Transcript Slide 1

Opioid Pharmacology and
Management Principles
Part I
Steven Stanos, DO
© 2005 Rehabilitation Institute of Chicago
© 2005 Rehabilitation Institute of Chicago
“Opiate”
“Opioid”
“Narcotic”
© 2005 Rehabilitation Institute of Chicago
© 2005 Rehabilitation Institute of Chicago
Can We Catch the Pendulum?
The pendulum rarely stops in the middle
Avoidance
Widespread Use
 Will not prescribe
opioids for any reason
 Driven by fear of
regulatory action or
antiquated views of
addiction exaggerating
the perception of risk
Balance
 Rational pharmacology;
application of principles of
addiction medicine
 Tailor therapy to risk in
individual patients
© 2005 Rehabilitation Institute of Chicago
Adapted from Rich A. APS Bulletin. 2005.
 Prescribing without
recognition of
dangers
Holy Grail ?
• Potent analgesic
• More less potent
agents
• Drugs for reduced
renal function
• Better formulations
• Less divertible
© 2005 Rehabilitation Institute of Chicago
Products Commonly Prescribed in the US
Atorvastatin
Lipitor
74
Lipitor
79
55
Amoxicillin
48
Other
H/C
Hydrocodone/Combo
11
114
6
30
Oxycodone/Combo
F
Propoxyphene/Combo
P/C
7
24
11
22
27
Tramadol/Combo
O/C
Codeine/Combo
C/C
18
110
13
Oxycodone
C/C
Fentanyl
F
19
7
26
Morphine
T/C
Hydromorphone
H
Highly Prescribed
Products in US
6
21
2
0
20
0
20
© 2005 Rehabilitation0
Institute of Chicago
20
40
40
40
60
60
60
80
80
80
100
100
100
Number of Prescriptions (in Millions)
120
120
120
IMS NPA+, 2006.
Current Treatment Armamentarium
Dosing Interval
24 Hour
Tramadol ER
Morphine CR
Celecoxib
Unmet
Needs
12 Hour
4-6 Hour
OXCD CR,
Morphine CR,
OXYM ER
Naproxen
APAP,
Aspirin
COD/APAP,
HC/APAP,
OXCD/APAP,
TRAM/APAP
Non-opioids
Combination Opioids
HYM, Morphine,
OXYM, PROP,
Tramadol
Single-Agent Opioids
Class of Therapeutic Agent
© 2005 Rehabilitation Institute of Chicago
Opioids—the Science
Mechanisms1
• Biogenesis of endogenous
peptides
• Anatomic distribution
• Endocrine changes
• Endogenous opioids and
stress2
• Receptor characteristics
1. Bailey CP, et al. Curr Opin Pharmacol. 2005;5:60–68 [Evidence Level C] 2. Bruehl S,
et al. Clin J Pain. 2004;20:283–292. [Evidence Level A]
© 2005 Rehabilitation Institute of Chicago
Genetic Polymorphisms and
Response to Opioids
• Subtype variants of mu opioid receptor1,2
– Alter binding affinities
– Change in receptor densities3
• Interindividual variability in pain perception and
sensitivity to analgesics1,2
–
–
–
–
Efficacy
Side effects
Tolerance profiles
Risk of drug abuse
1. Landau
Anesthesiology.
[Evidence Level C]; 2. Pasternak GW. J Pain Symptom Manage.
© 2005R.Rehabilitation
Institute2006;105;235–237
of Chicago
2005;29(suppl):S2–S9 [Evidence Level C]; 3. Ross JR, et al. Pharmacogenomics J. 2005;5:324–336. [Evidence Level B]
Mu-opioid Receptor Activation and
Incomplete Cross Tolerance
Level of Activation
Receptor Variation for Same Patient with Different Drug
Drug 1
Drug 2
MOR-1
Variant 1
MOR-1
Variant 2
MOR-1
Variant 3
MOR-1
Variant 4
Receptor
Adapted from Pasternak GW. Trends Pharmacol Sci. 2001;22:67-70.
