Comparative Opioid Pharmacology: 101 Alternatives to Morphine

1
Comparative Opioid Pharmacology101 Alternatives
to Morphine
Steven L. Shafer, M.D. Professor of Anesthesia,
Stanford University Adjunct Professor of
Biopharmaceutical Sciences, UCSF Editor-in-Chief,
Anesthesia Analgesia
2
Disclosure

• Analgesia is a labeled indication for all of the
  approved drugs I will be discussing.
• 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)

3
Classical Opioid Pharmacology

• Analgesia
• modest to profound with no ceiling effect
• Sedation
• modest to profound, but has a ceiling effect
• unconsciousness cannot be assured
• Reduces MAC
• with a ceiling effect
• Synergy with hypnotics
• modest at causing sedation
• profound at suppressing movement response to
  noxious stimulation

4
Classical Opioid Pharmacology

• High dose opioids are associated with hemodynamic
  stability
• High dose opioids attenuate the stress response

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Classical Opioid Pharmacology

• Urinary retention
• Ileus
• Addiction potential
• Opioid Induced Hyperalgesia

• Ventilatory depression
• Muscle Rigidity
• Nausea, Vomiting
• Pruritis

6
Pure m agonists (intravenous)

• Intraoperative
• Fentanyl
• Alfentanil
• Sufentanil
• Remifentanil

• Postoperative
• Morphine
• Hydromorphone
• Meperidine
• Methadone

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Distinguishing Characteristics

• Pharmacokinetics
• Rate of Onset
• Rate of Offset
• Pharmacodynamics
• Potency
• Most have one or two peculiarities

8
Opioid Onset
100
Hydromorphone
Methadone
Meperidine
80
Morphine
Sufentanil
60
site concentration
Percent of peak effect
Fentanyl
40
Alfentanil
20
Remifentanil
0
0
5
10
15
20
Minutes since bolus injection
9
Opioid Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
Meperidine
20
Methadone
Fentanyl
Sufentanil
Alfentanil
0
Remifentanil
0
30
60
90
120
Minutes since bolus injection
10
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
• Releases histamine
• Not as full efficacy as fentanyl series of opioids

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Morphine Onset
100
80
60
site concentration
Percent of peak effect
40
20
0
0
30
60
90
120
Minutes since bolus injection
12
Simulation of MorphineTime Course
Dahan et al. Anesthesiology. 20041011201-9.
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Morphine Pharmacokinetics
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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
16
Morphine vs. Fentanyl PK
17
Morphine vs. Fentanyl Onset
100
80
Morphine
60
site concentration
Percent of peak effect
Fentanyl
40
20
0
0
5
10
15
20
Minutes since bolus injection
18
Morphine vs. Fentanyl Onset
100
Morphine
80
60
site concentration
Percent of peak effect
40
20
Fentanyl
0
0
30
60
90
120
Minutes since bolus injection
19
Morphine vs. Fentanyl PK
20
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
22
Comparative Hydromorphone PK
23
Hydromorphone Onset
100
Hydromorphone
80
Morphine
60
site concentration
Percent of peak effect
Fentanyl
40
20
0
0
5
10
15
20
Minutes since bolus injection
24
Hydromorphone Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
20
Fentanyl
0
0
30
60
90
120
Minutes since bolus injection
25
Comparative Hydromorphone PK
26
Sufentanil

• 10 fold more potent than fentanyl
• Slightly slower onset than fentanyl
• More rapid recovery (context sensitive half
  time) than fentanyl
• Very clean pharmacologically

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Comparative Sufentanil PK
100
10
Percent of initial concentration
Sufentanil
Morphine
Fentanyl
Hydromorphone
1
0
5
10
15
20
25
30
Minutes since bolus injection
28
Comparative Sufentanil PK
100
10
Percent of initial concentration
1
Sufentanil
Fentanyl
Hydromorphone
0.1
Morphine
0.01
0
240
480
720
960
1200
1440
Minutes since bolus injection
29
Sufentanil Onset
100
Hydromorphone
80
Morphine
Sufentanil
60
site concentration
Percent of peak effect
Fentanyl
40
20
0
0
5
10
15
20
Minutes since bolus injection
30
Sufentanil Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
20
Fentanyl
Sufentanil
0
0
30
60
90
120
Minutes since bolus injection
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50 effect sitedecrement curves
120
fentanyl
90
alfentanil
Minutes required
60
sufentanil
30
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
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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
• Possibly useful as a local anesthetic

