© 2005 Rehabilitation Institute of Chicago Opioid Pharmacology and Management Principles Part I...

© 2005 Rehabilitation Institute of Chicago

Opioid Pharmacology and Management Principles

Part I

Steven Stanos, DO


“Opiate”

“Opioid”

“Narcotic”


Can We Catch the Pendulum?

Avoidance

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

Widespread Use

Prescribing without recognition of dangers

The pendulum rarely stops in the middle

Adapted from Rich A. APS Bulletin. 2005.


Holy Grail ?

• Potent analgesic

• More less potent agents

• Drugs for reduced renal function

• Better formulations

• Less divertible


Products Commonly Prescribed in the US

IMS NPA+, 2006.Number of Prescriptions (in Millions)

0 20 40 60 80 100 120

Tramadol/Combo

Propoxyphene/Combo

Codeine/Combo

Hydrocodone/Combo

Oxycodone/Combo

Oxycodone

Morphine

Hydromorphone

Fentanyl

Atorvastatin

Amoxicillin

Highly PrescribedProducts in US


Current Treatment Armamentarium

4-6 Hour

12 Hour

24 Hour

Do

sin

g In

terv

al

HYM, Morphine,OXYM, PROP,

Tramadol

Non-opioids Combination Opioids Single-Agent Opioids

Class of Therapeutic Agent

Unmet Needs

OXCD CR,Morphine CR,

OXYM ER

Tramadol ERMorphine CR

APAP, Aspirin

Naproxen

Celecoxib

COD/APAP,HC/APAP,

OXCD/APAP,TRAM/APAP


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]


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 R. Anesthesiology. 2006;105;235–237 [Evidence Level C]; 2. Pasternak GW. J Pain Symptom Manage. 2005;29(suppl):S2–S9 [Evidence Level C]; 3. Ross JR, et al. Pharmacogenomics J. 2005;5:324–336. [Evidence Level B]


Le

vel o

f A

cti

vati

on

MOR-1 Variant 1

Drug 1

Drug 2

Receptor

Mu-opioid Receptor Activation and Incomplete Cross Tolerance

Adapted from Pasternak GW. Trends Pharmacol Sci. 2001;22:67-70.

MOR-1 Variant 2

MOR-1 Variant 3

MOR-1 Variant 4

MOR-1 Variant 5

Receptor Variation for Same Patient with Different Drug

55


OpioidsI. Syntheric phenylpiperidines

Meperidine, Fentanyl,

II. Synthetic PseudopiperidinesMethadone, Propoxyphene

III. Naturally Occurring AlkaloidsA. Natural: Heroin, Morphine, CodeineB. Semi-synthetic: Hydromorphone, Oxycodone,

OxymorphoneC. Tramadol


Opioid EffectsGeneral• Analgesia• Altered mood• Decreased anxiety• Respiratory depression• Inhibition central reflexes• (-) GI motility• Cough suppression• (-) CRF, ACH• Miosis• Pruritus, nausea, vomiting

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 end-of- 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

McCarberg BH, Barkin Rl. Amer J Ther. 2001;8:181-186.


Around-the-Clock (ATC) Medication - Treating Persistent Pain*

Therapeutic Window

ATC Medication

Pain ReliefThreshold

Over Medication

*Baseline or persistent pain is controlled by ATC medication.

Persistent PainPersistent Pain

TimeTime


Treating Cancer Pain – Inadequate Management of Breakthrough Pain

Traditional BTP Medications*ATC Medication

Over Medication

*Delayed onset of action, type and dose may not adequately treat a BTP episode.


TimeTime


Treating Cancer Pain – Ideal Management

Ideal Breakthrough Pain Medication* ATC

Medication

Over Medication

*Breakthrough pain treatment has rapid onset and matches the intensity and duration of BTP episode.