© 2004 Rehabilitation Institute of Chicago
55
MOR-1
Variant 5
Opioids
I. Syntheric phenylpiperidines
Meperidine, Fentanyl,
II. Synthetic Pseudopiperidines
Methadone, Propoxyphene
III. Naturally Occurring Alkaloids
A. Natural: Heroin, Morphine, Codeine
B. Semi-synthetic: Hydromorphone, Oxycodone,
Oxymorphone
C. Tramadol
© 2005 Rehabilitation Institute of Chicago
Opioid Effects
General
• Analgesia
• Altered mood
• Decreased anxiety
• Respiratory depression
• Inhibition central
reflexes
• (-) GI motility
• Cough suppression
• (-) CRF, ACH
• Miosis
• Pruritus, nausea,
vomiting
© 2005 Rehabilitation Institute of Chicago
Reinforcing effects
• Reduce anxiety
• Decrease boredom
• Decrease aggression
• Increase self-esteem
Epstein S. In: Clinical Manual Addiction Psychopharmacology,
2005.
Characteristics of
Immediate- and Extended-Release Opioids
Immediate-release opioids
•
•
Quick onset of action (within
minutes)
Potential use for some types of
acute pain and some types of BTP
•
Can be used for dose finding during
initial treatment
•
Inconvenient repetitive dosing
•
Peak and trough phenomenon
– Not ideal for chronic pain
– May increase frequency of endof- dose (trough) breakthrough
pain
– Increased potential for euphoria
and adverse effects (peaks)
Extended-release
opioids
•
More stable blood levels
•
Potential benefit for
persistent acute pain and
chronic pain because avoids
peaks and troughs
•
May reduce frequency of
end-of-dose BTP
•
Potential for lower incidence
of side effects (fewer peaks)
•
May decrease pain-related
sleep interference
•
Potential improvement in
compliance and quality of life
© 2005 Rehabilitation Institute of Chicago
McCarberg BH, Barkin Rl. Amer J Ther. 2001;8:181-186.
Around-the-Clock (ATC) Medication Treating Persistent Pain*
Over Medication
ATC Medication
Therapeutic
Window
Pain
Relief
Threshold
Persistent Pain
Time
© 2005 Rehabilitation Institute of Chicago
*Baseline or persistent
pain is controlled by ATC
medication.
Treating Cancer Pain –
Inadequate Management of Breakthrough Pain
Over Medication
Traditional BTP
Medications*
ATC Medication
Persistent Pain
© 2005 Rehabilitation Institute of Chicago
Time
*Delayed onset of action,
type and dose may not
adequately treat a BTP
episode.
Treating Cancer Pain – Ideal Management
Over Medication
Ideal Breakthrough
Pain
Medication*
ATC
Medication
Persistent Pain
© 2005 Rehabilitation Institute of Chicago
Time
*Breakthrough pain treatment
has rapid onset and matches the
intensity and duration of BTP
episode.
Opioid Pharmacokinetics
Opioid
BioavailHalf Life ability(%)
Active Metabolites
Morphine
2–4
10%–50%
Codeine, M6G, M3G
Pethidine,
Meperidine
3–4
30–60
Norpethidine,
Normeperidine
Methadone
6–150
60–90
None
Fentanyl
3–7
<2
None
Hydrocodone
4–4.5
Codeine
3–4
60–90
Morphine, Hydrocodeine
Oxycodone
2–6
40–130
Oxymorphone
35–80
None
Hydromorphon 2–4
e © 2005 Rehabilitation Institute of Chicago
Hydromorphone,
Norcodeine
Propoxyphene (Darvocet)
•
•
•
•
With acetaminophen (Darvocet-N100)
Structurally related to methadone
Peak plasma concentration 2 h
Liver metabolism to norproxyphene
© 2005 Rehabilitation Institute of Chicago
FDA ruling on Propoxyphene
•
•
•
•
•
UK: phased removal in 2005
Pubic Citizen petitioned for removal
ASHSP recommends FDA withdrawal (Jan ‘09)
No more effective than APAP alone, similar to tramadol
Supported by Beers Criteria as inappropriate for the
elderly
• FDA Advisory Committee (Jan.’09):14-12 in support of
removing from market
• July 7, 2009: FDA: black box warning, remain on market
© 2005 Rehabilitation Institute of Chicago
Morphine (Gold Standard)
Hydrophilic
• Slower entry into
CNS
• Active metabolites
(M3G, M6G)
Morphine-3glucuronide
• inactive?, CNS excitation
Morphine-6-glucuroide
• Active analgesic, 2-100x
more potent (centrally),
Induces liver enzymes
© 2005 Rehabilitation Institute of Chicago
MS IR®: 15, 30 mg
MS Contin®: 15, 30, 60,
100, 200 mg
Kadian®: 20, 30, 50, 60 mg
Avinza®: 30, 60, 90, 120
mg
Modified Release Opioids
Product
Dosage Form Strength (mg)
Dosing
frequency (h)
Avinza
ER capsules
30 ,60,90,120
24
Kadian
SR capsules
20,30,50,60,100
12-24
Oramorph
SR tablets
15,30,60,100
8-12
MS Contin
CR tablets
15,30,60,100,200
8-12
CR tablets
10,20,40,80,160
12
ER tablet
15,10,20,40
12
Morphine
sulfate
Oxycodone HCL CR tablets
Oxycontin
Oxymorphone
HCL
Opana
© 2005 Rehabilitation Institute of Chicago
Amabile C, Bowman B. Ann Pharmacother 2006;40.
