1. 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

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

3. 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

4. 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):

6. What are opioids?

7. Codeine
Morphine
Oxycodone
Diacetyl-
morphine
Hydrocodone

8. Meperidine
Fentanyl
Methadone

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

10. Incident cancer pain
Temporal profile

11. Rate of onset = route + lipophilicity10 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.

12. Lipid Solubility and CNS Equilibrium Times
Morphine Oxycodone Fentanyl
Octanol/H2O partition
coefficient (lipid solubility)
Keo T1/ min N/A 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.

13. 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

14. Fentanyl Concentration-Time Profiles – Different Routes of Administration

15. Ketamine NMDA antagonist History in pediatric anesthesia
Analgesic and anti-inflammatory
May induced dissociative states
Dosing
Intranasal 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.

16. Osseous cancer pain

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

19. Opioids for neuropathic cancer pain

20. 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

21. Opioids are effective for neuropathic pain

22. 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

23. Neuropathic Pain 2° Diabetic Neuropathy Subject Daily Diary VAS2 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

24. 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