Opioid Tolerance and Opioid Induced Hyperalgesia David J

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Opioid Tolerance and Opioid. Induced Hyperalgesia David J. Clark

Opioid Tolerance and Opioid. Induced Hyperalgesia David J. Clark

Chronic Opioid Use: Long-Term Difficulties Loss of Effect • • • Advancing disease Analgesic

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

Opioid Tolerance (Does it matter? ) • Tolerance is relevant? – Clinicians • Bhamb

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

Analgesic Tolerance vs. Opioid-Induced Hyperalgesia

Analgesic Tolerance vs. Opioid-Induced Hyperalgesia

Analgesic Tolerance • Pharmacokinetic etiologies – Quantities and ratios of morphine and major metabolites

Analgesic Tolerance • Pharmacokinetic etiologies – Quantities and ratios of morphine and major metabolites (M 6 G, M 3 G) • Pharmacodynamic etiologies – – – Receptor density, efficiency Second messenger system alterations Target “effector” molecule alterations Diminished activity of antinociceptive circuits Enhanced activity of pronociceptive circuits

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

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

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

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

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

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

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

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

Human Opioid Tolerance (Indirect Studies) Rapp et al. 1995 • 180 Control/180 CPOC patients

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. 7 mg Average Daily PCA Morphine Control CPOC 42. 8 mg 135. 8 mg • 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

Human Opioid Tolerance (Indirect Studies) de Leon-Casasola et al. , 1993 • 99 Control,

Human Opioid Tolerance (Indirect Studies) de Leon-Casasola et al. , 1993 • 99 Control, 17 CPOC patients having major surgery • Average pre-op opioid use 183 mg • Epidural bupivacaine/morphine post-op management Total epidural MSO 4: Total IV breakthrough: Length of therapy: 137 vs. 44 mg 48 vs. 10 mg 218 vs. 76 hrs (CPOC vs. Control)

Human Opioid Tolerance (Indirect Studies) Intraoperative opioid administration versus postoperative opioid consumption • Supporting

Human Opioid Tolerance (Indirect Studies) Intraoperative opioid administration versus postoperative opioid consumption • Supporting Crawford et al. 2006 – • Guignard et al. 2000 – • Remifentanil Chia et al. 1999 – • Remifentanil vs. Morphine 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) Intrathecal morphine dose escalation in patients with FBSS Rainov

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

Human Opioid Tolerance (Indirect Studies) Fentanyl dose escalation in patients with chronic non-malignant pain

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

Opioid Dose Escalation and Tolerance (Factors Involved) Increasing Doses • Advancing disease • Tolerance

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

Tolerance vs. Hyperalgesia

Tolerance vs. Hyperalgesia

Opioid-Induced Hyperalgesia (Historical perspective) “when dependence on opioids finally becomes an illness of itself,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Tolerance and Opioid-Induced Hyperalgesia: What should we do in clinic? • Inform: – Tolerance

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

Perioperative Management of Opioid Consuming Patients • Preoperative – Identify, quantify, stabilize, collaborate •

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

Tolerance and Opioid Related Hyperalgesia: Perioperative Management 1. Carroll, I. R. , M. S.

Tolerance and Opioid Related Hyperalgesia: Perioperative Management 1. 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. 2. 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.

Thank You

Thank You