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Meperidine Onset
100
Hydromorphone
Meperidine
80
Morphine
Sufentanil
60
site concentration
Percent of peak effect
Fentanyl
40
20
0
0
5
10
15
20
Minutes since bolus injection
34
Meperidine Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
Meperidine
20
Fentanyl
Sufentanil
0
0
30
60
90
120
Minutes since bolus injection
35
Alfentanil

• Less potent than fentanyl
• Much more rapid onset (including more rapid onset
  of rigidity and respiratory depression)
• Much more evanescent 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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Onset of fentanyl series opioids
sufentanil
100
80
fentanyl
Percent of peak effect site opioid concentration
60
alfentanil
40
20
remifentanil
0
0
2
4
6
8
10
Minutes since bolus injection
Minto et al, Anesthesiology 8610-23, 1997
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Comparative Onset ofAlfentanil and Remifentanil
39
Remifentanil Metabolism

• Extremely rapid
• Not influenced by
• Hepatic disease
• Renal disease
• Pseudocholinesterase deficiency
• Administration of neostigmine
• Very young age
• Modest decrease in elderly patients

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The remifentanil Unit Disposition Function

• Expected plasma concentration
• following bolus of 1 unit
• Age range 20-85 yrs
• Very rapid decrease
• Less variability than with other anesthetic drugs

Minto et al, Anesthesiology 8610-23, 1997
41
PK of fentanyl series opioids
100
10
Percent of peak plasma opioid concentration
fentanyl
1
sufentanil
alfentanil
remifentanil
0.1
0
120
240
360
480
600
Minutes since bolus injection
Minto et al, Anesthesiology 8610-23, 1997
42
50 effect sitedecrement curves
120
fentanyl
90
alfentanil
Minutes required
60
sufentanil
30
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
43
20 effect sitedecrement curves
60
fentanyl
40
Minutes required
alfentanil
20
sufentanil
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
44
80 effect sitedecrement curves
300
fentanyl
240
alfentanil
180
Minutes required
120
sufentanil
60
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
45
Methadone

• Longest terminal half-life (about 1 day)
• May accumulate during titration to steady state
• VERY BAD IDEA TO SEND PATIENTS HOME ON METHADONE
• 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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Methadone Onset
100
Hydromorphone
Methadone
Meperidine
80
Morphine
Sufentanil
60
site concentration
Percent of peak effect
Fentanyl
40
Alfentanil
20
Remifentanil
0
0
5
10
15
20
Minutes since bolus injection
47
Methadone Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
Meperidine
20
Methadone
Fentanyl
Sufentanil
Alfentanil
0
Remifentanil
0
30
60
90
120
Minutes since bolus injection
48
Methadone PK
100
Methadone
10
Meperidine
Percent of initial concentration
Sufentanil
Alfentanil
Morphine
Fentanyl
Hydromorphone
Remifentanil
1
0
5
10
15
20
25
30
Minutes since bolus injection
49
Methadone PK
100
10
Percent of initial concentration
Methadone
1
Sufentanil
Fentanyl
Meperidine
Hydromorphone
0.1
Morphine
Alfentanil
Remifentanil
0.01
0
240
480
720
960
1200
1440
Minutes since bolus injection
50
Context Sensitive Half Time
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Rise to Steady State
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Morphine-6-glucuronide

• Very slow transit across blood brain barrier.
• Not a substrate for p-glycoprotein, but appears
  to be a substrate for probenecid inhibited
  transporters (Anesthesiology 2004101 1394)
• Recently a peptide based carrier demonstrated 4
  fold increase in uptake and potency (JPET 200512
  epub).
• Some data show higher affinity for ?1, and lower
  affinity for ?2, compared to morphine.
• Some suggestion that M6G is associated with less
  ventilatory depression for the amount of
  analgesia
• (e.g., Romberg et al, Anesthesiology 2004
  100120)

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Opioid Induced Hyperalgesia

• Increase in pain sensitivity following exposure
  to opioids
• Well documented in animal models of pain
• Evidence in humans is accumulating
• Mechanical nociceptive pathways appear more
  sensitive then thermal (heat) nociceptive
  pathways
• NMDA antagonists (i.e., ketamine) blocks
  hyperalgesia
• Suggests a spinal mechanism

Clark and Angst, Anesthesiology 2006104570
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OIH High Dose Opioids

• Pain and hypersensitivity are observed in opioid
  addicts during withdrawal.
• Addicts on methadone maintenance have increased
  sensitivity in various pain models compared with
  addicts not on methadone maintenance
• High dose fentanyl (22 ?g/kg) and remifentanil
  (0.3 ?g/kg/min) have been associated with
  increased pain and opioid requirements in the
  post operative period.
• Associated with very high opioid doses.
• Not always replicated (0.23 ?g/kg/min
  remifentanil did not cause hyperalgesia).
• Seen with IT opioids (25 ?g fentanyl)
• Nearly impossible to distinguish hyperalgesia
  from tolerance in patients in such trials.
• Efficacy of ketamine at blocking effect suggests
  it is hyperalgesia, not tolerance.

