opioid analgesics: pharmacology and methods of · pdf fileraymond s. sinatra md, ph.d...
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Raymond S. Sinatra MD, Ph.DDirector: Yale Pain Management ServiceYale-New Haven Hospital
Opioid Analgesics: Pharmacology and Methods of Administration
Opioids: The Foundation of Surgical & Chronic Pain Management
Large number of compounds with variable pharmacokinetics & pharmacology
Multiple delivery systems (oral, parenteral, transdermal, neuraxial)
High safety profile No ceiling effect for achievable pain relief
(full agonists)
“A class of analgesics that bind & activate endorphin receptors in spinal cord & brain”
EndogenousOpioids
(Natural peptides)
Cannabinoids Opioids Cocaine Barbituates
Opiates (Derivatives of Opium)
Semi-synthetics(Substituted derivatives of morphine or codeine)
Synthetics(Non morphinians)
Opioids: Agents that bind to opioid receptors
Narcotics: Drugs that lead to habituation, physical and psychological dependence
MorphineCodeineThebaine
Hydromorphone OxymorphoneOxycodoneHydrocodone
Agonist/AntagonistsNalbuphine, Butorphanol,
AntagonistsNaloxone, Naltrexone
PhenylpiperidinesMeperidineFentanylSufentanilAlfentanil, Remifentanil
DiphenylpropylaminesMethadone, PropoxypheneDextromethorphan
EnkephalinEndorphanDynorphin
Dual ActingTramadolTapentadol
Opioid Analgesics: Categories of Drug
Agonists: bind and activate opioid receptors providing dose dependent analgesia (morphine, fentanyl, methadone, oxycodone, hydromorphone, etc)
Partial agonists: bell-shaped analgesic curve effect (buprenorphine)
Agonist-antagonists: bind multiple receptors; ceiling analgesic curve (pentazocine, butorphanol, dezocine, nalbuphine)
Antagonists: block action of agonists by binding to opioid receptors/no analgesia (naloxone, naltrexone)
(Gilman AG, Limbird LE, Hardman JG, eds. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 9th ed. McGraw-Hill. 1995)
The Opioid Receptor
.
OH
.
O
OH
NH3
AnionicBindingSite
TertiaryNitrogenBindingSite
Flat PhenolicBinding Site
Morphine
R Sinatra 2003
Ion Channel Axonal Membrane Lipid Bilayer
G-protein G1/G0
OpioidReceptor
o
N-CH3
AdenylateCyclase
cAMP
Opioid Binding: Increased Na+ Conduction and Neuronal Hyperpolarization
Na+
Decreased Electrical Excitability
X
K+
X
R Sinatra 2004
Opioid Receptors on Spinal Cord
Spinal Sensory Neuron
InhibitoryInterneuron
Pain Fiber
DescendingInhibitory Fiber
(-)
Postsynaptic Opioid
Receptors
Presynaptic Opioid Receptors
(+)
ENK
ENK
ENKENK
(-)(-)
Opioid Pharmacology
OnsetHigh lipid solubility, Low degree of ionization, High receptor affinity
Potency High Lipid Solubility
DurationLow lipid solubility (CSF trapping), High receptor affinity, Large volume of distribution, Low hepatic/renal clearance, active metabolites
Safety Mu receptor specificity
EfficacyMultiple receptor specificity, high receptor affinitiy, high intrinsic efficacy
Opioid Dose Response Curves
PerceptableAnalgesia
ProfoundAnalgesia
Anesthesia
Increasing Dose (mg)
Incr
easi
ng E
ffect
Fentanyl Hydromorphone Morphine
Butorphanol
Naloxone
Sufentanil
Substitutions at the Tertiary Amine and Phenolic Ring Influence Receptor Binding and Efficacy
.
