Opioid Analgesics: Pharmacology and Methods of · PDF fileRaymond S. Sinatra MD, Ph.D...

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 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








0

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45.0

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90.0

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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

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







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


0

22.5

45.0

67.5

90.0

#1 (n=86) #2 (n=52) #3 (n=30) #4 (n=18) #5 (n=7)



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cent

of p

atie

nts


Prescription #

Opioid Analgesics: Pharmacology and Methods of · PDF fileRaymond S. Sinatra MD, Ph.D...

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