Transcript Pharmacology and Clinical Use of Opiates

Opioids: Should Tolerance
Affect our Management?
Pamela Pierce Palmer, MD PhD
Medical Director, UCSF Pain Center
Associate Professor, Department of
Anesthesia and Perioperative
Medicine, UCSF
Topics
 Opioids and Pain Pathways
 Clinical Use of Opioids
 Opioid Tolerance Mechanisms
 Managing Your Patients on Opioids
Neuroanatomy of Pain Pathways
Somatosensory
cortex
Limbic forebrain system
Intralaminar thalamic
nucleus
Periaqueductal gray area
Ventroposterolateral
thalamic nucleus
Rostroventral medulla
Descending pathway
Peripheral
nerves
Ascending pathways
Hyman SE, Cassem NH. Pain. In: Scientific American Medicine. Vol XIX. 1996: Chap 11.
Mechanisms of Action of Opioids
Primary
afferent
Presynaptic
terminal
Postsynaptic
neuron
Spinal paintransmission
neuron
Basic and Clinical Pharmacology. 8th ed. 2001.
{
, d, k receptors cause
 gCa++
 Transmitter release
{
 receptors cause
 gK+, IPSP
Peripheral Nerve Terminal
Blood
Vessel
PGE2
NPY
Sympathetic
Terminal
Mast cell
BK
IL
histamine
SP
CGRP
NKA
5-HT
TBX
Nociceptor
Platelets
Peripheral Nerve Terminal
PGE2
+cAMP
EP1
BK
-endorphin,
Mu agonists
+PI, +Ca
BK2
-cAMP,
-Ca
MOR
Nociceptor
“Short-Acting” Opioids
hydrocodone (Vicodin, Lortab, Norco)
propoxyphene (Darvocet)
oxycodone (Percocet)
hydromorphone (Dilaudid)
Roller-coaster plasma levels - leading to
breakthrough pain especially at night
Acetaminophen content - limits usefulness
in severe pain
“Short-Acting” Opioids
 Keep acetaminophen under 4 gms/day
 Vicodin (5/500), Vicodin ES (7.5/750)
 Lortab (5/500, 7.5/500, 10/500)
 Norco (5/325, 7.5/325, 10/325)
 Darvocet (50/325, 100/650)
“Long-Acting” Opioids
 Methadone, levorphanol - long-acting based
on chemical nature of molecules
 MSContin, Oxycontin, Duragesic long-acting based on formulation
 Avoid acetaminophen toxicity and provide
more constant opioid plasma levels
Analgesic Rollercoaster
Methadone
 Half-life: 25-50 hours
 Tablets: 5 and 10 mg, BID-TID dosing
 Warn patients to decrease “effective” dose
after day 2
 NMDA antagonist activity - may be more
effective for neuropathic pain
 Easy to titrate dose
Levorphanol
 Half-life: 12-20 hours
 Tablets: 2mg, TID dosing
 Five-times more potent than morphine
 Not easy to obtain
MSContin
 Tablets are controlled-release: 15, 30, 60,
100 and 200 mg
 Same side-effects as morphine
 Often needs TID dosing instead of BID
 Build-up of M3G and M6G metabolites
OxyContin
 Tablets: 10, 20, 40 and 80 mg
 Oxycodone can result in fewer side-effects
than morphine
 Approximately 5-10% of patients have
stimulant effects with OxyContin
 Often needs TID dosing instead of BID
Duragesic Patch
 Transdermal preparation of fentanyl:
25, 50, 75, and 100 mcg/hr
 Onset of action occurs over 12 hours
 Steady-state dosing over 48-72 hours
 After patch removal, 50% decrease in dose
after 17 hours
 Patch irritation sometimes treated with
Azmacort spray, etc.
Actiq (transmucosal fentanyl)
 Available as 200, 400, 600, 800, 1200 and
1600 mcg doses
 FDA approved for cancer pain only
 Onset in 5-10 minutes, up to 3-4 hours
duration of pain relief
What is Tolerance?
 Tolerance is the need to increase the dose of
a drug over time in order to maintain a given
pharmacological effect
 Pharmacodynamic effects (what the drug
does to the body) versus pharmacokinetic
effects (what the body does to the drug)
HIERARCHY OF CRITICALITY
“FIGHT OR FLIGHT” RESPONSE
AROUSAL CENTERS
SENSORY INPUT
GUT FUNCTION
alertness
sight
smell
hearing
COMPLEX SYSTEMS
 Example: Hi-tech aircraft (auto-pilot vs. toilet)
 Critical systems need robustness
 Critical systems are highly regulated with
feedback and feedforward loops
 Alertness and sensory systems are designed to
maintain homeostasis (whether perturbed by
stimulant or depressant)
OPIOID TOLERANCE
Follows the rules of complex system analysis:
Robustness
AROUSAL CENTERS
sedation
SENSORY INPUT
analgesia
GUT FUNCTION
constipation
Tolerance
OPIOID TOLERANCE
 Highly regulated systems are difficult to study,
which has led to conflicting viewpoints
 Advancing from a single cell to chronic pain
patient, layers of complexity are added
LEVELS OF COMPLEXITY
Tolerance in:
• cell cultures (consistently reproducible)
• in vivo animal studies (fairly reproducible)
• in humans (actively debated)
It’s not that tolerance does not occur in humans,
but that the design of studies does not take into
account the complexity of the system
What May Affect Development of
Tolerance to Opioids?