NH
R Sinatra 2003
Pure Agonist(Morphine)
Partial Agonist(Buprenorphine)
Mixed Agonist(Butorphanol)
Antagonist(Naloxone)
R1
R2
Mu Kappa
+
+/- +/-
+
- -
-
+
Opioid Pharmacokinetics (IV administration)
EffectiveAnalgesia
ProfoundAnalgesia,RespiratoryDepression
Morphine 0.15mg/kgFentanyl 4mcg/kg
Time (Minutes)
T1/2 π
T1/2α
T1/2β
PerceptibleAnalgesia
2 20 200
(Redistribution in Plasma)
(Redistribution in VRG)
(Elimination)
Cp
Opioid Pharmacokinetic Modeling
VRC(Vc)
VPC(V2)
CNS
IV Dose
VRC(Vc)
BBB
Elimination
VPC(V2)
Elimination
IV Dose
Morphine
FentanylCNS
Opioid Side Effects
Common (annoying)• Constipation• Nausea• Somnolence• Dizziness• Vomiting• Pruritus• Headache
– May improve over time, except constipation
Cherny NI. Drugs. 1996;51:714-37.
Serious (Life threatening)• Respiratory depression• Apnea• Respiratory arrest• Circulatory depression• Hypotension• Shock
Incidence and severity of side effects are generally dose dependent
Opioid Toxicity
• Potentially toxic metabolites– Normeperidine from meperidine
• Anxiety, tremors, myoclonus, and seizure– Norpropoxyphene from propoxyphene
• Accumulation with repetitive dosing– Morphine-6-glucuronide (M-6-G) from morphine
• Accumulation and toxicity may occur in severe renal impairment
• Can be lethal in overdose– Overdose varies by dose, patient, and
circumstanceAPS. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 4th ed. 1999. Goodman & Gilman’s: The Pharmacological Basis of
Therapeutics. 10th ed. 2001.
Opioid Dependence• Psychological dependence: need for a
specific drug, either for its pleasurable effect, or to avoid negative effects associated with its withdrawal.
• Physical dependence: a physiological state of adaptation to a specific drug, characterized by a withdrawal syndrome during abstinence, which is relieved by the drug.
Patient Variability in Opioid Response
Significant inter-individual variability in sensitivity to opioids (efficacy, side-effect, & tolerance profiles) are well described
Mu receptor (OPRM1) polymorphisms Genetic differences in opioid metabolism (CYP450) Non Mu receptor genetic differences Transporter P-glycoprotein COMT, Β-arrestin (signaling) Incomplete cross-tolerance
Somogyi AA, et al. Clin Pharmacol Ther. 2007;81;429-44. Ross JR, et al. Oncol. 2006;11:765-73. Reyes-Gibby, et al. Pain. 2006;Epub. Ross JR, et al. Pharmacogenet J. 2005;5:324-336.
Incomplete Cross Tolerance Observed when analgesic efficacy is
maintained with one agonist despite decreasing efficacy with other agonist(s)
Proposed mechanisms include Differing agonist selectivities for receptor
subtypes Pharmacogenetics, eg:
• OPRM1 receptor polymorphisms• CYP2D6 polymorphisms• Downstream events
Mercadante S. Cancer. 1999;86:1856-66. Mercadante S, Bruera E. Cancer Treat Rev. 2006;32:304-15. Pasternak GW. Trends Pharmacol Sci. 2001;67-70. Fine PG, Portenoy RK. A clinical guide to opioid analgesia. 2004. Somogyi AA, et al. Clin Pharmacol Ther. 2007;81;429-44. Ross JR, et al. Oncol. 2006;11:765-73. Ross JR, et al. Pharmacogenet J. 2005;5:324-336.
