Pain ManagementDrug Therapy
Presented by Robert A. Ancker, MD
Medical Director, Hospice of North Idaho
Module Objectives
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Review the role of acetaminophen and
NSAIDS in pain management
Learn the difference between Psychological
vs. Physiological Dependence
Learn the key pharmacological principles of
opioid analgesics and proper usage
Learn the key opioid side effects
Learn the indications and use of Relistor ® for
Opioid Induced Constipation
Pain Assessment
1. Basic History
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–
–
–
When did it start?
Where is it?
What is the pain intensity? 0-10 scale
What does it feel like? (quality)
•
•
•
–
Somatic – localized, achy, dull
Visceral – colicky, pressure, referred, diffuse
Neuropathic – burn, numb, radiate, hyperalgesia
What makes the pain better or worse?
2. Analgesic History—Medications
3. Analgesic History: Non-Pharmacological
4. Impact and Meaning of Pain
5. Pain Causality and Patient Goals
Visual Analog Scale (VAS)
Psychological vs. Physiological
Dependence
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Psychological Dependence (Addiction)
– Compulsive use of drugs
– Loss of control
– Use in spite of harm
– Occurs in only ~0.1% of chronic opioid patients
– Drug seeking behavior: missed appointments, off-hours calls
for renewals, multiple physicians
Physiological Dependence (Tolerance)
– Physical withdrawal Sx on abrupt discontinuation
– Expect after 1 month of opioid use
– Long term use results in tolerance & thus increased doses
(NORMAL)
– Usually does not occur during acute pain management
– Risk of MD directed addiction is NOT a concern in treating
cancer pain
Tolerance and Dependence

Tolerance is not an inevitable
consequence of chronic opioids therapy– RARE in cancer patients
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– Increased dose correlates with
disease progression
Physical dependence is expected with
chronic therapy
Do not confuse physical dependence
with ADDICTION (psychological
dependence)
*Drayer et al. J Pain Symptom Manage 1999;17:434-40
Beware of the Pseudoaddict!!
Pseudoaddiction is ..
 The behavioral manifestations of
addiction that occur as a result of under
treated pain
–
–
–
–
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Moaning/crying when you enter the room
Clock watching
Frequent requests for more medication
Pain that seems “excessive” for the stimulus
Patient has no other history to suggest
addiction
– Behaviors cease with adequate pain treatment
Pseudoaddiction
May occur in the hospitalized patient, in pain,
who has opioids ordered:
– At inadequate potency or dose
– At excessive dosing intervals
– And when the behavior is reinforced by MD or RN
behavior that tends to limit opioid use:
“you really shouldn’t be having this much pain”
“you have to wait another two hours for your next dose of
medication”
Checkpoint
Pain Type:
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Somatic – localized, achy, dull
Visceral – colicky, pressure, referred,
diffuse
Neuropathic – burn, numb, radiate,
hyperalgesia
Classes of Analgesics
Non-opioids (NSAIDS, acetaminophen,
aspirin, tramadol)
 Opioids (morphine is the prototype)
 Adjuvant Analgesics (antidepressants,
anticonvulsants, steroids, others)

Analgesics for Mild Pain
Acetaminophen
 NSAIDS/Aspirin
 Tramadol

Acetaminophen
Why is Tylenol,
the pain reliever
recommended
by most doctors?

