Optimizing Opioids in Pain Optimizing Opioids in Pain ManagementManagement

Roman D. Jovey, M.D.Physician Director

Alcohol & Drug Treatment ProgramCredit Valley Hospital

Complex Pain ConsultantMississauga, Ontario, Canada

April 1, 2003

An 89-year-old man who smothered his 85-year-old wife in her nursing home bed to end her pain will face murder charges, U.S. prosecutors said yesterday.

Morris Meyer, who uses a wheelchair, told police his wife had begged him to help her die, so he made his way to her bed and held a pillow over her face.

The Dorsal Horn SynapseThe Dorsal Horn Synapse

BaclofenBaclofenEndorphinsEndorphins

OpioidsOpioidsEnkephalinsEnkephalins

ClonidineClonidine

2-methylserotonin2-methylserotonin

GABAB µ§

a2

5-HT3Nociceptor

MidozalamMidozalam CitalopramCitalopram

5-HT1BDorsal Horn Cell

GABAA

Brookoff, 2000Brookoff, 2000

Pain and SufferingPain and Suffering The Importance of Genetics The Importance of Genetics

Environment

SUFFERINGSUFFERING

PP

AA

II

NN

NNOOCCIICCEEPPTTIIOONN

Emotions

Cognition (vigilance)

GENETICS

COMTCOMT

MORs

Codeine

Placebo Effect

2D6

Clinical Significance Clinical Significance of the Basic Science of Painof the Basic Science of Pain

Not all pains are the same Not all patients have the same pain sensitivities Not all patients have the same pain relief from

opioids Not all patients have the same side effects of

opioids Not all opioids are the same

Not all opioid receptors are the same Not all mu opioid receptors are the same

Pasternak, 2001

Why use opioids at all?Why use opioids at all?

Chronic Pain- Chronic Pain- Treatment OptionsTreatment Options

PHYSICALPHYSICAL PSYCHOLOGICPSYCHOLOGIC PHARMACOLOGICPHARMACOLOGIC INTERVENTIONALINTERVENTIONAL

Normal activitiesAquafitnessPhysio Passive ActiveStretchingConditioningWeight trainingSplinting / TapingTENSTMS / TCNSMassageChiropracticAcupunctureDolphin

HypnosisStress ManagementCognitive-BehaviouralFamily therapyPsychotherapyMindfulness- Based Stress Reduction

OTC medicationCAMTopical medicationsNSAIDs / COXIBsDMARDsImmune modulatorsTricyclics / AEDs

OpioidsLocal anestheticcongenersMuscle relaxantsSympathetic agentsNMDA blockersCGRP blockers

I.A. steroidsI.A. hyaluronanTrigger Pt TherapyIMS / ProlotherapyNerve BlocksBotoxEpiduralsOrthopedicNeurotomyNeurectomyImplantable stimulatorsImplantable pain pumps

Future PharmacotherapiesFuture Pharmacotherapies

CGRP antagonist NMDA blockers Cannabinoids COX inhibitors Bradykinin antagonists Glutamamte antagonists Substance P and Neurokinin antagonists Tetrodotoxin / Omega conotoxins CCK blockers TRPVR1 agonist

Opioids continue to be our Opioids continue to be our most potent pain relievermost potent pain reliever

Treating Chronic Pain… Treating Chronic Pain… PharmacotherapyPharmacotherapy

BENEFIT RISK

AcetaminophenAcetaminophen

Used for mild-moderate nociceptive pain Good evidence in post-op pain No placebo-controlled evidence in chronic

arthritis pain (Case, 2003)

Acetaminophen – not a benign drugAcetaminophen – not a benign drug

Hepatotoxicity GI bleeding / perforation Chronic renal failure Hypertension

Zimmerman, 1995, 2000; Bromer, 2003; Garcia Rodriguez, 2001; FDA 2004; Health Canada Feb. 2003; Curhan 2002.

U.S. Mortality Data, 1997U.S. Mortality Data, 1997

0

5000

10000

15000

20000

25000

Singh G. Am J Med 1998Wolfe M. NEJM, 1999

If you take an NSAID > 2 mo…If you take an NSAID > 2 mo…

1/5 chance of an endoscopic ulcer 1/70 chance of a symptomatic ulcer 1/150 chance of a bleeding ulcer 1/1200 chance of dying

Henry McQuay 10th World Congress on Pain, 2002

http://www.jr2.ox.ac.uk/bandolier/booth/painpag/nsae/nsae.html

Approximately 1900 Canadians die annually due to NSAID-related adverse effects *

Canadian Arthritis Society

www.arthritis.ca

* more than the total number of deaths due to MVCs, fires and gunshot wounds combined

COXIBsCOXIBs

Concurrent ASA nullifies the GI protective effect

Increased cardiovascular risk (Vioxx)

Howard PA, 2004

Topol E, NEJM 2004

Delayed fracture healing in animals Simon AM. 2002

Gerstenfeld LC, 2004

NSAIDs and COXIBsNSAIDs and COXIBs

10-17% of patients develop increased BP Cheng HF. Hypertension, 2004

Acute and chronic kidney toxicity DeMaria AN. JPSM 2003

Double the risk of hospitalization for CHF Garcia-Rodriguez LA. Epidemiology 2003

Increased miscarriage risk Li DK. BMJ 2003

Adjuvant AnalgesicsAdjuvant AnalgesicsToxicityToxicity

Carbamazepine – liver, hematological Valproic Acid – liver, hematological Gabapentin – liver Tricyclics – cardiac, anticholinergic Mexiletine – cardiac, liver, hematological Topiramate - kidney stones

Opioids have never been Opioids have never been shown to cause organ shown to cause organ damage when taken damage when taken

therapeutically.therapeutically.