Moderate to Severe
Mild to Moderate
Pain Intensity
Combination Opioids
Duration of
Action
Equianalgesic
Oral Dose*
DEA
Sched
Agent
Onset
Oxycodone
Combos
10-15
min
4-6 hrs
30 mg†
II
Hydrocodone
Combos
30-60
min
4-6 hrs
30 mg
III
Codeine
Combos
30-60
min
4-6 hrs
130 mg
III
Propoxyphene
Combos
15-60
min
4-6 hrs
130 mg
IV
Tramadol
Combos
60 min
6-7 hrs
100 mg
Not
sched
*Doses reflect opioid component only and are equianalgesic to 30 mg morphine
†Doses for moderate to severe pain not necessarily equivalent to 30 mg morphine
‡NA, not applicable
Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, et al. Goodman & Gilman’s
© 2005 Rehabilitation Institute of Chicago
The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001:569-619.
www.musc.edu/pharmacyservices/medusepol/opiodanalgesicfinal.pdf.
Hydrocodone/ Oxycodone
– Prodrug (nonactive in form delivered)
– Dependent on P450 2D6 enzyme system
– Concurrent medication therapy may affect
prodrug metabolism if drug(s) inhibit P450 2D6
– Tylenol combination: Norco, Lortab, Percocet,
Roxicet
© 2005 Rehabilitation Institute of Chicago
© 2005 Rehabilitation Institute of Chicago
Acetaminophen (Tylenol)
© 2005 Rehabilitation Institute of Chicago
FDA Decisions: June 30,2009
• 20-17: ban combination
products
• 21-16: lower maximum daily
APAP
• 24-13: limit maximum single
dose APAP
• 26-11: 1,000 mg dose APAP
prescription
• Final decision pending
© 2005 Rehabilitation Institute of Chicago
Acetaminophen (APAP)
•
A centrally acting analgesic that increases the pain threshold
•
Mechanism of action is not fully known
–
–
May selectively inhibit a distinct form of COX (COX-3)
Most likely has no affinity for the active site of COX, but blocks
activity by reducing the active oxidized form of COX to an inactive
form
•
Indicated to reduce fever and for the temporary relief of minor
aches and pains
•
Fewer GI side effects than NSAIDs/COX-2 inhibitors
•
Adverse effects associated with chronic use
Roberts LJ II, et al. In: Hardman JG, et al, eds. Goodman & Gilman’s
The Pharmacological Basis of Therapeutics. 2001:703-705.
Lucas R, et al. FASEB J. 2005;19:635-637.
© 2005 Rehabilitation Institute of Chicago
Breakthrough Pain Medications
Onset of
analgesia
(min)
Duration of effect
(h)
30–40
4
Oxycodone
30
4
Hydromorphone (oral)
30
4
Methadone
10–15
4–6
Fentanyl
(transmucosal)
Oxymorphone
5–10
1–2
30
6-9
Immediate-Release
Opioid
Morphine
Bennett
et al. Pharmacol
2005;30:296–301. [Evidence Level C]
© 2005D,Rehabilitation
InstituteTher.