Doesn’t affect stomach,
kidney, platelets
– But, it has no
inflammatory mediators
– But, it has a ceiling
dose: 4 Grams/24
hours
– AND, is hepatotoxic in
overdose
Checkpoint
What is the dose of acetaminophen
(APAP) in the following preparations:
– Lorcet Plus ® = 650 mg APAP
– Vicodin ES ® = 750 mg APAP
– Ultracet ®
= 325 mg APAP
– Norco ®
= 325 mg APAP
Acetaminophen toxicity
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Acetaminophen overdose is one the most
common causes of OTC drug poisoning in
the United States.
More than 78,000 ER cases w/ 33,000
hospital admits per year of acetaminophen
overdoses per report by the Consumer
Products Safety Commission
About 300 deaths per year
50/50 accidental to intentional
Leading cause of drug-induced liver failure in
the United States (Bartlett D 2004).
Bartlett D. Acetaminophen toxicity. J Emerg Nurs. 2004 Jun;30(3):281–3.
NSAIDs
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Effective for relief of mild pain & have
opioid dose-sparing effect
Pain relief via their anti-inflammatory effect by
inhibiting prostaglandins, thus are very
effective in relieving pain from bone mets.
Dosage: use patient response to determine
effective dose
If max. dose achieved w/o pain relief try
another drug from this same category
Route of Admin.: Use oral route; some
suppositories available; Toradol via IM or IV
NSAIDs - toxicity
Has significant end organ toxicity
– Should be used with great caution in
the elderly
– ~16,500 deaths, ~100,000 hospitalizations
annually due to adverse effects from NSAIDS
– ~3500 deaths from GI bleed

Note! No NSAID has greater analgesic
efficacy compared to any other NSAID
– However, patients may report greater effect from
a particular preparation
NSAIDs - toxicity
Gastropathy
 Renal insufficiency
 Decreased platelet aggregation
 Hypersensitivity
 Hepatitis with some
 2nd Generation NSAID’s reported to
have less GI toxicity

– Maybe??
– Vioxx® fiasco……
Tramadol (Ultram ®)

A synthetic non-opioid(?) analog of codeine
– mu-receptor agonist
– Weak inhibitor of serotonin, norepinephrine reuptake
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Analgesic effect roughly equivalent to
Tylenol #3 ®
– Efficacy variable; has an analgesic ceiling
No anti-inflammatory effects
Side effects similar to opioids at high dose-nausea,
confusion, dizziness, constipation
Seizure risk
Dependence may occur
Not currently on a DEA schedule!
PDR.net. 2003: Ultram® (tramadol hydrochloride).
Cherny NI. Opioid analgesics. Comparative features and prescribing guidelines. Drugs.
1996;51:714-37.
Opioid Pharmacology

Opioid refers to
– Alkaloids derived from opium
– Natural and synthetic agents whose actions are
mediated by selectively binding to opioid receptors
in the brain/spinal cord and perhaps via peripheral
opioid receptors

Receptor types include mu, delta, & kappa
– Further divided into receptor subtypes, eg: mu1 &
mu2
– The mu receptor is the dominant analgesic
receptor, but other receptors play a role in
analgesia for certain opioids
– There is no dose ceiling for pure agonists opioids,
only for acetaminophen in combination products
Cherny NI. Drugs. 1996; 51:714-37.
Responses Mediated by
Opioid Receptors
Receptor
mu
Response on activation
Analgesia, respiratory depression,
miosis, euphoria, reduced GI motility
delta
Analgesia
kappa
Analgesia, dysphoria,
psychotomimetic effects, miosis,
respiratory depression
Adapted from: Cherny NI. Drugs. 1996; 51:714-37.
Mu Receptor Activation of Opioids
morphine
mu receptor site
FULL AGONIST activation of
mu receptor
Stadol ®
mu receptor site
PARTIAL AGONIST activation of
mu receptor
naloxone
mu receptor site
ANTAGONIST - Prevents or reverses
activation of mu receptor
Zuurmond WW, et al. Acta Anaesth Belg. 2002;53:196-201.
Cherny NI. Drugs. 1996; 51:714-37.
Walsh SL, et al. Clin Pharmacol Ther. 1994;55:569-80.
Mixed Agonist-Antagonists
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Claim to have less respiratory depressant
effects—not substantiated
Claim to be less addicting—not substantiated
Will potentiate withdrawal in patients being
treated with pure agonists
– NEVER administer to a patient on a pure
agonist
Have an analgesic ceiling
Are psychotomimetic – can cause psychoses
No real indication in end of life patients
Opioid pharmacology

