endogenous ligand
• Slow rise to peak effect
• Absolute peak analgesic effect is at 90 minutes
  after bolus injection!
• Active metabolite
• Morphine-6-glucuronide is unlikely to contribute
  to analgesic effects at standard OR doses. Will
  contribute to effects with chronic dosing
• Especially in renal failure
• Not as full efficacy as fentanyl series of opioids

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Morphine Pharmacokinetics
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Morphine Pharmacokinetics
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Morphine Onset
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Simulation of MorphineTime Course
Dahan et al. Anesthesiology. 20041011201-9.
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Fentanyl

• Pharmacologically clean
• 100 efficacious (in contrast to morphine)
• The first of the fentanyl series (obviously)
• Available in transdermal, submucosal, sublingual,
  and (soon) inhaled forms.
• Free!

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Morphine vs. Fentanyl PK
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Morphine vs. Fentanyl PK
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Morphine vs. Fentanyl Onset
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Hydromorphone

• A rapid onset morphine
• No histamine release
• About 8 fold more potent than morphine
• No active metabolite
• Good choice for PCA, post-op analgesia

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Comparative Hydromorphone PK
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Comparative Hydromorphone PK
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Comparative Onset of Hydromorphone
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Sufentanil

• 10 fold more potent than fentanyl
• Slightly slower onset
• More rapid recovery
• Very clean pharmacologically

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Comparative Onset of Sufentanil
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Meperidine

• Bad Drug! No role in the management of pain
• Toxic metabolite
• Normeperidine ? seizures
• Renally excreted
• Negative inotrope
• Causes tachycardia (anticholinergic)
• Complex interactions
• MAO syndrome when combined with MAO inhibitors
• Useful for shivering, perhaps as a local
  anesthetic

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Comparative Onset of Meperidine
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Alfentanil

• Less potent than fentanyl
• Much more rapid onset (including more rapid onset
  of rigidity and respiratory depression)
• Much more evenascent effect with a single bolus
• With brief infusions will be almost
  indistinguishable from fentanyl, except for
  potency

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Remifentanil

• Similar potency to fentanyl
• Pharmacokinetics are in a class by themselves
  (ester metabolism)
• Reduce the dose by about 2/3s in the elderly
• No pharmacokinetic interactions
• Onset is similar to alfentanil

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Comparative Onset ofAlfentanil and Remifentanil
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Methadone

• Longest terminal half-life (about 1 day)
• May accumulate during titration to steady state
• Supplied as a racemic mixture
• L methadone is an opioid agonist
• D methadone is an NMDA antagonist
• Underutilized in anesthesia practice

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Comparative Onset of Methadone
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Fundamental PK/PD Parameters
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Comparative Opioid PK
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Context Sensitive Half Time
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50 Effect Site Decrement Time
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Equivalent doses at 10 minto 50 ?g fentanyl
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Intraoperative potency100 ?g/hour fentanyl at 2
hours
m
Sufentanil
20
g/hr
m
g/kg/min
Remifentanil
0.1
Morphine
7
mg/hr
Methadone
5
mg/hr
Hydromorphone
4
mg/hr
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Case 1

• 40 y.o. 81 kg ASA PS2 male
• Anterior cervical discectomy
• 3 hour anesthetic with sevoflurane, N2O
• Intraoperative
• Midazolam 4 mg
• Fentanyl 500 mg
• Hydromorphone (Dilaudid) 1 mg
• Post op orders
• Morphine 2-4 mg q 5 min to 30 mg
• Fentanyl 25-50 mg q 5 min to 500mg
• Meperidine 5-10 mg q 5 min to 50mg
• Naloxone 0.1 mg for RRlt6

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Case 1
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Case 1
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Case 1
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Case 1

• 40 y.o. 81 kg ASA PS2 male
• Anterior cervical discectomy
• 3 hour anesthetic with sevoflurane, N2O
• Intraoperative
• Midazolam 4 mg
• Fentanyl 500 mg
• Hydromorphone (Dilaudid) 1 mg
• Post op orders
• ? Do whatever the hell you want
• ? Give naloxone if you screw up
  

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Case 2

• 52 y.o. 128 kg ASA PS2 male
• Scalp advancement
• 4 hour anesthetic with isoflurane, N2O
• Intraoperative
• Midazolam 2mg
• Fentanyl 600 mg
• Post op orders
• Morphine 2-4 mg q 5 min to 10mg
• in first 90 minutes patient was drowsy and
  received nothing

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Case 2
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Case 3

• 81 y.o. 80 kg ASA PS2 male
• Lumbar decompression
• 3 hour anesthetic with N20 and propofol infusion
  at 75-100 mg/kg/min
• Intraoperative
• fentanyl 250 mg
• Post op orders
• Morphine 1mg q 5 min to 12 mg
• Fentanyl 25-50 mg q 5 min to 150 mg
• Meperidine 12.5 mg q 5 min to 25 mg for
  shivering

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Case 3
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Case 3
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Interindividual Variability 1
Woodhouse and Mather Anaesthesia 52949-955, 1997
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Interindividual Variability 2
Flood and Daniel, Anesthesiology 2004
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Interindividual Variability 3
Nieuwenhuijs et al, Anesthesiology 2003,98312-22
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Recommendation 1

• Just use fentanyl for post-op analgesia
• 25 mg q 5 min
• Max of 250 in young patients, 150 in elderly
• 3-5 minute peak onset provides rapid relief, but
  no so rapid that the patient stops breathing
• Rapid peak makes it easy to titrate
• Nurses are familiar with it
• Logical choice for PCA
• Free
• If you cant get the patient comfortable with
  fentanyl, you wont succeed with another opioid
• possible exception of methadone

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Recommendation 2

• Hydromorphone 1 mg q 5-10 min
• Max of 10 mg in young patients, 6 mg in elderly
• 5-10 minute peak onset provides rapid relief, but
  no so rapid that the patient stops breathing
• Still easy to titrate
• Nurses are familiar with it
• Also a logical choice for PCA
• Inexpensive

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Recommendation 2
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Opioids cant do it all

• Differences in ventilatory control with sleep
• PACU nurses understand this better than
  anesthesiologists
• Local anesthetics should be first line of
  analgesic therapy
• Many drugs show analgesic synergy with opioids
• Clonidine, dexmedetomidine (a2 agonists)
• Ketamine / magnesium (NMDA antagonists)
• NSAIDs (COX antagonists)
• Nicotine?

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Recommendation 3

• If severe post-op pain is expected
• Methadone 5-15 mg 1 hour before the end of the
  case
• Ketamine 10-20 mg 30-60 min before the end of the
  case
• Magnesium 1 gm 30-60 min before the end of the
  case
• Ketorolac 30 mg 30 min before the end of the case
• Post-Op
• Fentanyl 25 mg q 5 min to max 250 or
• Hydromorphone 1 mg q 5 to max 10

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Recommendation 4

• Listen to your PACU nurses
• Infinitely more experience than you have
  titrating opioids to pain
• Recognize changes in ventilatory drive between
  awake and asleep states
• Know to start with bigger dose, more frequent
  dosing, and then move to smaller doses, less
  frequent dosing
• Know when pain is out of proportion to surgery

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Edward Tufte, PhD