•
•
•
•
•
presence/absence of painful afferent input
type of opioid agonist
opioid dosing regimen
type of pain (neuropathic vs. nociceptive)
age-dependent tolerance
Painful Afferent Input
• Pain patients versus drug abusers
• Animal studies have produced conflicting
reports (review - Gutstein, Pharmacol Rev.,
1996)
Type of Opioid Agonist
 RA/VE (relative activity vs. endocytosis)
 Agonist ability to promote internalization of
opioid receptor is related to rate of tolerance
development
 Morphine = High RA/VE value
DAMGO = Low RA/VE value
 Multiple mu-opioid receptor splice variants
Opioid Dosing Regimen
• Yaksh and colleagues (J Neurosci, 16, 1996;
Pain, 70, 1997) demonstrated increased spinal
EAA release after naloxone-precipitated
withdrawal from IT MSO4
• Rats that underwent periodic withdrawal from
IT MSO4 developed more rapid tolerance to
MSO4
Intrathecal Tolerance Development
naloxone
DRG
EAA
IT
MSO4
(faster tolerance)
NMDA
IT
MSO4
(slower tolerance)
Intrathecal Tolerance Development
naloxone
DRG
EAA
IT
MSO4
(faster tolerance)
NMDA
IT
MSO4
(slower tolerance)
Duragesic (fentanyl)
Transdermal Patch
Medtronic SynchroMed Pump
Intrathecal Therapy
 Paice et al. reported on 429 patients with IT
morphine pump studied over 15 months
 Morphine dose averaged 5 mg/day at week 1
 After one year, morphine dose increased to
9.2 mg/day (two-thirds of patients had nonmalignant pain)
 Reasonable limit is 25 mg/day
Intrathecal Therapy
 Paice et al., J Pain Symptom Manage 11, 1996
 429 patients in survey study of IT MSO4
Type of Pain
(neuropathic vs. nociceptive)
• Rat studies demonstrate that neuropathic
pain models may develop tolerance less
rapidly than nociceptive pain models
• Human intrathecal morphine study found
only a 1.2-fold increase in MS dose over 4
months in neuropathic/nociceptive pain and a
3.8-fold increase in MS dose for nociceptive
only pain
Environmental/Psychosocial
Issues and Tolerance
• Environment affects tolerance in rats new cage reverses morphine tolerance
• Human study by Rowbotham and colleagues
demonstrates that pill number rather than
dose is related to pain relief.
Rat and Human Study of
Age-Dependent Tolerance
 Neurons age with time - 80 year old patients
have 80 year old neurons
 Can older neurons learn new tricks??
 Cellular tolerance requires some degree of
“molecular gymnastics”
Studies of Opioid Tolerance
 Have never addressed differing age groups
 Attitudes biased by early cancer pain studies:
-many cancer patients are over 50 and have
rapidly increasing tumor burden
-therefore, disease progression outpaces
tolerance development as a reason for
opioid dose escalation
False Assumptions
 Treatment of non-malignant pain in younger
patients has not been differentiated from the
assumptions reached in the older cancer
population
 Dosage escalation may not be underlying
disease progression but rather tolerance to the
analgesic effects of opioids
Chronic Non-Malignant Pain
• Moulin et al., Lancet 347:143-147, 1996
• Randomized, DB, crossover study, up to 120mg po MS
• 46 patients, average age 40 yrs.
Reasons not to Escalate Opioids
 Lack of opioid escalation does not mean lack of
tolerance development
 Side effects, fear of “addiction”, cost, etc.
 Portenoy and Foley, Pain 25:171, 1986
- 38 non-cancer patients, chart reviews
- most patients treated on opioids for >2yrs
- over 50% of patients < 20 mg MS
- 14 of 38 reported inadequate pain relief
Managing Opioids in Patients
 Have clear understanding of goals/rules
 Use adjuvants to minimize opioid dose
 In non-malignant pain, tolerance can be an
issue in many patients
 Use of frequent “breakthrough” opioids can
possibly increase the rate of tolerance
development
Non-Opioid Treatments
 COX-2 inhibitors
 Membrane-stablizing agents
 Muscle relaxants
 Local anesthetics (cream, patch)
 PT/TENS therapy
 Ice-packs, heating pad
 Pacing issues
Intermittant Opioids
 Daily use of opioids leads to tolerance
 Intermittant use can avoid this problem
 Allowing at least three days in between opioid
dosing can possibly avoid dose escalation
 Truly using opioids for “breakthrough” pain
only and not daily in the young age groups can
be useful in the long-term
Conclusion
1) Tolerance to opioids does occur, but the
system is highly complex with many variables
2) We need to admit that opioid tolerance is a
significant issue so that we can critically
analyze the system and find the “fragile”
point(s)
3) Development of novel analgesics with less
tendency for tolerance development is critical,
especially for younger pain patients