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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 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