of Chicago
New Short-Acting Opioids for
Breakthrough Pain (BTP)
•
•
•
•
Transmucosal fentanyl (Actiq®)
Fentanyl buccal tablet (Fentora™)
Oxymorphone (Opana®)
Tapentadol (Nucynta®)
© 2005 Rehabilitation Institute of Chicago
Oral Transmucosal
Fentanyl Citrate (OTFC)
•
•
•
•
First rapid-onset formulation
50% bioavailability
Median onset of relief: 15 min
Peak plasma concentration
± 22 min
• Approved for cancer
breakthrough pain
Lichtor JL, et al. Anesth Analg. 1999;89:732–738 [Evidence Level A]; Streisand JB, et al. Anesthesiology. 1991;75:223–229
[Evidence
Level
B]; Portenoy
et al. Pain. 1999;79:303-312 [Evidence Level A]; Payne R, et al. J Pain Symptom
© 2005
Rehabilitation
InstituteRK,
of Chicago
Manage. 2001;22:575-583. [Evidence Level B]
Fentanyl Buccal Tablet (FBT)*
• OraVescent® drug delivery technology generates a
reaction that releases carbon dioxide when the tablet
comes in contact with saliva1,2
– Transient pH changes optimize dissolution (at a lower
pH) and membrane permeation (at a higher pH)
1. Pather
SI,Rehabilitation
et al. Drug Institute
Delivery
© 2005
of Tech.
Chicago2001;1:54–57 [Evidence Level B]; 2. Durfee S, et al. Am J Drug Delivery.
2006;4:1–5. [Evidence Level B]
Multiple Pathways of Pain Transmission:
Neuronal Integration of Signaling1-3
Ascending pathway
to the brain
Secondary afferent
Descending pathway
from the brain
Primary afferent
Painful stimulus
1. Terlinden R et al. Eur J Drug Metab Pharmacokin. 2007;32(3):163-169. 2. Vanderah TW. Med Clin North Am. 2007;91(1):1-12.
3. Tzschentke TM et al. J Pharmacol Exp Ther. 2007;323(1):265-276.
© 2005 Rehabilitation Institute of Chicago
Drug Mechanism of Action (in vivo):
Dual μ-Opioid Receptor Agonist and Norepinephrine
Reuptake Inhibitor1,2
Descending pathway
from the brain
Ascending pathway
to the brain
NE
Tapentadol*
+
-
μ-OR
2-AR
–
SP
+
Pain signal
Glut
Primary afferent
Secondary
afferent
The yellow cylinder with the purple NE ball represents the NE reuptake transporter protein.
NE = norepinephrine; 2-AR = alpha2-adrenoceptor; -OR = μ-opioid receptor; SP = substance P; Glut = glutamate.
1. Tzschentke TM et al. J Pharmacol Exp Ther. 2007;323(1):265-276. 2. American Pain Society.
http://www.npcnow.org/resources/PDFs/painmonograph.pdf. December 2001. Accessed March 7, 2008.
© 2005
Rehabilitation
Institute of Chicago
*The exact
mechanism
of NUCYNTA™
is unknown.
Tapentadol and Tramadol:
Different Molecular Structures
Tapentadol
Tramadol
OCH3
OH
(R)
(R)
N
© 2005 Rehabilitation Institute of Chicago
OH
·HCl
HO
H
N
·HCl
Tapentadol and Tramadol:
Prescribing Information Differences
Feature
Tapentadol
Tramadol
Pain severity
Moderate to severe
Moderate to moderately severe
Mechanism of
action
• Binds to μ-receptors
• Inhibits reuptake of
norepinephrine
• Binds to μ-receptors
• Inhibits reuptake of norepinephrine
• Inhibits reuptake of serotonin
Activity of
metabolites
Metabolites are not
active
M1 metabolite with 6- and 200-fold
greater potency than parent drug for
analgesia and μ-OR affinity, respectively
Metabolism
Primarily Phase 2
conjugation to
glucuronide and sulfate
O-demethylation produces M1 (CYP2D6);
N-demethylation (CYP3A4 and CYP2B6);
sulfation/glucuronidation
Federal
scheduling
Schedule II
Unscheduled
OR = opioid receptor.
© 2005 Rehabilitation Institute of Chicago
Tapentadol: Indication and Dosing
•
•
•
Tapentadol is indicated for the relief of
moderate to severe acute pain in patients
18 years of age or older
The dose is 50 mg, 75 mg, or 100 mg every 4 to 6 hours
depending upon pain intensity
– Good clinical practice dictates that the lowest starting dose
be used and, as always, the dose should be individualized for the
patient
– 50 mg is the lowest dose available
– Daily doses on first day of therapy above 700 mg and on
subsequent days above 600 mg have not been studied in
controlled clinical trials and are not recommended
Clinical considerations should include:
–
–
–
–
Patient's medical history and concomitant medication use
Previous experience prescribing similar drugs
Severity of the pain being treated
Ability to monitor the patient
© 2005 Rehabilitation Institute of Chicago
Tapentadol: Clinical Pharmacokinetics
• Bioavailability is 32% after single-dose administration in
fasted state
• Low plasma protein binding (~20%)
• 97% metabolized
– Occurs mainly via Phase 2 pathways (55% O-glucuronide, 15%
sulfate of tapentadol)
– Other metabolism (15%) via P450 enzymes (13% by CYP2C9
and CYP2C19, 2% by CYP2D6)
• 99% of tapentadol and its metabolites eliminated via renal clearance
• Metabolites lack analgesic activity
• Time to maximum serum concentration (Tmax): 1.25 h
• Half-life (t1/2): 4 h
© 2005 Rehabilitation Institute of Chicago
Osteoarthritis Hip/Knee Study: Efficacy Results
Mean Cumulative SPID Score1
The higher the SPID score,
the greater the pain relief
250
*†
229.2
*†
*
236.5
223.8
200
150
N=659
130.6
100
50
0
SPID-5 Days (Primary Endpoint)
SPID = sum of pain intensity differences, where a higher score indicates greater pain relief.