Ion Channel Axonal Membrane Lipid Bilayer
G-protein G1/G0
OpioidReceptor
o
N-CH3
AdenylateCyclase
cAMP
Opioid Tolerance: Increased K+ Conduction and Neuronal Depolarization
Na+
Increased Electrical Excitability
PO4
K+
PKCReceptor Down-regulation
Altered RNA and Protein SynthesisNMDA Receptor Activation
Opioid Rotation
Use incomplete cross-tolerance to clinical advantage by employing opioid rotation
“Failure to respond to one opioid does not mean the patient will not respond to others. Rotating
from one opioid to another may result in or recapture effective analgesia while improving
tolerability”
Quest for “Holy Grail” of Opioid Analgesia
“Analgesia with limited-to-no risk of respiratory depression, abuse/ diversion, & tolerance development”
• After 100 yrs of semisynthetic and synthetic development, opioids can provide effective analgesia for short to prolonged periods of time with minimal side effects1,2”
• Highly unlikely that a single molecule will be safe and effective in all patients
Corbett AD. Br J Pharmacol. 2006;147:S153-62. Sinatra RS. J Am Board Fam Med. 2006;19:165-77.
Mu-Opioid Receptor Pharmacology
Primary site of analgesic activity for most commonly used opioids
Multiple subtypes (eg, mu1, mu2, mu3 etc) Structural differences at C-terminus affect signal
transduction and G-protein activation Opioid agonists differ in their ability to activate
various mu subtypes Pharmacologic effects of a given agonist reflect
the sum of all receptors activated (mu subtypes as well as kappa and delta).
Pasternak GW. Neuropharmacology. 2004;47(Suppl 1):312-23. Pasternak GW. J Pain Symptom Manage. 2005;29:S2-9. Waldhoer M, et al. PNAS. 2005;102:9050-5. Gupta A, et al. AAPS J. 2006;8:E153-9.
Mu-Opioid Receptor Polymorphisms
More than a dozen splice variants of the mu-opioid receptor have been detected; Pasternak GW, et al. 2006. http://www.mskcc.org/mskcc/html/11384.cfm.
Genetic Polymorphisms & Response to
Single nucleotide polymorphisms of the mu opioid receptor gene OPRM1: Alter receptor structure & influence agonist binding
affinities Alter receptor densities & distribution Influence receptor activation and G-protein
transduction SNPs at position 118 (A118G) OPRM1 influence
morphine sensitivity in animal and human studies
Landau R. Anesthesiol. 2006;105;235-7. Pasternak GW. J Pain Symptom Manage. 2005;29 (suppl):S2-9. Ross JR, et al. Pharmacogenetics J. 2005;5:324-36. Ikeda K, et al. Trends Pharmacol Sci. 2005;26:311-7. Nagashima M, et al. Curr Pain Headache Rep. 2007;11:115-23.
118A-G Polymorphism of OPRM1 Influences Post-op Morphine Use
First “bench-to-bedside” evaluation of opioid receptor polymorphism
OPRM1 genotypes of patients undergoing TKA A118 homozygous (AA): 74 patients (62%) A118 Heterozygous (AG): 33 (27%) G118 homozygous (GG): 13 (11%)
Group GG self-administered significantly more PCA morphine in first 48 h post-op
Genotype 24-h Dose 48-h Dose AA 16.0 mg (±8.0) 25.3 mg (±15.5) AG 14.8 (±7.1) 25.6 (±11.7) GG 22.3 (±10.0)* 40.4 (±22.0)*
TKA=total knee arthroplasty; *Significant difference vs AA & AGChou WY, et al. Acta Anaesthesiol Scand. 2006;50:787-92.
(Mean±SD)
Opioid Metabolism: CYP2D6
Oxymorphone
MorphineCodeine
Oxycodone
CYP450-2D63-O-demethylation
Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. McGraw-Hill Companies. 2004. Ross JR, et al. Pharmacogenetics J. 2005;5:324-36. Goodman & Gilman’s Pharmacology. 11th ed. McGraw-Hill. 2006.
Opioid Selection
• Short-acting– Incident pain– To permit activity
• eg, physical therapy– Exacerbations of pain
• Long-acting– Persistent moderate to severe pain– Baseline analgesia
Cherny NI. Drugs. 1996;51:714-37.Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 10th ed. 2001.