TimeTime


Opioid Pharmacokinetics

Opioid Half LifeBioavail-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 Hydromorphone, Norcodeine

Codeine 3–4 60–90 Morphine, Hydrocodeine

Oxycodone 2–6 40–130 Oxymorphone

Hydromorphone

2–4 35–80 None


Propoxyphene (Darvocet)

• With acetaminophen (Darvocet-N100)

• Structurally related to methadone

• Peak plasma concentration 2 h

• Liver metabolism to norproxyphene


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


Hydrophilic• Slower entry into

CNS• Active metabolites

(M3G, M6G)

Morphine-3-glucuronide

• inactive?, CNS excitation

Morphine-6-glucuroide• Active analgesic, 2-100x

more potent (centrally), Induces liver enzymes

Morphine (Gold Standard)

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 OpioidsProduct Dosage Form Strength (mg) Dosing

frequency (h)

Morphine sulfate

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

Oxycodone HCL CR tablets

Oxycontin CR tablets 10,20,40,80,160 12

Oxymorphone HCL

Opana ER tablet 15,10,20,40 12

Amabile C, Bowman B. Ann Pharmacother 2006;40.


Combination Opioids

Agent OnsetDuration of

ActionEquianalgesic

Oral Dose*

DEA Sched

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 mgNot

sched

Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, et al. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw Hill; 2001:569-619.

www.musc.edu/pharmacyservices/medusepol/opiodanalgesicfinal.pdf.

Mild

to

Mo

der

ate

Mo

der

ate

to S

ever

e

Pai

n In

tens

ity

*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


– 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

Hydrocodone/ Oxycodone


Acetaminophen (Tylenol)


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


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.


Breakthrough Pain Medications

Immediate-Release Opioid

Onset of analgesia

(min)Duration of effect

(h)

Morphine 30–40 4

Oxycodone 30 4

Hydromorphone (oral) 30 4

Methadone 10–15 4–6

Fentanyl (transmucosal)

Oxymorphone

5–10

30

1–2

6-9

Bennett D, et al. Pharmacol Ther. 2005;30:296–301. [Evidence Level C]


New Short-Acting Opioids for Breakthrough Pain (BTP)

• Transmucosal fentanyl (Actiq®)

• Fentanyl buccal tablet (Fentora™)

• Oxymorphone (Opana®)

• Tapentadol (Nucynta®)


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 RK, et al. Pain. 1999;79:303-312 [Evidence Level A]; Payne R, et al. J Pain Symptom 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, et al. Drug Delivery Tech. 2001;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

Painful stimulus

Ascending

Descending

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.

Ascending pathwayto the brain

Descending pathwayfrom the brain

Primary afferentSecondary afferent


Drug Mechanism of Action (in vivo): Dual μ-Opioid Receptor Agonist and Norepinephrine

Reuptake Inhibitor1,2

Pain signal

Glut+

SP

Ascending pathwayto the brain

Descending pathwayfrom the brain

NE

2-AR

–

μ-OR

Tapentadol*

+

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.

*The exact mechanism of NUCYNTA™ is unknown.

-

Secondary afferentPrimary afferent

-


Tapentadol and Tramadol: Different Molecular Structures

OH

·HClN

(R)(R)

Tapentadol Tramadol

OH

OCH3

HOH ·HCl

N


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-foldgreater 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.


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


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


Mea

n C

um

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tive

SP

ID S

core

1

The

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SP

ID s

core

,th

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f

Osteoarthritis Hip/Knee Study: Efficacy Results

Placebo

Oxycodone IR 10 mg

Tapentadol IR 75 mg

Tapentadol IR 50 mg

N=659

130.6

229.2236.5

*

0

50

150

250

SPID-5 Days (Primary Endpoint)

100

200

223.8

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.

* † * †


Osteoarthritis Hip/Knee Study: Composite Incidence of Nausea and Vomiting1,2

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.

N=666

8.3%

21.7%

57.0%

29.8%

0

30

50

Composite of Nausea and Vomiting

60

Placebo

Oxycodone IR 10 mg

Tapentadol IR 75 mg

Tapentadol IR 50 mg

20

40

10

Inci

den

ce (

%)

*

*


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]


Once-Daily ULTRAM ER

ULTRAM® ER (tramadol HCl) Extended-Release Tablets Prescribing information.