*P<.001 for all comparisons vs placebo.1,2 † Both doses of tapentadol were noninferior
to oxycodone IR 10 mg (prespecified analysis).
1. Data on file. 2. Hartrick C et al. Clin Ther. 2009;31(2):260-271.
© 2005 Rehabilitation Institute of Chicago
Placebo
Tapentadol IR 50 mg
Tapentadol IR 75 mg
Oxycodone IR 10 mg
Osteoarthritis Hip/Knee Study: Composite Incidence of
Nausea and Vomiting1,2
57.0%
60
N=666
Incidence (%)
50
40
*
29.8%
30
*
21.7%
20
10
8.3%
0
Composite of Nausea and Vomiting
IR = immediate release; GI = gastrointestinal.
*Nominal P<.001 for both doses of tapentadol IR vs oxycodone IR 10 mg.
1. Hartrick C et al. Clin Ther. 2009;31(2):260-271. 2. Data on file.
© 2005 Rehabilitation Institute of Chicago
Placebo
Tapentadol IR 50 mg
Tapentadol IR 75 mg
Oxycodone IR 10 mg
New Long-Acting Opioids
• Tramadol ER (Ultram® ER) oral tablet
– Q24h ER technology1
• Oxymorphone ER (Opana ER®) oral
tablet2–4
– Q12h ER technology
• Hydrophilic gel matrix with slowly eroding core
• Tramadol HCL ER (Ryzolt®)
1. Gana TJ, et al. Curr Med Res Opin. 2006;22:1391–1401 [Evidence Level A]; 2. Prommer E. Support Care Cancer.
2006;14:109–115 [Evidence Level C]; 3. Durfee S. Am J Drug Deliv. 2006;4:1–5 [Evidence Level B]; 4. McIIwain H, et al.
Am J Ther. 2005;12:106–112. [Evidence Level B]
© 2005 Rehabilitation Institute of Chicago
Once-Daily ULTRAM ER
Mean steady-state tramadol plasma concentrations on day 8 post-dose after
administration of ULTRAM ER once-daily and tramadol every 6 hours
Tramadol concentration
(ng/mL)
350
300
250
200
150
100
ULTRAM ER 200 mg qd
50
0
Tramadol 50 mg q6h
0
2
4
6
8
10
12
14
Time (h)
16
© 2005 Rehabilitation Institute of Chicago
ULTRAM® ER (tramadol HCl) Extended-Release Tablets Prescribing information.
18
20
22
24
Tramadol HCL ER (Ryzolt)
100mg, 200mg, 300mg
© 2005 Rehabilitation Institute of Chicago
Molecular Structures of Morphine
and Oxymorphone
Morphine
Oxymorphone
N – CH3
N – CH3
OH
SO4
HO
O
HCl
HO
HO
O
OPANA® Tablets. Full Prescribing Information. Chadds Ford, PA. Endo Pharmaceuticals. 2006.
Morphine Sulfate Extended-Release Tablets. Full Prescribing Information. Chadds Ford, PA. Endo Pharmaceuticals. 2004.
O
Methadone (Dolophine)
• Synthetic, μ agonists,
NMDA antagonist
• L/D enantiomers (50:50)
• Oral bioavailability varies
(40%–99%)
• Biphasic plasma level
decline
• No active metabolites
• Metabolized by liver (CYP
3A4)
© 2005 Rehabilitation Institute of Chicago
L/D = light/darkness ratio; NMDA = N-methyl-D-aspartate.