Opioid Selection
• Pharmacologically long-acting– Methadone
• Elimination t½ >> analgesic duration
– Levorphanol• Pharmaceutically long-acting
– Controlled-release preparations of short-acting opioids
Cherny NI. Drugs. 1996;51:714-37.Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 10th ed. 2001.
Prolonged Duration Opioids: Therapy of Choice For Chronic Pain
• Sustained release oral morphine: (MS-Contin, Kadian, Opana), Duration 8 to 24 hours
• Sustained release oral oxycodone: (Oxycontin), Duration 8 to 24 hours
• Sustained release oral oxymorphone: (Opana), Duration 12hrs
• Sustained release oral tapentadol: (Nucynta CR)• Transdermal fentanyl delivery system:
(Duragesic), Duration 72hrs.
(Jaffe, 1990)
Opioid Tolerance: Analgesia Response Curves
Pain
PerceptableAnalgesia
ProfoundAnalgesia
Increasing Dose
Incr
easi
ng E
ffect
Low GradeTolerance
High GradeTolerance
Hyperalgesia
Naïve Response
Opioid Induced Hyperalgesia
PKC
Ca++
NMDA Receptor
N-Type CalciumChannel
Chronic Morphine Exposure
Pain Fiber Terminal
Dorsal HornNeuron Opioid
Receptor
Ketamine
Dextromethorphan
CCG
THANKS- ANY QUESTIONS?
6 8 10 12 14
Relationship Between Opioid Plasma
Pain
Analgesia
Sedation
Ferrante FM, et al. Anesth Analg. 1988;67:457-61.
Ana
lges
ic d
rug
conc
entra
tion
Time (hours)
Dose Dose Dose
Dose
Minimum analgesic
concentration
IMPCA
IM=intramuscular; PCA=patient controlled analgesia
L1-2 L 3-4T11-12
T8-9
Site of Opioid Analgesia(Opioid Receptors in Dorsal Horn)
Sites of Spinal Analgesia
Epidural Space
Spinal Sac
Site of Local Anesthetic Analgesia (Spinal Nerves)
Spinal Cord
Opioid
• Mixed agonist-antagonists– Conventionally defined as mu receptor antagonists and
kappa agonists; Include butorphanol, nalbuphine, pentazocine
– Advantages• Ceiling effect to respiratory depression• Milder withdrawal
– Disadvantages• Precipitate withdrawal if physically dependent
on full agonist opioids• Reverse analgesia of full agonist opioids• Ceiling effect to analgesia• Possible psychotomimetic, dysphorigenic effects
Cherny NI. Drugs. 1996;51:714-37. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 10th ed. 2001.
Opioid
• Mixed agonist-antagonists– Conventionally defined as mu receptor antagonists and
kappa agonists; Include butorphanol, nalbuphine, pentazocine
– Advantages• Ceiling effect to respiratory depression• Milder withdrawal
– Disadvantages• Precipitate withdrawal if physically dependent
on full agonist opioids• Reverse analgesia of full agonist opioids• Ceiling effect to analgesia• Possible psychotomimetic, dysphorigenic effects
Cherny NI. Drugs. 1996;51:714-37. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 10th ed. 2001.
Opioid
• Mixed agonist-antagonists– Conventionally defined as mu receptor antagonists and
kappa agonists; Include butorphanol, nalbuphine, pentazocine
– Advantages• Ceiling effect to respiratory depression• Milder withdrawal
– Disadvantages• Precipitate withdrawal if physically dependent
on full agonist opioids• Reverse analgesia of full agonist opioids• Ceiling effect to analgesia• Possible psychotomimetic, dysphorigenic effects
Cherny NI. Drugs. 1996;51:714-37. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 10th ed. 2001.
Opioid Rotation in Outpatients With Chronic Non-Cancer Pain
0
22.5
45.0
67.5
90.0
#1 (n=86) #2 (n=52) #3 (n=30) #4 (n=18) #5 (n=7)
Side effectIneffectiveEffectiveTotally effective
Quang-Cantergrel ND, et al. Anesth Analg. 2000;90:933-7.