Mean steady-state tramadol plasma concentrations on day 8 post-dose after administration of ULTRAM ER once-daily and tramadol every 6 hours

ULTRAM ER 200 mg qd

Tramadol 50 mg q6h

0 4 8 12 16 20 240

50

100

150

200

250

300

350

Time (h)

Tra

ma

do

l co

nc

en

trat

ion

(n

g/m

L)

2 6 10 14 18 22


Tramadol HCL ER (Ryzolt)100mg, 200mg, 300mg

OPANAOPANA®® Tablets. Full Prescribing Information. Chadds Ford, PA. Endo Pharmaceuticals. 2006. Tablets. Full Prescribing Information. Chadds Ford, PA. Endo Pharmaceuticals. 2006.

Morphine Sulfate Extended-Release Tablets. Full Prescribing Information. Chadds Ford, PA. Endo Pharmaceuticals. 2004. Morphine Sulfate Extended-Release Tablets. Full Prescribing Information. Chadds Ford, PA. Endo Pharmaceuticals. 2004.

OxymorphoneOxymorphone

HOHOOO

N – CHN – CH33

HOHO

SOSO44

MorphineMorphine

OO

HClHCl

N – CHN – CH33

HOHO

OHOH

OO

Molecular Structures of Morphineand Oxymorphone


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)

L/D = light/darkness ratio; NMDA = N-methyl-D-aspartate.


Methadone Dosing: Gradual ConversionMor-E (mg/d)

Calculate Meth (mg/d)

Initial Meth Dose Increment Example

<200 15 mg 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 ~7% Morph dose

1/3 calculated dose q8h

Add 1/3 dose q5d; ↓ previous opioid q5d

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]

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 EffectsCases

Risk Stratification

American Greetings.

Formulation Strategies Intended to Reduce Abuse

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.

Pharmacologic Approach1,2

Examples include• Addition of antagonist• Prodrug formulation

Physical Approach1,2

Examples include• Advanced dispensing formulations• Tamper-resistant formulations

Aversive Approach1,2

Examples include• Addition of non-treatment-related

ingredients such as niacin or capsaicin

EMBEDA™

2. If EMBEDA™ is crushed, chewed or extracted:

A. the naltrexone (opioid antagonist) releases and mixes with morphine

B. the morphine-naltrexone mixture is intended to prevent euphoria from morphine by competing for the same opioid receptor in the brain…thus deterring abuse of the product

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

How Does the EMBEDA™ Pharmacologic Abuse-deterrent Technology Work?

Naltrexone Core Releases and Mixes

Chewing or Crushing Force

NALTREXONE CORE

MORPHINE SULFATEALO

-01

Opioid Receptor

Naltrexone Morphine

Aversion® Technology

Common Methods of Abuse Aversion Technology

InjectionExtract active ingredients from dissolved tablets or capsules

Gel-Forming Agenta

(polyethylene oxide)makes it difficult to extract active ingredient

Snorting Crushed tablets or capsules

Tissue Irritant (sodium lauryl sulfate)

Oral Ingestion Excessive Quantities

Niacincauses temporary unpleasant effects with ingestion of higher than recommended doses

1. Data on file. King Pharmaceuticals®, Inc.

a Two additional excipients synergize polyethylene oxide

Adverse Effects: Nausea and Vomiting

Chemoreceptor trigger zone (CTZ)

Cortex

Peripheral pathways

Vestibular sensitivity

Copyright restrictions may apply.Wood, G. J. et al. JAMA 2007;298:1196-1207.

