Daniel S. Sitar, BScPharm, PhD, FCP
Email: [email protected]
Professor Emeritus University of Manitoba
Editor: Journal of Clinical Pharmacology
March 8, 2011
DEFINITIONS
 Pain: The unpleasant sensory and emotional
experience associated with a noxious event,
including, tissue damage or inflammation
 Nociception: The process of encoding and sensing
tissue injury and inflammation
Significant developmental/maturational changes
 Analgesia: Relief of the perception of pain
Accompanying sedation unintended
ANATOMY/PHYSIOLOGY

Pain Initiation: Pain fiber stimulation in response to
tissue injury
Bradykinin, serotonin, substance P, prostaglandins, histamine

Pain Propagation: Transmission of signal from nerve
endings to spinal cord
A-δ and C-fibers
 Pain Integration: Modulation (amplification/inhibition)
of pain signal
In spinal cord and cortex
THE GOLD STANDARD OF PAIN ASSESSMENT
IS SELF REPORT - BUT HARDLY FEASIBLE IN
COGNITIVELY IMPAIRED PERSONS
INADEQUATE PAIN MANAGEMENT
– PHYSICAL MANIFESTATIONS
 Best studied in preterm infants
 Sleep disturbances
 Feeding difficulties
 Intraventricular hemorrhage
 Chronic pain syndromes

Altered pain thresholds/hyperalgesia
ASSESSMENT OF PAIN
Can caregivers or relatives rate pain in nursing home
residents?
“Proxy report of caregivers and relatives on presence
and intensity of pain is unreliable, especially for
cognitively impaired persons.”
J Clin Nurs 2009;18(17): 2478-85
PAIN MANAGEMENT STRATEGIES
DRUG MANAGEMENT OF PAIN
World Health Organization
Three-Step Analgesic Ladder
Figure 1: Percentage of Seniors Who Reported Having 1 or More of 11 Chronic
Conditions, for Canada and by Province (Age–Sex Standardized)
76%
Canada
79%
Y.T.
N.W.T.
P.E.I.
Nun.
85%*
N.L.
75%
B.C.
82%*
Alta.
76%
74%
70%
Sask. Man.
75%
Que.
Ont.
N.B.
81%
N.S.
81%
Canadian Survey of Experiences With Primary Health Care, 2008, Statistics Canada;
Canadian Institute for Health Information. –from Jan 2011 CIHI Report
SENIOR CITIZENS STATISTICS
 Manitobans with one or more chronic conditions:
70 % (76 % for Canada)
 For all of Canada:
Chronic pain prevalence 17 %
Arthritis – 1.2 million Canadians
(second most common chronic condition)
 3+ Chronic conditions 24 %
 1-2 chronic conditions 50 %
Canadian Survey of Experiences With Primary Health Care, 2008, Statistics Canada;
Canadian Institute for Health Information –from Jan 2011 CIHI Report
NUMBER OF DRUGS
J Am Geriatr Soc 1988;36:1092-8
Choices for Analgesia
• Nonopioid
• Opioid
• Co-analgesics
OTC ANALGESICS - CANADA
 Acetylsalicylic acid (ASA)
 Acetaminophen (Paracetamol – UK)
 Ibuprofen
 Naproxen
 Combination products with codeine phosphate
– up to 8 mg/tablet - Not recommended
Biopharm Drug Disposit 1986;7:21-5
Acetaminophen is not an NSAID
PHARMACOLOGY OF ACETAMINOPHEN
• Rapidly and completely absorbed
• Peak plasma concentrations in 30 to 60 minutes
• Half-life of 2 hours in adults
PHARMACOKINETICS OF
ACETAMINOPHEN - I.V.
Fit young
Fit elders
Mean age 25 years
73
Frail
elders
82
Liver
volume
Half life
1124 ml
1091
843
123 min
144
226
Clearance 4.7 ml/min/kg 3.7
2.5
RATIONAL NONOPIOID ANALGESIC
COMBINATIONS
 ASA + Acetaminophen
 ASA + Caffeine
 Acetaminophen + Caffeine
 ASA + Acetaminophen + Caffeine
DRUG USE PRINCIPLE
 Don’t mix NSAIDs
Increased cardiovascular risk
Illogical therapeutic approach due to same mechanism of
action
PROBLEMS WITH NONOPIOID DRUGS
FOR PAIN MANAGEMENT
 Cardiovascular – NSAIDS
 Bleeding – NSAIDS
 Hypertension – NSAIDS
 Hepatotoxicity – mostly with acetaminophen
 Kidney toxicity – both NSAIDs and acetaminophen
 Brain toxicity – mostly with NSAIDs
CODEINE
FOR
ANALGESIA
CYP2D6 AND ETHNICITY
Population
% Poor Metabolizers
Caucasian
Canadian Native Indian
Inuit
Chinese
African
Int J Clin Pharmacol Ther 2000;38:61
5 - 10
1.1
3.3
1
0 - 20
DRUG SUBSTRATES FOR CYP2D6
•
Cardiovascular
• Propafenone
• Flecainide
• Mexiletine
• Metoprolol
• Propranolol
• Timolol
Pediatrics 1999;104:640
•
CNS active
• Amitriptyline
• Nortriptyline
• Imipramine
• Desipramine
• Fluoxetine
• Paroxetine
• Codeine
• Haloperidol
ANTIDEPRESSANTS AND
POLYPHARMACY
Setting
Patients
Only drug
28%
And 1+
other
drugs
72%
And 3+
other
drugs
34%
Primary
care
2045
Psychiatric 224
clinic
VAMC
1076
29%
71%
30%
7%
93%
68%
J Pract Psychiatry Behav Hlth 1998:37-40
ISSUES WITH OPIOID ANALGESICS
 Respiratory Depression
 Constipation
 Bladder Evacuation Difficulties
ADVERSE PERSON EVENTS
AFTER CODEINE
• Consistent with literature on lack of analgesic
effect of codeine in persons lacking CYP2D6
• Same incidence of adverse events regardless of
analgesic efficacy (sedation, dizziness etc. but
not nausea)
• Beware: large placebo response in effectiveness
of analgesics
ANALGESICS EFFICACY
TYLENOL® WITH CODEINE ORDERS
• One tablet “T3” equals 2 tablets of plain
acetaminophen
• Tylenol #1® has an ineffective dose of codeine
• Analgesic range should be allowed:
e.g. 2 tablets Tylenol #2 or #3® QID
as a regular dose
March 9, 2011
TYLENOL ORDERS
Tylenol #3 1-2 tabs OH4 prn
March 9, 2011
CONCLUSIONS
• Acute and chronic pain are very prevalent and an
important issue for person satisfaction
• Simple analgesics are among the most
frequently used medications
• Clinicians need to carefully monitor analgesic
use (and abuse) and optimize regimens using
pharmacologic principles