Per
cent
of p
atie
nts
Percentage of patients for whom opioid prescription was effective or stopped because ineffective or intolerable side effects
Prescription #
Opioid • Partial agonists
– Advantages• Longer duration of analgesia vs morphine• Ceiling effect to respiratory depression• Includes Buprenorphine
– Disadvantages• May have ceiling effect to analgesia• If respiratory depression should occur, large
doses of naloxone may be necessary for reversal
Cherny NI. Drugs. 1996;51:714-37. Hoskin PJ, Hanks GW. Drugs. 1991;41:326-44.
Opioid Analgesics
Cherny NI. Drugs. 1996;51:714-37.
l Agonists– Bind to one or more opioid receptor
subtypes (mu, kappa, sigma, delta) – eg, morphine, hydromorphone,
oxycodone, fentanyl– No apparent ceiling to analgesic effect,
except as imposed by side effects (respiratory depression, excessive sedation, intractable nausea/vomiting)
Opioid Metabolism & Response Many opioids metabolized by CYP-450
system Eg: CYP2D6 codeine, hydrocodone,
oxycodone, tramadol Patients may lack normal enzymatic activity
Genetics (enzyme deficiency) Interaction with drugs affecting CYP-450
• Alters analgesic/side-effect profile Hydromorphone, morphine, oxymorphone
metabolized chiefly by conjugation (UGT enzymes) Not affected by CYP-450 drug-drug
interactionsArmstrong SC, Cozza KL. Psychosomatics. 2003;44:167-71; 515-20. Fine PG, Portenoy RK. A Clinical Guide to Opioid Analgesia. McGraw-Hill Companies. 2004. Ross JR, et al. Pharmaco-genetics J. 2005;5:324-36. Susce MT, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1356-8. Tirkkonen T, et al. Clin Pharmacol Ther. 2004;76:639-47.
CYP=cytochrome; UGT=uridine diphosphate-glucuronosyltransferase
Opioid Rotation Indications
Poorly controlled pain with inability to increase dose because of side effects
Adverse event/toxicity of current opioid Rapid tolerance development Development of opioid hyperalgesia
Availability of multiple opioids may help improve clinical outcomes
Key to safe rotation includes familiarity with range of opioids & use of equianalgesic dosing tables
Mercadante S, et al. J Clin Oncol. 1999;17:3307-12. Mercadante S, Bruera E. Cancer Treat Rev. 2006;32:304-15. Riley J, et al. Support Care Cancer. 2006;14:56-64. Sinatra RS. J Am Board Fam Med. 2006;19:165-77. Cherny NI, Portenoy RK. Cancer. 1993;72(11 suppl):3393-415. McAuley D. Narcotic analgesic converter. GlobalRPh Inc. 2007.
Time course of opioid withdrawal.
Opioid Onset Peak Intensity
Duration
MeperidineFentanyl
2-6 hours 6-12 hours 4-5 days
MorphineHeroin
6-18 hours 36-72 hours 7-10 days
Methadone 24-48 hours 3-21 days 6-7 weeks
Stoelting RK, et al.: Anesthesia and Co-Existing Disease. 2nd edition, 1988, p. 731
Opioid
• Mixed agonist-antagonists– Conventionally defined as mu receptor antagonists and
kappa agonists; Include butorphanol, nalbuphine, pentazocine
– Advantages• Ceiling effect to respiratory depression• Milder withdrawal
– Disadvantages• Precipitate withdrawal if physically dependent
on full agonist opioids• Reverse analgesia of full agonist opioids• Ceiling effect to analgesia• Possible psychotomimetic, dysphorigenic effects
Cherny NI. Drugs. 1996;51:714-37. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 10th ed. 2001.
Opioid Rotation in Outpatients With Chronic Non-Cancer Pain
0
22.5
45.0
67.5
90.0
#1 (n=86) #2 (n=52) #3 (n=30) #4 (n=18) #5 (n=7)
Side effectIneffectiveEffectiveTotally effective
Quang-Cantergrel ND, et al. Anesth Analg. 2000;90:933-7.
