©2011 MFMER | slide-1 Cancer Pain: Bridging the Knowledge Gap – Linking Musculoskeletal Medicine...

©2011 MFMER | slide-1

Cancer Pain:Bridging the Knowledge Gap – Linking Musculoskeletal Medicine with Opioid Therapy

Andrea L. Cheville, MD, MSCEProfessor and Research ChairDepartment of Physical Medicine and RehabilitationMayo Clinic, Rochester

AAPMR Annual AssemblyOctober 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 pain2,31. 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):15-20.3. 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?



Morphine

HydrocodoneDiacetyl-morphine

Oxycodone

Codeine


Methadone

MeperidineFentanyl

Visceral cancer pain

• Associated with distention• Colicky• Dull achy

• Challenging to localize

• Pharmacotherapy• Anti-inflammatories

• Dexamethasone• Delta receptor agonists


Incident cancer pain

• Temporal profile



Adapted from Weinberg DS, et al. Clin Pharm Ther. 1988;44:337.

0

10

20

30

40

50

60

70

80

Mea

n %

Abs

orbe

d

Mor

phine

(5.0)

Oxyco

done

(2.5)

Levor

phan

ol (1

.0)

Hydro

morph

one (

1.0)

Naloxo

ne (1

.0)

Meth

adon

e (5.0

)

Heroin

(2.5)

Meth

adon

e (0.8

)

Fentan

yl (0

.5)

Bupren

orph

ene (

0.1)

Opioid (dose in mg)

Rate of onset = route + lipophilicity


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.

Lipid Solubility and CNS Equilibrium Times

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


1. 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

2. 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• 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 NeuropathySubject Daily Diary VAS

0

2

4

6

8

10

Basel

ine 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

PLACEBO CR OXYCODONE

Overall Treatment P = < .002

Day

OxycodonePlacebo

Leas

t S

quar

e M

eans

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


©2011 MFMER | slide-1 Cancer Pain: Bridging the Knowledge Gap – Linking Musculoskeletal Medicine...

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