Cmax after
– PO
 1 hr
– SC, IM  30 min
– IV
 6 min

Half-life at steady-state
– PO/PR/SC/IM/IV  3-4 hrs
. . . Opioid pharmacology
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Steady state after 4-5 half-lives
– Steady state after 1 day (24 hours)
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Duration of effect of “immediaterelease” formulations (except
methadone)
– 3-5 hours PO/PR
– Shorter with parenteral bolus
Plasma Concentration
IV
SC / IM
Cmax
0
po / pr
Half-life (t1/2)
Time
OPIOIDS—Duration of Action
A. Ultra short
B. Short
C. Long
A. Ultra Short Acting Opioid

Fentanyl
– IV has 50-100 x potency of morphine
– transdermal
– Transmucosal
 Good
role in Renal and/or Liver failure
patients
B. Short Acting Opioids
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Parenteral or Oral

– morphine
– hydromorphone
(Dilaudid ®)
– meperidine (Demerol ®)
– codeine
Oral only
– oxycodone (Percocet ®,
Tylox ® , OxyIR)
– hydrocodone (Vicodin ®
Lortab ®, Norco ®)
– propoxyphene (Darvon
®, Wygesic ®)
– Note: hydrocodone is
only available as a
combination product.
B. Short Acting Opioids
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Oral dosing:
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onset in 20-30 min
peak effect in 60-90 minutes
duration of effect 2-4 hours
Can be dose escalated or re-administered
every 2-4 hours for poorly controlled pain
as long as the daily Acetaminophen dose
stays < 4 grams
Opioid Combination Products
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Opioids available as combination
products with acetaminophen or aspirin
• Codeine; hydrocodone; oxycodone;
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Typically used for
• Moderate episodic (PRN) pain
– UOOB, BSC, ROM
– May not need any med OR need PRE-MED
• Breakthrough pain in addition to a long-acting
opioid – KEEP TRACK

Never prescribe more than one
combination drug at any one time
How to Choose a Combination
Product (cont)
Toxicity:
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–
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All the combination products can cause
opioid toxicities: nausea, sedation,
constipation, etc.
There is little published data that
supports the use of one product over
another in terms of toxicity; however …
codeine is probably the most emetogenic
opioid
Meperidine
Shortest acting (only 2-3 hr duration)
 Weak potency;

– 300 mg po = 30 mg po morphine

Converted to a long acting toxic
metabolite--a CNS stimulant
– Tremor, myoclonus and seizure
– Risk highest with prolonged use and
renal insufficiency
C. Long Acting Opioids
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Oral
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–
–
–
MS Contin®
Oramorph SR®
Oxycontin®
methadone

Transdermal
– Fentanyl Patch
(Duragesic®)
MS Contin® / Oxycontin®
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No clear benefit of one product over another
– MS Contin contains morphine
– Oxycontin contains oxycodone
– No difference in toxicity; No difference in
addiction potential
All must be taken intact—they cannot be
crushed; they do not fit down GI tubes.
– Exception: Kadian ®
All provide 8-12 hours of analgesia
– Minimum dosing interval is q 8 hours
– All provide onset of analgesia within 2 hours
– All can be dose escalated every 24 hours
Transdermal Fentanyl
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Slow onset of action: 13-24 hours
– Duration of action: 48-72 hours
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Should only dose escalate q 3 days
– Fentanyl stays in circulation for up to 24
hours after patch removal
Place on hairless, non-irradiated skin
 No ceiling dose
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Conversions from/to Transdermal
Fentanyl (Duragesic®)
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When converting fentanyl patches, published
data suggest that a 25 mg patch is equivalent to
45-135 mg of oral morphine/24h.
However, clinical experience suggests that most
patients will use the lower end of the range of
morphine doses (i.e., for most patients 25 mcg is
≈ 50 mg of oral morphine/24h).
THUS, 24 hour total dose of oral morphine,
divided by 2 = dose in micrograms of
transdermal fentanyl;
Conversions from/to Transdermal
Fentanyl (Duragesic®)

Example:
• MS Contin® 30 mg q 12 = 60 mg MS/24
hours
• 60 divided by 2 = 30; rounded to one 25 ug
Fentanyl Patch

