CONTENTS. Disclosure of Conflict of Interest. None. Is opioid effective in long-term use? Can opioid exacerbate pain? Why are we still using opioids?

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1 Why Are We Still Using Opioids If Opioid Therapy Are So Problematic? Jianren Mao, MD, PhD Richard J. Kitz Professor of Anesthesia Research Harvard Medical School, Harvard University Vice Chair for Research Chief, Division of Pain Medicine Director, MGH Center for Translational Pain Research Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Disclosure of Conflict of Interest None CONTENTS Is opioid effective in long-term use? Can opioid exacerbate pain? Why are we still using opioids? How can we improve opioid therapy? 1

2 OPIOID RECEPTORS Three opioid receptor classes Mu: -endorphin; morphine Kappa: dynorphin; butorphanol Delta: enkephalin; its derivatives Each class of opioid receptors has been cloned Adopted from Goodman & Gilman s The Pharmacological Basis of Therapeutics camp G -OR K + PKA 2

3 Opioid Sites of Action OPIOIDS Brain Injury (+) Dorsal Root Ganglion Dorsal Horn (-) Descending Inhibition Peripheral Nerve Spinal Cord Modified from WebMD Scientific American Medicine Analgesia Hyperalgesia OPIOID THERAPY Addiction Side Effects Does opioid dose adjustment change clinical pain score? An analysis of a subgroup of over 100 chronic pain patients 3

4 Opioid Dose Increase and Pain Score Change % change in MED % change in Pain Score Opioid Dose Decrease and Pain Score % change in MED % change in Pain Score 60.00% 40.00% 20.00% 0.00% % Change % % % % % % Subjects TOLARANCE Pharmacological effect characteristic of opioids Tolerance to various opioid effects occurs at differential rates Change in the pain state (disease progression, infection) mimicking tolerance 4

5 PHYSICAL DEPENDENCE Pharmacological effect characteristic of opioids Withdrawal or abstinence syndrome related to abrupt discontinuation of medication substantial dosage reduction administration of antagonist ADDICTION Psychiatric disorder Cravings and compulsive behaviors Physical, psychological, or social harm Continued drug use despite harm Opioid-Induced Hyperalgesia 5

6 OPIOID DESENSITIZATION (TOLERANCE) SENSITIZATION (INCREASED PAIN) PRONOCICEPTIVE presynaptic -OR Glia ggt - NMDAR NMDAR - ngt -OR + PKC - G -OR Ca ++ 6

7 REPEATED OPIOID EXPOSURE A PATHOLOGICAL PAIN STATE DECREASED ANALGESIC EFFICACY NO INTRA-OP OPIOID INTRA-OP OPIOID Cooper et al., 1997; Vinik & Igor, 1998; Guignard et al., 2000 Quantitative Sensory Testing 7

8 Altered Heat Pain Threshold Stimulation Temprature * Group 1 Group 2 Group 3 Chronic Pain Management Reset pain threshold (analgesic vs. antihyperalgesia) Retain the ability to feel pain but not constantly in pain New additions to various categories of pain medications Opioid analgesics NSAIDs; COX-2 inhibitors Ion channel (Ca ++, Na + ) blockers Antidepressants (TCA, SSRI, SNRI) *Triptan drugs (5-HT1b, 1d receptor agonists) for migraine *Others (gabapentin, pregabalin) 8

9 Copyright restrictions may apply. Backonja, M. et al. JAMA 1998;280: Nociceptive Processing (nociceptive signal) Pain Perception (intensity, affect) Clinical Pain Individual Response (taking action) RELEVANCE: rat human No complaint (affect, emotion) No secondary gain No comorbidity No addiction No legal issues No illicit drug abuse No socioeconomic challenge 9

10 PAIN ASSESSMENT TOOL Bench Evoked response Clinical Pain rating Pain questionnaires Quantitative sensory testing WHAT DOES PAIN SCORE TELL US? VAS: 10/10 VAS:?? Why are we still using opioid (for chronic pain management)? No Better Choice! 10

11 OPIOID TREATMENT CELLULAR MECHANISMS PHARMACOLOGICAL TOLERANCE OPIOID-INDUCED HYPERALGESIA APPARENT TOLERANCE WORSENING PAIN STATE OPIOID DOSE ESCALATION Opioid Rotation Adjunctive Medication NMDAR Antagonist Dose Decrease NMDAR Antagonist Adjunctive Medication Analgesia (tolerance) Hyperalgesia ACKNOWLEDGEMENT NIH R01 and P20 Grants R01 DA08835 (Y1-5); R01 DA08835 (Y6-10); R01 NS42662; R01 NS45681; R01 DA022576; R01 DA036564; R01 DE018538; R01 DA036564; R01 DE022901; R01 AT005819; R01 DA33925; P20 DA22576 MGH Center for Translational Pain Research Lucy Chen, Shihab Ahmed, Yi Zhang, Shiqian Shen, Zerong You, Charlen Malarick, Lindsey Seefeld, Mary Houghton, Christy Santana, Kristin Hilaire, Backil Sung, Grewo Lim, Shuxing Wang, Qing Zeng, Liling Yang, Yang Chang, Gabriel Rusanescu, Hyagine Kim, Connie Chou, Yinghong Tian, Wei Zhang, Li Song, Xu Jin, Yonghui Tan, Kaiyuan Fu, Masashi Ueda, Shuzhuo Zhang, Weihua Ding, Jason Doheny, Matthew McBride, Michael McCabe, Katherine Pokrass, Samuel Tate, Trang Vo, Megan Marx, Abigail Sara Cohen, Cynthia Retamozo, Corrie Fisher, Sarah Roth, Arissa Opalacz, Evgenia Jen Filatava 11