Methadone Dosing: Gradual Conversion
Mor-E
(mg/d)
Calculate
Meth (mg/d)
<200
15 mg
Initial Meth
Dose
Increment
Example
5 mg q8h
5–7 d
Mor 90 mg/d
Meth 5 mg q8h
200–500 ~7% Morph
dose
Calculated
dose given
q8h
5–7 d
300 mg Mor =
21 mg/d Met
7.5 mg q8h
>500
1/3 calculated Add 1/3
dose q8h
dose q5d;
↓ previous
opioid q5d
~7% Morph
dose
Complete
conversion in 15
d
Goodman F, et al. Methadone Dosing Recommendations for Treatment of Chronic Pain. Available at:
http://www.pbm.va.gov/monitoring/Methadone%20Dosing%20Final%20(Rev%20081103).pdf. Accessed November 28,
2006. [Evidence Level C]
© 2005 Rehabilitation Institute of Chicago
Methadone: prolonged QT and
Torsade de Pointes (TdP)
 Risk Factors: heart disease, hypokalemia,
hypomagnesemia, concomitant CYP3A4
inhibitors
 MedWatch System (N= 5503)
— <1% with TdP or PQ prolongation
— Average dose 410 -/+ 349/day
— 30% within recommended range (60-100mg/day)
— 75% with risk factors
Pearson E. Pharmacoepidem Drug Saf 2005:14:747-53.
“Adverse Effects
Cases
Risk Stratification
American Greetings.
Formulation Strategies Intended to
Reduce Abuse
Physical Approach1,2
Pharmacologic Approach1,2
Examples include
• Advanced dispensing formulations
• Tamper-resistant formulations
Examples include
• Addition of antagonist
• Prodrug formulation
Aversive Approach1,2
Examples include
• Addition of non-treatment-related
ingredients such as niacin or capsaicin
1. Gershell L et al. Nat Rev Drug Discov. 2006;5(11):889-890. 2. Katz NP et al. Clin J Pain. 2007;23(8):648-660.
EMBEDA™
How Does the EMBEDA™ Pharmacologic
Abuse-deterrent Technology Work?
MORPHINE SULFATE
NALTREXONE CORE
Chewing or
Crushing Force
Naltrexone Core
Releases and Mixes
Naltrexone
Morphine
1. If taken as directed, EMBEDA™ is
intended to provide effective pain relief
with long-acting morphine pellets; the
naltrexone passes out of the body
without effect
2. If EMBEDA™ is crushed, chewed
or extracted:
A. the naltrexone (opioid antagonist)
releases and mixes with morphine
B. the morphine-naltrexone mixture is
Opioid
Receptor
intended to prevent euphoria from
morphine by competing for the same
opioid receptor in the brain…thus
deterring abuse of the product
Aversion® Technology
Common Methods of Abuse
Oral Ingestion
Excessive
Quantities
a Two
Aversion Technology
Niacin
causes temporary
unpleasant effects
with ingestion of
higher than
recommended doses
Snorting
Crushed tablets
or capsules
Tissue Irritant
(sodium lauryl sulfate)
Injection
Extract active
ingredients from
dissolved tablets
or capsules
Gel-Forming Agenta
(polyethylene oxide)
makes it difficult to
extract active
ingredient
additional excipients synergize polyethylene oxide
1. Data on file. King Pharmaceuticals®, Inc.
Adverse Effects: Nausea and
Vomiting
 Chemoreceptor trigger zone (CTZ)
 Cortex
 Peripheral pathways
 Vestibular sensitivity
Neural Pathways That Mediate Nausea
and Vomiting
Copyright restrictions may apply.
Wood, G. J. et al. JAMA 2007;298:1196-1207.
Common Clinical Scenarios of Nausea/
Vomiting (N/V)
Wood, G. J. et al. JAMA 2007;298:1196-1207.