Example:
• Duragesic 50 mcg/hr = ~100 mg oral
morphine per day
Breakthrough Pain
Patients on any long-acting med always
need a second, short-acting med,
available for breakthrough pain
 Take at least every 4 hours, preferably
less
 Guideline, dose of breakthrough opioid
should be:

10-20% of 24 hour dose of analgesics
and made available q. 1-4 hours
Methadone
Complex pharmacology
 Duration of action increases with
prolonged use from 4 hours to as much
as 12 hours
 Dose conversions to:from other opioids
are complex—seek consultation
 Least expensive potent opioid
 Does not need special DEA license to
use for pain; special license only
needed if used as treat for substance
abuse (methadone maintenance clinic)

Opioid Dose Escalation
Always increase by a percentage of the present dose
based upon patient’s pain rating and current
assessment
50-100% increase
25-50% increase
25% increase
Mild pain
1-3/10
Moderate pain
4-6/10
Severe pain
7-10/10
Frequency of dose escalation

The frequency of dose escalation (oral
opioids) depends on the particular
opioid
– Short acting oral: q 2-4
– Long acting oral, except methadone: q 24
hours
– Methadone: q 4-6 DAYS
– Transdermal fentanyl: q 72 hours
Parenteral Opioids

IV is the route of choice if
access is available
– There is no indication for IM opioids
– All standard opioids can be given SQ, by either
bolus dose or by continuous infusion

Can use a SQ button
– Change 2x/week
– Limit 3ml/hr

PCA (basal rate plus a patient initiated dose)
is an effective and well accepted modality;
either IV or SQ
Parenteral Opioids
IV or SQ bolus doses have a shorter
duration of action that oral doses;
typically 1-3 hours
 The peak effect from an IV bolus dose
is 5-15 minutes
 Dose escalation of parenteral opioids is
the same as with oral—always by a
percentage of the starting dose

Analgesic drug concentration
Theoretical Relation Between Analgesic
Drug Level, Dosing Interval, and Clinical
Response
IM
PCA
Sedation
Dose
Analgesia
Minimum
analgesic
concentration
Dose
Dose
6
8
Dose
10
12
Time (hours)
IM=intramuscular; PCA=patient controlled analgesia
Ferrante FM, et al. Anesth Analg. 1988;67:457-61.
Pain
14
Equianalgesia
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Since all potent opioids produce analgesia by
the same pharmacological mechanism, they
will produce the same degree of analgesia if
provided in equianalgesic doses.
Thus, there is little basis to say, “morphine did
not work, but hydromorphone did work”.
Such a statement generally means that nonequianalgesic doses were used.
There is no dose ceiling.
The word “potent” is irrelevant!
Non-opioids are not included when
performing equianalgesic calculations.
Equianalgesia
Common Conversions
 10 po MS = 3.3 mg IV MS (3:1)
 5 mg po Dilaudid = 1 mg IV Dilaudid (5:1)
 10 mg po MS = 2.5 mg po Dilaudid® (4:1)
 10 mg po MS = 10 mg po oxycodone **
 10 mg po MS = 10 mg po hydrocodone (!)
Note: Conversions factors are only a rough
guide to approximate the correct dose.
** Controversial: some recommend 3:2 or 1.5:1
ratios for MS: oxycodone
Incomplete Cross-tolerance
If a switch is being made from one opioid
to another because of tolerance,
it is recommended to start the new opioid
at 50% of the equianalgesic dose
Opioids Side Effects
Sedation, confusion, respiratory
depression
 Dizziness, dysphoria
 Nausea
 Constipation
 Itching, uticaria, bronchospasm

– NOT AN ALLERGY!!!
Urinary retention
 Opioid hyperexcitability syndrome

– Hyperesthesia, myoclonus, seizure
Sedation / Respiratory
Depression

With increasing dose, all opioids lead
to a predictable sequence of CNS
events:
– Sedation with or without delirium then
• Further decrease consciousness then
– Coma and respiratory depression
Respiratory Depression

Risk Factors
– Renal insufficiency
– Liver failure
– Parenteral opioids; especially rapid dose
escalation in opioid naïve patients
– Severe pulmonary disease (CO2 retainers)
– Sleep apnea
– Rapid dose escalation of transdermal
fentanyl or methadone
Naloxone (Narcan®)