Per
cent
of p
atie
nts
Percentage of patients for whom opioid prescription was effective or stopped because ineffective or intolerable side effects
Prescription #
Pseudo-addiction
• Increased drug seeking/drug use in a setting of chronic pain
• May be related to progression of disease, tolerance development, and a need to up-titrate opioid dose to compensate for an increase in functional activity
• May be distinguished from “true addiction” in that the behavior resolves when the patients pain is more effectively treated
Weissman & Haddox, 1989
Opioid Addiction
• “A primary chronic neurobiological disease, with genetic, psychosocial, and environmental factors”
• Increased drug seeking and drug administration for purposes other than pain control.
• Characterized by behavior that includes the following: impaired control, compulsive use, continued use despite harm, and craving
• Rarely observed in patients suffering moderate to severe chronic pain.
AAPM Joint Consensus Statement, 2000
Viscusi ER. Reg Anesth Pain Med. 2005;30:292-4.
Fentanyl Iontophoretic Transdermal System
Opioid withdrawal syndrome
• A normal physiological response to a sudden discontinuation of opioids
• Characterized by: Increased autonomic activity Physiological and behavioral responses
(‘wet dog shakes’, yawning, leg jerks)• Rarely life-threatening
Opioid Induced Hyperalgesia: Do Opioid Dependent Patients
Feel More Pain?
• Opioid addicts are relatively pain-intolerant, and demonstrate significantly decreased pain tolerance
• Continued opioid receptor occupation produces hyperalgesia in pain free states, thus they are less able to cope with sudden acute pain
Compton et al: J Pain Sympt Management. 20:237, 2000
Opioid Dependence and Pain Relief
• Opioid dependent patients pose special challenges for perioperative pain control.
• Patients on chronic opioid drugs – 1. Legitimate users 2. Patients with substance use
disorders
Agonist-Receptor Binding Affinities: Why “Dirty” Drugs Work Best for Chronic pain
Morphine ++ + + + - -Hydromorphone ++ + + + - -Oxycodone ++ + + + - -Fentanyl +++ - - - - -Sufentanil +++ - - - - -Butorphanol - ++ + - - -Buprenorphine + + + - - -Methadone ++ + + + + +
Mu Kappa Sigma DeltaPotentiation of Opioid Analgesia
Potentiation of Opioid Analgesia
NMDA Alpha
R Sinatra 2003
Agonist-Receptor Binding Affinities: Why “Dirty” Drugs Work Best for Chronic pain
Morphine ++ + + + - -Hydromorphone ++ + + + - -Oxycodone ++ + + + - -Fentanyl +++ - - - - -Sufentanil +++ - - - - -Butorphanol - ++ + - - -Buprenorphine + + + - - -Methadone ++ + + + + +
Mu Kappa Sigma DeltaPotentiation of Opioid Analgesia
Potentiation of Opioid Analgesia
NMDA Alpha
R Sinatra 2003
NMDA Receptor • NMDA receptors increase the excitability of
spinal neurons (windup) and potentiate pain.• NMDA antagonists block the Ca++ channel and
prevent intracellular Ca++ flux. • Non specific NMDA antagonists (Ketamine)• Specific antagonists (Dextromethorphan,
Ziconitide, Memantine) reduce pain intensity and analgesic requirements in settings of acute and chronic pain.