Neural Pathways That Mediate Nausea and Vomiting

Common Clinical Scenarios of Nausea/ Vomiting (N/V)

Clinical Mechanisms First-line

Opioid Induced Stim CTZ (D2)

Gastroparesis (D2)

Constipation (H1, Muscarinic)

Sensitization Ear (H1, Muscarinic)

Metoclopramide

Prochlorperazine

Impaired Motility Gastroparesis (D2) Metoclopramide

Radiation Associated

N / V

Stimulation peripheral pathways via 5HT3

5HT3 Antagonists

Motion Associated Stimulation via vestibulocohclear nerve (Muscarinic acetylcholine )

Scopolamine

Diphenhydramine

Promethazine

Wood, G. J. et al. JAMA 2007;298:1196-1207.

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 IVSwegle 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 promoted wakefulness without widespread CNS stimulation• PROVIGIL is thought to work selectively in areas of the brain believed

to regulate normal wakefulness

H = hypothalamusCA = caudate

PROVIGIL MethylphenidateAmphetamine

Lin JS, et al. Proc Natl Acad Sci USA. 1996;93:14128 14133.

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

Prolactin

Testosterone Estradiol, Progesterone

INHIBITED

Pulsitile GnRH

LH

FSH

Christo PJ. Anesthes Clin N Am. 2003;21:699-713.

Hypogonadism: (OPIAD)

Sexual dysfunction, infertility

Depression

Decreased energy level

Muscle wasting and osteoporosis

Lowered pain threshold

Impaired wound healing

“Opioid Induced Androgen Deficiency” (OPIAD)

Lab

Free testosterone (FT)

Total testosterone (TT)

Luetinizing hormone (LH)

Follicle-stimulating (FSH)

Estradiol (E2)

Prostate specific antigen (PSA)

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

Propoxyphene abuse3

1.Oh AK. et al. Neurology 2000;54:2345.

2. Ho et al. Pain Physician 2007;10:467-72.

3. Harell M. et al. Laryngoscope 1978;88:1518-21.

Waldhoer M, et al. Annu Rev Biochem. 2004;73:953-990.

Opioid Receptor Structure

INHIBITORY

ECITATORY

Gi / Go

Gs


Opioid-Induced Abnormal Pain Sensitivity

• Desensitization process leading to opioid tolerance

• Sensitization (pronociceptive) process leading to opioid-induced pain sensitivity

Increased spinal dynorphinIncreased spinal dynorphinDescending facilitationDescending facilitationGlutamatergic systemGlutamatergic system


OPIOID

PRONOCICEPTIVE

DESENSITIZATION (TOLERANCE)

SENSITIZATION(INCREASED PAIN?)


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


“Men in general are quick to believe that with which they wish

to be true.”

- Julius Caesar


TOLERANCE

and

DEPENDENCE

= ADDICTIONX


Volkow ND. In: Madras et al. eds. Cell Biology of Addiction, 2006.


Inadequate Pain ManagementInadequate Pain Management

ANGERANGER FRUSTRATIONFRUSTRATION

ISOLATIONISOLATION AVOIDANCEAVOIDANCE

CRISISCRISIS

PATIENTPATIENT TEAMTEAM

Weissman,Haddox, Pain (1989)Weissman,Haddox, Pain (1989)

“Pseudoaddiction”


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.


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. 863-903.


Predicting opioid misuse at 1 year

Misuse (32%)• Predictors

cocaine abuseDUI convictionmalecannabinoids

“Opioid misuse”

• (-) tox screen• (+) for other• Multiple providers• Diversion• Forgery• Stimulant use

Ives TJ, et al. BMC Health Ser Res 2006;6:46.


• 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

• 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 Controlled Substances for the Treatment of Pain. May 2004.

None of these are absolute

contraindications and lack predictive validity at this point

Patients Who May Not Benefit From Opioid Therapy


A Chronic Pain Patient vsan 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


Total Pain Population

Aberrant Behavior: 40%

Abuse: 20%

Addiction: 2%–5%

Aberrant Behavior vs Abuse

Webster LR, Webster RM. Pain Med. 2005;6:432–442;

Webster LR, et al. 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 Opioid Pharmacology and Management Principles Part I...

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