In palliative care, Narcan is only indicated
when:
– **The goals of care are such that reversing CNS
depression is indicated**
• ?? Intentional/accidental overdose
– And patients have decreased level of
consciousness and decreased respirations
– Administer Narcan
• 1 amp (0.4 mg) diluted in 9 ml saline
• 1 ml per minute until level of consciousness improves
– CAUTION: may propagate a severe pain crisis!
Nausea and Vomiting

Caused by stimulation of the CTZ
(chemoreceptor trigger zone) at base of
4th ventricle.
– Nausea is not an allergy!!
Morphine and codeine are the most
emetogenic opioids
 Tolerance develops within 3-7 days for
most patients
 Standard anti-emetics can reduce
symptoms

Itching and Urticaria
Tolerance may or may not develop.
 Not life threatening

– not anaphylaxis, NOT AN ALLERGY!
– does not mean that opioids can never be
used

Drug treatment of symptoms is not very
effective (anti-histamines, steroids)
– Trial of different opioids indicated as some
patients will itch with one product but not
another
Constipation
Multi-factorial cause
 Tolerance does not develop
 Start a bowel stimulant at the time
opioids are started

– Senna or MOM good first choices
Goal is one BM qod, or what is
“normal” for the patient
 Relistor SQ

Methylnaltrexone
Bromide
Relistor
®
12mg/0.6ml solution for SQ
injection
Etiology of Opioid-Induced
Constipation (OIC)
 Opioids:
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suppress forward peristalsis
raise sphincter tone
increase fluid absorption
reduce intestinal secretions
Largely mediated by peripheral mu
()-opioid receptors:
 on myenteric and submucosal
neurons in the gut
Gutstein HB, Akil H. Opioid Analgesics. Goodman and Gillman’s: The Pharmacological Basis of
Therapeutics. 11th ed. New York: NY: McGraw-Hill; 2006. Schumacher MA, Basbaum AI, Way WL.
Opioid analgesics & antagonists. Basic and Clinical Pharmacology. 10th ed. New York, NY: Lange
Medical Books/McGraw-Hill; 2007.
Methylnaltrexone:

Acts peripherally to directly counteract the
constipating effects of opioid analgesics in patients
receiving palliative care who are not sufficiently
responsive to laxatives1,2
– Brings prompt relief from OIC within 4 hrs1
– Reduces the need for enemas3
– Is generally well tolerated with most treatmentemergent adverse events rated as mild or
moderate in severity1
1.
2.
3.
Thomas J et al. NEJM 2008;358:2332-43
Holzer Expert Opinion Investig Drugs 2007; 16(2): 181-194
Wyeth Data on File MNTX02/2008
Dosing Schedule
The recommended dose of Methylnaltrexone bromide is:
• 8 mg (for patients weighing 38-61 kg)
• 12 mg (for patients weighing 62-114 kg)
• Patients whose weight falls outside of the range should be dosed at
0.15mg/kg
• The injection volume for these patients should be calculated:
Dose (ml) = patient weight (kg) x 0.0075

Methylnaltrexone should be added to induce prompt bowel movement
when response to laxative therapy has been insufficient
 The usual administration schedule is one single dose every other day.
Doses may also be given with longer intervals, as per clinical need.
 Patients may receive two consecutive doses 24 hours apart, when
there has been no response (bowel movement) to the dose on the
preceding day
 Local clinical guidelines may be taken into consideration
Methylnaltrexone SmPC July 2008, Wyeth Pharmaceuticals
Final comments……
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BELIEVE THE PATIENT’S PAIN
COMPLAINTS & ESTABLISH
REALISTIC PAIN RELIEF GOALS
TITRATE OPIOIDS TO PAIN RELIEF
PROGRESSION OF THE DISEASE, NOT
TOLERANCE, IS THE USUAL CAUSE
FOR DOSE INCREASES
CONSIDER PALLIATIVE CARE
CONSULT FOR PAIN SYMPTOMS