Opioid Tolerance and Opioid-Induced Hyperalgesia

1. Opioid Tolerance and Opioid-Induced Hyperalgesia David J. Clark

2. Loss of Effect Advancing disease Analgesic tolerance Hyperalgesia Creation of Problems Side Effects CNS Gastrointestinal Sweating Physical Dependence Abuse, Addiction Chronic Opioid Use: Long-Term Difficulties

3. Opioid Tolerance(Does it matter?) • Tolerance is relevant? • Clinicians • Bhamb et al. 2006, 61% of primary care physicians concerned about tolerance occurring when managing chronic pain • Researchers, Clinical and Basic (~5500 publications, key words “opioid tolerance”) • Drug manufacturers, “Black Box” warnings • Tolerance is irrelevant? “Pharmacological tolerance is not a significant determinant of opioid dosing requirements.” South and Smith, 2001 “ In terms of analgesic efficacy, clinically significant tolerance does not seem to be an issue for acute or cancer pain or in most patients with chronic pain.” Auret and Schug, 2005

4. Analgesic Tolerance vs. Opioid-Induced Hyperalgesia

5. Analgesic Tolerance • Pharmacokinetic etiologies • Quantities and ratios of morphine and major metabolites (M6G, M3G) • Pharmacodynamic etiologies • Receptor density, efficiency • Second messenger system alterations • Target “effector” molecule alterations • Diminished activity of antinociceptive circuits • Enhanced activity of pronociceptive circuits

6. Human Opioid Tolerance(Direct Studies, Chronic) Athanasos et al. 2006

7. Human Opioid Tolerance(Direct Studies, Chronic) Chu et al., 2006

8. Human Opioid Tolerance(Direct Studies, Acute) Model: Cold Pressor Vinik et al. 1998

9. Human Opioid Tolerance(Direct Studies, Acute) Gustorff et al., Anesth Analg 2002

10. Human Opioid Tolerance(Indirect Studies) Rapp et al. 1995 • 180 Control/180 CPOC patients having surgery • Average CPOC pre-op daily parenteral morphine equivalent use 12.7mg Average Daily PCA Morphine ControlCPOC 42.8mg 135.8mg • CPOC pain scores were worse despite larger morphine use. • Greater side effects including sedation (50%) in CPOC group • On-service approximately 3 times as long

11. Human Opioid Tolerance(Indirect Studies) de Leon-Casasola et al., 1993 • 99 Control, 17 CPOC patients having major surgery • Average pre-op opioid use 183mg • Epidural bupivacaine/morphine post-op management Total epidural MSO4: 137 vs. 44mg (CPOC vs. Control) Total IV breakthrough: 48 vs. 10mg Length of therapy: 218 vs. 76 hrs

12. Supporting Crawford et al. 2006 Remifentanil vs. Morphine Guignard et al. 2000 Remifentanil Chia et al. 1999 Fentanyl Cooper et al. 1997 Intrathecal fentanyl Refuting Cortinez et al. 2001 Remifentanil Hansen et al. 2005 Remifentanil/Epidural Higher 2 hr pain scores Human Opioid Tolerance(Indirect Studies) Intraoperative opioid administration versus postoperative opioid consumption

13. Human Opioid Tolerance(Indirect Studies) Intrathecal morphine dose escalation in patients with FBSS Rainov et al., 2001

14. Human Opioid Tolerance(Indirect Studies) Fentanyl dose escalation in patients with chronic non-malignant pain Milligan et al., 2001

15. Increasing Doses Advancing disease Tolerance Hyperalgesia Limiting Doses Better controlled pain Side effects Lack of efficacy Fear of addiction Cost Stigmatization Opioid Dose Escalation and Tolerance(Factors Involved)

16. Tolerance vs. Hyperalgesia

17. Opioid-Induced Hyperalgesia(Historical perspective) “when dependence on opioids finally becomes an illness of itself, opposite effects like restlessness, sleep disturbance, hyperasthesia, neuralgia and irritability become manifest” Rossbach, Pflugers Archieve 1880

18. Opioid-Related Hyperalgesia(Direct Studies, Chronic) Doverty et al., 2001

19. Opioid-Related Hyperalgesia(Direct Studies, Chronic) Chu, Clark and Angst; J Pain 2006

20. Opioid-Related Hyperalgesia(Direct Studies, Acute) Remi (30min) Remi (30min) Model: Electrical Pain/Hyperalgesia Koppert et al. 2003

21. Opioid-Related Hyperalgesia(Direct Studies, Acute) Model: Heat/Capsaicin Hood et al. 2003

22. Opioid-Related Hyperalgesia(Direct Studies, Acute) Compton, Journal of Pain 2003

23. Opioid-Related Hyperalgesia(Direct Studies, Acute) Angst et al., Pain 2003

24. Opioid-Related Hyperalgesia(Direct Studies, Chronic) Galer et al., 2005

25. Opioid-Related Hyperalgesia(Direct Studies, Acute) Koppert et al., 2006

26. Tolerance and Opioid-Induced Hyperalgesia:What should we do in clinic? • Inform: • Tolerance and hyperalgesia may reduce the efficacy of therapy. • More pain might be experienced during or after surgical procedures. • Follow: • Pain control, dose escalation • Distribution of pain • Consider: • Detoxification in certain circumstances

27. Perioperative Management of Opioid Consuming Patients • Preoperative • Identify, quantify, stabilize, collaborate • Intraoperative • Opioids: doses, short versus long acting • Adjuvants: NSAIDS, ketamine, alpha-2, etc. • Regional anesthesia • Postoperative • Opioids, adjuvants, regional analgesia • Transition planning

28. Tolerance and Opioid Related Hyperalgesia:Perioperative Management • Carroll, I.R., M.S. Angst, and J.D. Clark, Management of perioperative pain in patients chronically consuming opioids. Reg Anesth Pain Med, 2004. 29(6): p. 576-91. • de Leon-Casasola, O.A., Cellular mechanisms of opioid tolerance and the clinical approach to the opioid tolerant patient in the post-operative period. Best Pract Res Clin Anaesthesiol, 2002. 16(4): p. 521-5. 3. Mitra, S. and R.S. Sinatra, Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology, 2004. 101(1): p. 212-27.

29. Thank You