Optimizing Opioids in Pain

Management

Roman D. Jovey, M.D.

Physician Director
Alcohol & Drug Treatment Program
Credit Valley Hospital
Complex Pain Consultant
Mississauga, 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 Synapse
Endorphins Enkephalins
Baclofen
Opioids Clonidine

2-methylserotonin
GABAB µ
§
a2
5-HT3
Nociceptor

Midozalam Citalopram

GABAA 5-HT1B
Dorsal Horn Cell

Brookoff, 2000
Pain and Suffering
The Importance of Genetics
GENETICS Placebo
Effect
N
O COMT
COMT
C Emotions
I P
C A
E Cognition (vigilance)
P MORs
I
T N
I Environment
O
N 2D6
Codeine
SUFFERING
Clinical Significance
of 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?
 Chronic Pain- Treatment Options
PHYSICAL PSYCHOLOGIC PHARMACOLOGIC INTERVENTIONAL
Normal activities Hypnosis OTC medication I.A. steroids
Aquafitness Stress CAM I.A. hyaluronan
Physio Management Topical medicationsTrigger Pt Therapy
 Passive Cognitive- NSAIDs / COXIBs IMS / Prolotherapy
 Active Behavioural DMARDs Nerve Blocks
Stretching Family therapy Immune modulators Botox
Conditioning Psychotherapy Tricyclics / AEDs Epidurals
Weight training Mindfulness- Opioids
Based Stress Orthopedic
Splinting / Taping Local anesthetic
Reduction Neurotomy
TENS congeners
Neurectomy
TMS / TCNS Muscle relaxants
Massage Implantable
Sympathetic agents stimulators
Chiropractic NMDA blockers Implantable pain
Acupuncture CGRP blockers pumps
Dolphin
Future 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
most potent pain reliever
Treating Chronic Pain…
Pharmacotherapy

BENEFIT RISK
 Acetaminophen

 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 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, 1997
25000

20000

15000

10000

5000

0
S s As a
mia
AI
D ID V ol m
a m r vix in s
ke A M th e gk
u NS My
e As C d
Le TOH Ca Ho
E
Singh G. Am J Med 1998
Wolfe M. NEJM, 1999
 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
COXIBs

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 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 Analgesics
Toxicity

 Carbamazepine – liver, hematological

 Valproic Acid – liver, hematological
 Gabapentin – liver
 Tricyclics – cardiac, anticholinergic
 Mexiletine – cardiac, liver, hematological
 Topiramate - kidney stones
Opioids have never been
shown to cause organ
damage when taken
therapeutically.
Opioids are physically the
safest pain reliever
available.
Opioids can cause harm
when they are misused.
Prescription Opioid Abuse
DAWN Data – United States

100000
90000
80000
70000
60000
Opioid Analgesic
50000
Related ED Visits
40000
30000
20000
10000
1996 1997 1998 1999 2000 2001
 New Users of Illicit Drugs
in the Past Year
Pain Meds
3,500,000 THC
3,000,000 Cocaine
Ecstacy
2,500,000
Tranquilizers
2,000,000 Heroin
1,500,000

1,000,000
500,000

0
1965 1970 1975 1980 1985 1990 1995 1999 2000
U.S. National Household Survey on Drug Abuse, 2001
Past Year Abuse or Dependence (DSM IV)
on Alcohol or Illicit Drugs by Age
25

20

15
%
10

0
3
-15
-17
-19
-21
-23
-25
-29
-34
-39
-44
-49
-54
-59
-64

5
--1

>6
14
16
18
20
22
24
26
30
35
40
45
50
55
60
12

Age
U.S. National Household Survey on Drug Abuse, 2001
Prescription Opioid Addiction
Treatment Episode Data System, TEDS

2.50

2.00
Percent of total admissions

1.50

1.00

0.50

0.00
96

97

98

99

00

01
19

19

19

19

20

20
It really comes down to a
question of balance
Appropriate Use vs Abuse:
Maintaining 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
misuse prescribed opioids?
Risk factors for misuse / addiction

 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
Opioidology 101
Optimizing opioid use for pain
When to Consider Opioid Therapy
for Chronic Pain …

Unrelieved pain
+
Decreased QoL
+

Failure of usual treatments

Opioids work best
when dosed to effect
Dosing to effect means…

Reasonable pain relief

or
Unmanageable and persistent
side effects
 Some people respond to a
small dose. Others require a
much higher dose to
adequately treat their pain.
 Each patient responds
uniquely to a given opioid at
a given dose with an
individual side effect
response.
 Opioid 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 does
not cause clinically significant 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
side effects vs. pain relief is to
switch opioids
 Optimizing 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

 Decrease pain
 Improve function
 Minimize adverse effects
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
to time, but most pick themselves up
and hurry off as if nothing happened.”

Winston Churchill