Opioids: Should Tolerance Affect our Management?

1. 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

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

3. 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.

4. 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.

5. Peripheral Nerve Terminal Blood Vessel Nociceptor BK IL SP CGRP NKA PGE2 NPY Sympathetic Terminal 5-HT histamine TBX Platelets Mast cell

6. Peripheral Nerve Terminal PGE2 +cAMP EP1 Nociceptor +PI, +Ca BK2 BK -cAMP, -Ca -endorphin, Mu agonists MOR

7. “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

8. “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)

9. “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

10. Analgesic Rollercoaster

11. 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

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

13. 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

14. 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

15. 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.

16. 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

17. 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)

18. HIERARCHY OF CRITICALITY “FIGHT OR FLIGHT” RESPONSE AROUSAL CENTERS alertness sight smell SENSORY INPUT hearing GUT FUNCTION

19. 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)

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

21. 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

22. 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

23. 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

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

25. 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

26. 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

27. Intrathecal Tolerance Development naloxone IT MSO4 EAA DRG (faster tolerance) NMDA IT MSO4 (slower tolerance)

28. Intrathecal Tolerance Development naloxone IT MSO4 EAA DRG (faster tolerance) NMDA IT MSO4 (slower tolerance)

29. Duragesic (fentanyl) Transdermal Patch

30. Medtronic SynchroMed Pump

31. 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

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

33. 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

34. 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.

35. 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”

39. 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

40. 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

41. 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.

42. 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

43. 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

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

45. 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

46. 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