Opioids are physically the Opioids are physically the safest pain reliever safest pain reliever

available.available.

Opioids can cause harm Opioids can cause harm when they are misused.when they are misused.

Prescription Opioid AbusePrescription Opioid AbuseDAWN Data – United StatesDAWN Data – United States

10000

20000

30000

40000

50000

60000

70000

80000

90000

100000

1996 1997 1998 1999 2000 2001

Opioid AnalgesicRelated ED Visits

New Users of Illicit Drugs New Users of Illicit Drugs in the Past Year in the Past Year

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

3,000,000

3,500,000

1965 1970 1975 1980 1985 1990 1995 1999 2000

Pain Meds

THC

Cocaine

Ecstacy

Tranquilizers

Heroin

U.S. National Household Survey on Drug Abuse, 2001

Past Year Abuse or Dependence (DSM IV) Past Year Abuse or Dependence (DSM IV) on Alcohol or Illicit Drugs by Age on Alcohol or Illicit Drugs by Age

0

5

10

15

20

25

%

Age

U.S. National Household Survey on Drug Abuse, 2001

Prescription Opioid AddictionPrescription Opioid AddictionTreatment Episode Data System, TEDSTreatment Episode Data System, TEDS

0.00

0.50

1.00

1.50

2.00

2.50

1996

1997

1998

1999

2000

2001

Per

cent

of t

otal

adm

issi

ons

It really comes down to a It really comes down to a question of balancequestion of balance

Appropriate Use vs Abuse:Appropriate Use vs Abuse:Maintaining the BalanceMaintaining the Balance

The FEW who misuse prescribed opioids should not penalize the OVERWHELMING MAJORITY who use opioids appropriately

Treat pain sufferers + minimize drug diversion Assess for risk factors Prescribe carefully Monitor behaviours suggestive of misuse/abuse, or

addiction

Can we predict who will Can we predict who will misuse prescribed opioids?misuse prescribed opioids?

Family history Previous history of alcohol abuse /

addiction Previous history of drug abuse / addiction Serious untreated psychiatric problems Previous criminal behaviour High risk home environment

Risk factors for misuse / addictionRisk factors for misuse / addiction

Opioidology 101Opioidology 101Optimizing opioid use for pain

When to Consider Opioid Therapy When to Consider Opioid Therapy for Chronic Pain …for Chronic Pain …

Failure of usual treatments

Unrelieved pain

+

Decreased QoL+

Opioids work best Opioids work best when dosed to effect when dosed to effect

Dosing to effect means…Dosing to effect means…

Reasonable pain reliefReasonable pain relieforor

Unmanageable Unmanageable andand persistent persistent side effectsside effects

Some people respond to a Some people respond to a small dose. Others require a small dose. Others require a

much higher dose to much higher dose to adequately treat their pain.adequately treat their pain.

Each patient responds Each patient responds uniquely to a given opioid at uniquely to a given opioid at

a given dose with an a given dose with an individual side effect individual side effect

response.response.

Opioid Side EffectsOpioid Side Effects

Nausea/constipation Sedation during titration (driving, work) Pruritis/sweats Dysphoria/psychotomietic effects Dry mouth/urinary retention Hyperalgesia/myoclonus Opioid-induced edema Hormonal effects Reflux symptoms (Immune dysfunction)

Stable dose, titrated, scheduled, LTO Stable dose, titrated, scheduled, LTO does not cause clinically significant does not cause clinically significant cognitive impairment:cognitive impairment:

Hendler N. et al. Amer J Psychiatr 1980 Zacny JP. Exp Clin Psychopharmacol 1995 Vainio A. et al. Lancet 1996 Zacny JP. Addiction 1996 Lorenz J. et. al. Pain 1997 Haythornthwaite JA, et al. JPSM 1998 Sjogren P,et al. Pain; 2000 Galski T, et al. JPSM 2000 Chapman S. Clin J Pain 2002 Sabatowski R. et al. JPSM 2003 Tassain V. et al. Pain; 2003 Fishbain DA. Et al. JPSM 2003

The response to an excess of The response to an excess of side effects vs. pain relief is to side effects vs. pain relief is to

switch opioidsswitch opioids

Optimizing Opioid TherapyOptimizing Opioid Therapy

“In short, we need to move beyond inadequate trials of single

opioids at fixed doses to sequential opioid trials, titration

for individual patients, and management of side effects.”

K. Foley, M.D. NEJM 2003; 348(26):2688-9

Treatment Goals Treatment Goals

Decrease pain

Improve function

Minimize adverse effects

Opioids are not magic !Opioids are not magic !

Not all pains in all patients will respond.

Opioids have side effects - like any other medication

High risk patients on therapeutic opioids can manifest abuse / addiction.

Prescribed opioids can be diverted.

We have a responsibility to society to prescribe and monitor carefully to minimize as much as possible the harm due to misuse and diversion

BUT…

Opioids are our most potent pain reliever

They do not cause organ damage

They are underutilized due to exaggerated fears of addiction

One cannot predict response without a trial of therapy

They work best as part of a multi-modal treatment approach

““Men stumble over the truth from time Men stumble over the truth from time to time, but most pick themselves up to time, but most pick themselves up

and hurry off as if nothing happened.”and hurry off as if nothing happened.”

Winston Churchill Winston Churchill