Opioids: Should Tolerance Affect our Management?

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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

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Topics

• Opioids and Pain Pathways
• Clinical Use of Opioids
• Opioid Tolerance Mechanisms
• Managing Your Patients on Opioids

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Neuroanatomy of Pain Pathways
Somatosensorycortex
Limbic forebrain system
Intralaminar thalamicnucleus
Periaqueductal gray area
Ventroposterolateralthalamic nucleus
Rostroventral medulla
Descending pathway
Peripheralnerves
Ascending pathways
Hyman SE, Cassem NH. Pain. In Scientific
American Medicine. Vol XIX. 1996 Chap 11.
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Mechanisms of Action of Opioids
Primary afferent

?, d, k receptors cause ? gCa ? Transmitter
release
Presynapticterminal

? receptors cause ? gK, IPSP
Postsynaptic neuron
Spinal pain-transmission neuron
Basic and Clinical Pharmacology. 8th ed. 2001.
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Peripheral Nerve Terminal
Blood Vessel
Nociceptor
BK IL
SP CGRP NKA
PGE2 NPY
Sympathetic Terminal
5-HT
histamine
TBX
Platelets
Mast cell
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Peripheral Nerve Terminal
PGE2
cAMP
EP1
Nociceptor
PI, Ca
BK2
BK
-cAMP, -Ca
?-endorphin, Mu agonists
MOR
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Short-Acting Opioids
hydrocodone (Vicodin, Lortab, Norco)
propoxyphene (Darvocet) oxycodone
(Percocet) hydromorphone (Dilaudid) Roller-coaste
r plasma levels - leading to breakthrough pain
especially at night Acetaminophen content -
limits usefulness in severe pain
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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)

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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

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Analgesic Rollercoaster
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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

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Levorphanol

• Half-life 12-20 hours
• Tablets 2mg, TID dosing
• Five-times more potent than morphine
• Not easy to obtain

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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

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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

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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.

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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

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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)

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HIERARCHY OF CRITICALITY
FIGHT OR FLIGHT RESPONSE
AROUSAL CENTERS
alertness
sight
smell
SENSORY INPUT
hearing
GUT FUNCTION
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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)

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OPIOID TOLERANCE
Follows the rules of complex system analysis
Robustness
Tolerance
AROUSAL CENTERS
sedation
analgesia
SENSORY INPUT
constipation
GUT FUNCTION
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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

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LEVELS OF COMPLEXITY

• Tolerance in
• cell cultures (consistently reproducible)
• in vivo animal studies (fairly reproducible)
• in humans (actively debated)
• Its not that tolerance does not occur in humans,
  but that the design of studies does not take into
  account the complexity of the system

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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

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Painful Afferent Input

• Pain patients versus drug abusers
• Animal studies have produced conflicting
  reports (review - Gutstein, Pharmacol Rev.,
  1996)

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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

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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

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Intrathecal Tolerance Development
naloxone
IT MSO4
EAA
DRG
(faster tolerance)
NMDA
IT MSO4
(slower tolerance)
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Intrathecal Tolerance Development
naloxone
IT MSO4
EAA
DRG
(faster tolerance)
NMDA
IT MSO4
(slower tolerance)
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Duragesic (fentanyl) Transdermal Patch
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Medtronic SynchroMed Pump
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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
  non-malignant pain)
• Reasonable limit is 25 mg/day

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Intrathecal Therapy

• Paice et al., J Pain Symptom Manage 11, 1996
• 429 patients in survey study of IT MSO4

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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

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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.

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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

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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

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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

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Chronic Non-Malignant Pain

• Moulin et al., Lancet 347143-147, 1996
• Randomized, DB, crossover study, up to 120mg po
  MS
• 46 patients, average age 40 yrs.

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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 25171, 1986
• - 38 non-cancer patients, chart reviews
• - most patients treated on opioids for gt2yrs
• - over 50 of patients lt 20 mg MS
• - 14 of 38 reported inadequate pain relief

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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

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Non-Opioid Treatments

• COX-2 inhibitors
• Membrane-stablizing agents
• Muscle relaxants
• Local anesthetics (cream, patch)
• PT/TENS therapy
• Ice-packs, heating pad
• Pacing issues

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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

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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