Clark and Angst, Anesthesiology 2006104570
55
Short-term infusion of the m-opioid agonist
remifentanilin humans causes hyperalgesia during
withdrawal
Mechanical Pain
Heat Pain
Angst et al, Pain 200310649
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Allodynia from VERY High Doses

• Morphine in very high doses can cause allodynia.
• Happens with both systemic and neuraxial
  administration
• Further escalating the morphine only exacerbates
  the pain.
• Also seen in several cases with very high dose
  methadone.
• Probably does not happen with the fentanyl series
  of opioids.

Clark and Angst, Anesthesiology 2006104570
57
OIH Naloxone Infusions

• Two studies suggested very low naloxone infusions
  improved post-operative analgesia in women
  undergoing hysterectomy
• Gan et al, Anesthesiology 1997871075
• Joshi et al, Anesthesiology 1999901007
• Subsequent studies failed to reproduce these
  results
• Cepeda et al, Pain 20029673
• Cepeda et al, Pain 200410741

Clark and Angst, Anesthesiology 2006104570
58
OIH and ?2 Adrenergic Receptors

• Clark et al measured propensity to develop OIH in
  15 mouse strains
• Used in-silico genetic mapping to determine the
  likely genetic cause
• The ?2 adrenergic receptor was the most likely
  genetic candidate
• Deletion of ?2-AR sharply reduced mechanical
  allodynia.
• Selective ?2 antagonist produced dose-dependent
  reversal of OIH
• Propranolol, anyone?

Liang et al, Anesthesiology 20061041054
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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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Relative Potency
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Equivalent doses at 10 minto 50 ?g fentanyl
1.5
1.5
Fentanyl 50 mcg
Fentanyl 50 mcg
Morphine 5.3 mg
Morphine 5.3 mg
Methadone 1.4 mg
Methadone 1.4 mg
Meperidine 28 mg
Meperidine 28 mg
1.0
1.0
Hydromorphone 0.4 mg
Hydromorphone 0.4 mg
Effect Site Fentanyl Equivalents
Effect Site Fentanyl Equivalents
(mcg/ml)
(mcg/ml)
0.5
0.5
0.0
0.0
180
0
30
60
90
120
150
180
0
30
60
90
120
150
Minutes
Minutes
63
50 ?g fentanyl at 10 minutes
m
g
Alfentanil
197
m
g
Sufentanil
4.4
m
g
Remifentanil
72
Morphine
5.3
mg
Methadone
1.4
mg
Meperidine
28
mg
Hydromorphone
0.4
mg
64
Intraoperative potency100 ?g/hour fentanyl at 2
hours
m
Sufentanil
10
g/hr
m
g/kg/min
Remifentanil
0.04
Morphine
3.5
mg/hr
Methadone
2
mg/hr
Hydromorphone
0.4
mg/hr
65
Interindividual Variability 1
Woodhouse and Mather Anaesthesia 52949-955, 1997
66
Interindividual Variability 2
Flood and Daniel, Anesthesiology 2004
67
Interindividual Variability 3
Nieuwenhuijs et al, Anesthesiology 2003,98312-22
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Post Op Analgesia 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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Post Op Analgesia 2

• Hydromorphone 0.2 mg q 10 min
• Max of 6 mg in young patients, 3 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 1 and 2
3.0
Fentanyl 25 q 5 to 250
Hydromorphone 0.2 q 5 to 10
2.0
Effect Site Fentanyl Equivalents
(mcg/ml)
1.0
0.0
0
10
20
30
40
50
60
Minutes
71
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)
• Dexamethasone
• Gabapentin

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Post Op Analgesia 3

• If severe post-op pain is expected
• Methadone 5-10 mg on induction of anesthesia
• Methadone 5-10 mg 1 hour before the end of the
  case
• Ketamine 20-40 mg on induction of anesthesia
• Ketamine 10-20 mg 30-60 min before the end
• 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 0.2 mg q 10 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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13 Individuals
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