Clinical
Mechanisms
First-line
Opioid Induced
Stim CTZ (D2)
Metoclopramide
Gastroparesis (D2)
Prochlorperazine
Constipation (H1, Muscarinic)
Sensitization Ear (H1,
Muscarinic)
Impaired Motility
Gastroparesis (D2)
Metoclopramide
Radiation
Associated
Stimulation peripheral pathways
via 5HT3
5HT3 Antagonists
Stimulation via vestibulocohclear
nerve (Muscarinic acetylcholine )
Scopolamine
N/V
Motion Associated
Diphenhydramine
Promethazine
Nausea:Treatment
 Antihistamines (H1)
— Diphenhydramin (Benadryl): 25-50mg PO
— Scopolamine: 1.5mg TD patch Q 72hrs
 Antipsychotics (D2/CTZ)
— Haloperidol (Haldol): 0.5 – 4mg PO
— Prochlorperazine (Compazine): 5-10mg PO; 25mg PR
— Promethazine (H1) (Phenergan): 12.5-25mg PO; 25mg PR
 Prokinetic agents (D2)
— Metoclopramide (Reglan): 5-20mg PO/IV
 Serotonin Antagonist (5HT3)
— Ondansetron (Zofran): 4-8mg PO or IV
Swegle JM, Logeman CL. Amer Fam Phys 2006;74:1347-54
Opoid Induced Sedation
 Methylphenidate1,2 (Sch II): 5-10 mg TID PRN
 Dextroamphetamine (Sch II): 2.5 – 7.5mg BID, PRN
 Caffeine
 Donepezil (Aricept)3,4: 2.5 – 10mg/day
 Modafinil (Provigil) (Sch IV): 100 – 600 mg/ day
 Differential Diagnosis5: depression, hypothyroidism,
opioid dose, opioid adverse effect, endocrine, sleep
disorder
1. Bruera E, et al. J Pain Symptom Manage 1989;4:3-6.
2. Bruera e, et al. Pain 1992;50:75-7.
3. Slatkin et al. J Pain Symptom Manage 2001;21:425-38.
4. Bruera E, et al. J Pain Symptom Manage 2003;26:1049-54.
5. Reissig JE, Rybarczyk A. Ann Pharmacother 2005;39:727-31.
Modafinil (Provigil): animal studies
PROVIGIL
Amphetamine
H = hypothalamus
Methylphenidate
CA = caudate
• PROVIGIL promoted wakefulness without widespread CNS stimulation
• PROVIGIL is thought to work selectively in areas of the brain believed
to regulate normal wakefulness
Lin JS, et al. Proc Natl Acad Sci USA. 1996;93:1412814133.
Modafinil (Provigil)
 Mechanisms: decrease GABA release in cortex,
weak dopamine release, amygdala?
 Scheduled IV: 100 mg, 200mg
 FDA: narcolepsy, shift work sleep disorder
 Webster L et al, Pain Medicine 2003;4:135-40
— Retrospective, N = 11, Epworth Sleepiness Scale (ESS)
— Dose range: 264 mg – 427mg/ day
— Opioid dose: 536 mg – 810 mg/ day
Opioid Induced Hypogonadism
Dopamine
INHIBITED
Prolactin
Pulsitile GnRH
LH
FSH
Testosterone
Estradiol, Progesterone
Christo PJ. Anesthes Clin N Am. 2003;21:699-713.
Hypogonadism: (OPIAD)
 Sexual dysfunction, infertility
Lab
 Depression
 Free testosterone (FT)
 Decreased energy level
 Total testosterone (TT)
 Muscle wasting and
osteoporosis
 Luetinizing hormone (LH)
 Lowered pain threshold
 Estradiol (E2)
 Impaired wound healing
 Prostate specific antigen
(PSA)
 “Opioid Induced Androgen
Deficiency” (OPIAD)
 Follicle-stimulating (FSH)
Testosterone Patch in Men with
OPIAD
 24 week, open label pilot, N =23
Results:
 (BL): subnormal FT, low normal
LH
 (Tx): elevated FT, TT, DHT, E2
Danniell H, et al. J Pain 2006;7:200-210.
Opioid Induced Sensorineural
Hearing Loss
 Hydrocodone/ APAP
abuse1
15-60 tablets/ day
cochlear toxicity
• Hydrocodone/APAP2
50-300mg/ day
association with Hep C
Severe impairment
1.Oh AK. et al. Neurology 2000;54:2345.
 Propoxyphene abuse3
2. Ho et al. Pain Physician 2007;10:467-72.
3. Harell M. et al. Laryngoscope 1978;88:1518-21.
Opioid Receptor Structure
Gi / Go
INHIBITORY
Gs
ECITATORY
Waldhoer M, et al. Annu Rev Biochem. 2004;73:953-990.
Opioid-Induced Abnormal Pain
Sensitivity
• Desensitization process leading to
opioid tolerance
• Sensitization (pronociceptive) process
leading to opioid-induced pain
sensitivity
Increased spinal dynorphin
Descending facilitation
Glutamatergic system
© 2005 Rehabilitation Institute of Chicago
OPIOID
DESENSITIZATION
(TOLERANCE)
SENSITIZATION
(INCREASED PAIN?)