Perioperative Opioid Anesthetic/ Analgesic Guidelines
• Maintain baseline opioid administration• Increase perioperative opioid dose 20% or
more to compensate for opioid tolerance• Use adjunctive analgesics, regional blockade,
NSAIDS, clonidine• Postoperatively increase baseline opioids, or
start IV-PCA opioids at 20% or more of usual dose
*Saberski L: Pain management in the dependent patient: In Sinatra etal: Acute Pain:Mechanisms and ManagementMosby-Yearbook, 1994
CYP2D6 Variants: Allele Frequencies & Phenotypic
CYP2D6 activity depends on allele polymorphisms Poor metabolizer ■ Intermediate
metabolizer Extensive metabolizer ■ Ultrarapid metabolizer
Poor CYP2D6 function alleles in 6%-10% Caucasians Poor-absent codeine metabolism to active
metabolite Tramadol O-demethylated metabolite has 200 X
mu- receptor-affinity, 2-4 X potency, & longer half-life
• Tramadol analgesia may be reduced in population with
Løvlie R, et al. Pharmacogenetics. 2001;11:45-55. Sachse C, et al Am J Hum Genet. 1997;60:284-95. Armstrong SC, Cozza KL. Psychosomatics. 2003;44:167-71; 515-20. Laugesen S, et al. Clin Pharmacol Ther. 2005;77:312-23. Ross JR, et al. Pharmacogenetics J. 2005;5:324-36. Susce MT, et al. Prog Neuro-psychopharmacol Biol Psychiatry. 2006;30:1356-8. Minami K, et al. J Pharmacol Sci. 2007;103:253-60.
Treatment Algorithm for Acute
Maintain Baseline Opioids!
Clonidine,Gabapentin,
Cox-2 InhibitorsAcetaminophen,
Anxiolyticsas required
IV-PCA,Epidural PCA, Neural Blockade
Ketamine as required
Recently Available Opioid Formulations
Q24h tramadol ER oral tablet for chronic pain
Q12h oxymorphone IR & ER oral tablet for chronic pain
Effervescent fentanyl buccal tablet for breakthrough pain
Fentanyl iontophoretic transdermal system Patient activated (PCA) dosing for acute pain
Prommer E. Support Care Cancer. 2006;14:109-15.Durfee S. Am J Drug Deliv. 2006;4:1-5.1
Fentanyl Iontophoretic Transdermal System
First needle-free patient-controlled analgesic system Indicated for acute pain management Utilizes iontophoresis to deliver subdermal doses of
fentanyl (40 µg every 10 min) Efficacy & side effects similar to standard IV-PCA Preprogrammed
• May avoid programming & medications errors Small credit card sized, self-contained
• No interference with patient mobility
Viscusi ER, et al. JAMA. 2004;291:1333-41. Sinatra R. Clin Pharmacokinet. 2005;44(suppl1):1-6. Viscusi ER, et al. Anesth Analg. 2006;102:188-94.
Summary Opioid analgesics remain the foundation of acute &
chronic pain management Inter-patient differences in opioid response may be
related to receptor polymorphism, metabolic variability, & incomplete cross tolerance
Transdermal & buccal delivery of opioids offer simplicity, convenience, & rapid analgesic effect
Sustained-release opioids offer advantages effective prolonged & uniform pain relief
Opioid
• Mixed agonist-antagonists– Conventionally defined as mu receptor antagonists and
kappa agonists; Include butorphanol, nalbuphine, pentazocine
– Advantages• Ceiling effect to respiratory depression• Milder withdrawal
– Disadvantages• Precipitate withdrawal if physically dependent
on full agonist opioids• Reverse analgesia of full agonist opioids• Ceiling effect to analgesia• Possible psychotomimetic, dysphorigenic effects
Cherny NI. Drugs. 1996;51:714-37. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 10th ed. 2001.
Opioid Dependence and Pain Relief
• Opioid dependent patients pose special challenges for perioperative pain control.
• Patients on chronic opioid drugs – 1. Legitimate users 2. Patients with substance use
disorders
Opioid Rotation in Outpatients With Chronic Non-Cancer Pain
0
22.5
45.0
67.5
90.0
#1 (n=86) #2 (n=52) #3 (n=30) #4 (n=18) #5 (n=7)
Side effectIneffectiveEffectiveTotally effective
Quang-Cantergrel ND, et al. Anesth Analg. 2000;90:933-7.
Per
cent
of p
atie
nts
Percentage of patients for whom opioid prescription was effective or stopped because ineffective or intolerable side effects
Prescription #