Cancer Pain: Bridging the Knowledge Gap – Linking Musculoskeletal Medicine with Opioid Therapy Andrea L. Cheville, MD, MSCE Professor and Research Chair Department of Physical Medicine and Rehabilitation Mayo Clinic, Rochester AAPMR Annual Assembly October 3, 2015

PAIN “Pain is a more terrible Lord of mankind than even death itself.” Albert Schweitzer

Overview Physiatric culture is opioid ambivalent Function versus comfort??1 Opioid-based pharmacotherapy is the international standard of care for cancer pain management “Dose to effect or side effect” is the longstanding paradigm Cancer is dynamic and deadly 1. Richard D. Zorowitz; Randall J. Smout; Julie A. Gassaway; Susan D. Horn. Usage of Pain Medications During Stroke Rehabilitation: The Post-Stroke Rehabilitation Outcomes Project (PSROP). Volume 12, Issue 4 (Fall 2005), pp. 37-49.

WHO Analgesic Ladder1 Rung III - for severe pain: “strong” opioid, +/- nonopioid, +/- adjuvant Rung II - for moderate pain: “weak” opioid, +/- nonopioid, +/- adjuvant Rung I - for mild pain: nonopioid (NSAID’S, acetaminophen), +/- adjuvant Effectively manages neuropathic pain2,3 1. WHO. Cancer Pain Relief with a Guide to Opioid Availability. Zurich: World Health Organization; 1996. 2. Grond S, Radbruch L, Meuser T, Sabatowski R, Loick G, Lehmann KA. Assessment and treatment of neuropathic cancer pain following WHO guidelines. Pain. Jan 1999;79(1):15-20. Mishra S, Bhatnagar S, Gupta D, Nirwani Goyal G, Jain R, Chauhan H. Management of neuropathic cancer pain following WHO analgesic ladder: a prospective study. Am J Hosp Palliat Care. Dec-2009 Jan 2008;25(6):447-451.

What are opioids?

Codeine Morphine Oxycodone Diacetyl- morphine Hydrocodone

Meperidine Fentanyl Methadone

Visceral cancer pain Associated with distention Colicky Dull achy Challenging to localize Pharmacotherapy Anti-inflammatories Dexamethasone Delta receptor agonists

Incident cancer pain Temporal profile

Rate of onset = route + lipophilicity 10 20 30 40 50 60 70 80 Mean % Absorbed Heroin (2.5) Oxycodone (2.5) Naloxone (1.0) Fentanyl (0.5) Levorphanol (1.0) Methadone (5.0) Methadone (0.8) Morphine (5.0) Hydromorphone (1.0) Buprenorphene (0.1) Opioid (dose in mg) Adapted from Weinberg DS, et al. Clin Pharm Ther. 1988;44:337.

Lipid Solubility and CNS Equilibrium Times Morphine Oxycodone Fentanyl Octanol/H2O partition 1.4 0.71 8132 coefficient (lipid solubility) Keo T1/2 17 min3 N/A 3-5 min2 (time into CNS) N/A=Not available. 1 - Oxycontin PI. 2 - ACTIQ PI. 3 - Kramer TH, d’Amours RH, Buetner C. Clin Pharmacol Ther. 1996;59:132.

Transmucosal fentanyl products Abstral® (fentanyl) sublingual tablets Actiq® (fentanyl citrate) oral transmucosal lozenge Fentora® (fentanyl buccal tablet) Lazanda® (fentanyl) nasal spray Onsolis® (fentanyl buccal soluble film) Subsys® (fentanyl sublingual spray) Generic equivalents

Fentanyl Concentration-Time Profiles – Different Routes of Administration

Ketamine NMDA antagonist History in pediatric anesthesia Analgesic and anti-inflammatory May induced dissociative states Dosing Intranasal 10-50 mg.1 Sublingual 25 mg.2 Carr D, Goudasa LC , Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Volume 108, Issues 1–2, March 2004, Pages 17–27 Mercadante S, Arcuri E, Ferrera P, et al. Alternative Treatments of Breakthrough Pain in Patients Receiving Spinal Analgesics for Cancer Pain. Volume 30, Issue 5, November 2005, Pages 485–491.

Osseous cancer pain

Polypharmacy Antiresorbtives Anti-inflammatories Co-analgesics Opioids Bisphosphonates Denosumab (Xgeva) Anti-inflammatories Dexamethasone NSAIDs Co-analgesics Calcitonin Ion channel stabilizers SNRIs Opioids

Opioids for neuropathic cancer pain

Cannot generalize from other neuropathic pain states RCT gabapentin ineffective for chemotherapy-induced peripheral neuropathy1 1. Rao RD, Michalak JC, Sloan JA. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy. Cancer Volume 110, Issue 9, Pages 2110–2118

Opioids are effective for neuropathic pain

CR oxycodone for DM-related Neuropathic Pain Objective: Evaluate analgesic efficacy and safety Study Design: 6-week, double-blind, randomized parallel study in 160 subjects Treatments: CR oxycodone 10 to 60 mg q12h versus placebo Concomitant: NSAIDs, acetaminophen, and adjuvants Medications: permitted at stable dose Duration of Pain: 1) Physical evidence of polyneuropathy confirmed by abnormality on neurologic exam: sensory, motor, or reflex abnormality. 2) Pain 5 in both feet

Neuropathic Pain 2° Diabetic Neuropathy Subject Daily Diary VAS 2 4 6 8 10 Baseline 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 PLACEBO CR OXYCODONE Overall Treatment P = < .002 Day Oxycodone Placebo   Least Square Means Day

Larger context Stage IV lung cancer is rapidly progressive Lung metastasizes to osseous and neural tissues Severe pain more common that in other cancers Uncouple acetaminophen