Daniel S. Sitar, BScPharm, PhD, FCP

Email: sitar@cc.umanitoba.ca

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 signalIn 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)

N.W.T.Y.T.

Nun.

B.C.Alta.

Sask. Man.

Ont.

Que.

N.B.N.S.

N.L.

P.E.I.

Canada

75% 82%*

76% 70%

75%

81%

79%

85%*

81%

76%

74%

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 Frail

elders

Mean age 25 years 73 82

Liver

volume

1124 ml 1091 843

Half life 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 5 - 10

Canadian Native Indian 1.1

Inuit 3.3

Chinese 1

African 0 - 20

Int J Clin Pharmacol Ther 2000;38:61

DRUG SUBSTRATES FOR CYP2D6

• Cardiovascular

• Propafenone

• Flecainide

• Mexiletine

• Metoprolol

• Propranolol

• Timolol

• CNS active

• Amitriptyline

• Nortriptyline

• Imipramine

• Desipramine

• Fluoxetine

• Paroxetine

• Codeine

• Haloperidol

Pediatrics 1999;104:640

ANTIDEPRESSANTS AND POLYPHARMACY

Setting Patients Only drug And 1+ other drugs

And 3+ other drugs

Primary care

2045 28% 72% 34%

Psychiatric clinic

224 29% 71% 30%

VAMC 1076 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

March 9, 2011

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

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