PRONOCICEPTIVE
© 2005 Rehabilitation Institute of Chicago
Opioid Induced Hyperalgesia (OIH)
• Mao, J (2002)
• Post-Surgical Studies: Increased pain and
analgesic use (Guignard B, 2006)
• Problems: opioid naïve patients, post-surgical,
methadone maintenance
• (Cohen S, et al 2008)
– 355 patients, interventional procedures
– Results: enhanced pain perception in opioid patients
with local lidocaine prep
– Correlated with dose and duration of Tx
© 2005 Rehabilitation Institute of Chicago
“Men in general are quick to
believe that with which they wish
to be true.”
- Julius Caesar
© 2005 Rehabilitation Institute of Chicago
TOLERANCE
and
DEPENDENCE
© 2005 Rehabilitation Institute of Chicago
X
=
ADDICTION
Volkow ND. In: Madras et al. eds. Cell Biology of Addiction, 2006.
© 2005 Rehabilitation Institute of Chicago
“Pseudoaddiction”
Inadequate Pain Management
FRUSTRATION
ANGER
PATIENT
TEAM
ISOLATION
AVOIDANCE
CRISIS
© 2005 Rehabilitation Institute of Chicago
Weissman,Haddox,
Pain (1989)
Predicting aberrant behaviors
• High risk
– Family history of substance abuse
– Legal problems
– Drug or alcohol abuse
• Other
– Cigarette use, higher opioid dose, less opioid
reported side effects, MVA
– Mental health disorders
Michna E, et al. J Pain Sym Management 2004;28:250-8.
© 2005 Rehabilitation Institute of Chicago
Aberrant Drug-Related
Behavior: Implications
• Differential diagnosis of aberrant drug-related behavior
– Addiction
– Pseudoaddiction
– Other psychiatric disorders
• Axis I and Axis II disorders
• Mild encephalopathy
• Family disturbances
– Criminal intent: diversion
Portenoy RK, et al. In Lowinson JH, et al.(eds): Comprehensive Textbook of
Substance Abuse, Fourth Edition. Baltimore: Williams and Wilkins, 2005, pp. 863903. © 2005 Rehabilitation Institute of Chicago
Predicting opioid misuse at 1 year
Misuse (32%)
• Predictors
cocaine abuse
DUI conviction
male
cannabinoids
Ives TJ, et al. BMC Health Ser Res 2006;6:46.
© 2005 Rehabilitation Institute of Chicago
“Opioid misuse”
•
•
•
•
•
•
(-) tox screen
(+) for other
Multiple providers
Diversion
Forgery
Stimulant use
Patients Who May Not Benefit
From Opioid Therapy
• Excessive pain intensity
• Extreme ratings of emotional distress
• Poor perception of coping effectiveness
• Use of multiple pain descriptions
• Poor perceived social support
• Multiple pain sites
• Poor employment history
None of these are
absolute
contraindications
and lack predictive
validity at this point
• Long-term reliance on health professionals
• Addiction risk factors
• History of failure with chronic opioid therapy or allergic sensitivity
Nedeljkovik SS, et al. Clin J Pain. 2002;18:S39-S51.
Portenoy RK, et al. J Pain Symptom Manage. 1990;5:S46-S62.
Federation of State Medical Boards of the United States, Inc. Model Guidelines for the Use of
© 2005 Rehabilitation
Institute
Chicago
Controlled
Substances
forofthe
Treatment of Pain. May 2004.
A Chronic Pain Patient vs
an Addicted Patient
Pain Patient
Abuse
Addicted Patient
Appropriate use
Inappropriate use:
inadequate dose or
excessive dose
Inappropriate use
Quality of life 
Quality of life  or 
Quality of life 
Function 
Function  or 
Function 
© 2005 Rehabilitation Institute of Chicago
Aberrant Behavior vs Abuse
Aberrant
Behavior: 40%
Abuse:
20%
Addiction:
2%–5%
Total Pain Population
Webster LR, et al. Pain Med. 2005;6:432–442.
© 2005 Rehabilitation Institute of Chicago
Webster LR, Webster RM. Pain Med. 2005;6:432–442;
Summary
• Remember opioid pharmacokinetics
• Side effect management important to
improving chances of success
• Opioid hyperalgesia
• Endocrine effects
• Risk stratify patients
© 2005 Rehabilitation Institute of Chicago