low dose naltrexone and chronic pain - | ldn research trust pradeep chopra - ldn 2013...pradeep...
TRANSCRIPT
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Low Dose Naltrexone and
chronic pain
Pradeep Chopra, MD
Assistant Professor (Clinical) Brown Medical School Director, Pain Management Center, RI
1
Copyright © 2013 by Pradeep Chopra. No part of this presentation may be
reproduced or transmitted in any form or by any means without written permission of
the author
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Disclosure and disclaimer
• I have no actual or potential conflict of
interest in relation to this presentation or
program
• This presentation will discuss “off-label”
uses of medications
• No financial interest in any pharmaceutical
company or otherwise
2
Copyright © 2013 by Pradeep Chopra. No part of this presentation may be reproduced or transmitted in
any form or by any means without written permission of the author
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Pradeep Chopra, MD
Introduction
• Training and Fellowship, Harvard Medical
school
• Pain Medicine specialist
• Assistant Professor – Brown Medical
School, Rhode Island
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Pradeep Chopra, MD
LDN and chronic pain
• Complex Regional Pain Syndrome
(CRPS), Reflex Sympathetic Dystropy
(RSD), Neuropathic pain
• Ehlers Danlos Syndrome (EDS),
Connective Tissue disorder
• Fibromyalgia
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Pradeep Chopra, MD
LDN and chronic pain
• Complex Regional Pain Syndrome
(CRPS), Reflex Sympathetic Dystropy
(RSD), Neuropathic pain
• Ehlers Danlos Syndrome (EDS),
Connective Tissue disorder
• Fibromyalgia
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Complex Regional Pain
Syndrome (CRPS)
or
Reflex Sympathetic Dystrophy
(RSD)
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Pradeep Chopra, MD
What is CRPS / RSD
• Complex Regional Pain Syndrome formerly
Reflex Sympathetic Dystrophy
• Continuing pain that is disproportionate to
the usual course of any trauma or lesion.
• Usually starts after a trauma,
immobilization.
• Maybe spontaneous or after a stroke.
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Pradeep Chopra, MD
How common is RSD?
.
• USA: estimated to be 50,000 new cases
per year
1 Andreas Kopf, Patel N, IASP 2010
2 DeMos M, de Bruijn AG, et al 2006
3 Van Den Eeden, Tanner, et al 2003
Deussing, Jankosky 2012
Marinus J, Moseley GL et al 2011 8
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Pradeep Chopra, MD
Signs and Symptoms of CRPS 1
• Pain starts in one limb but can present in the trunk (spine, abdomen, perineum)
• Constant pain, even at rest with intermittent exacerbations. Unexplained and diffuse
• Severe pain - burning, tearing, shooting
• Temperature, color change.
• Edema
• Area of pain larger than the primary injury
• Limited range of motion
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Pradeep Chopra, MD
Signs and Symptoms of CRPS 2
• Allodynia - pain on light touch
• Hyperalgesia - increased pain to mildly painful stimulus
• Trophic changes - nail growth changes (faster, distorted), hair growth changes (coarser, darker, rapid growth, hair falling), skin changes (atrophy of skin), skin lesions
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Pradeep Chopra, MD
Color, temperature and swelling
11
88
°
94
°
Swelling
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Pradeep Chopra, MD 12
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Pradeep Chopra, MD
Bilateral CRPS
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Pradeep Chopra, MD 19
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Pradeep Chopra, MD 20
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Pradeep Chopra, MD
CENTRAL SENSITIZATION
Key concept to understanding all
chronic pain
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Pradeep Chopra, MD
Central Sensitization
• The increased excitability is due to a barrage of signals from the peripheral nociceptors.
• This barrage alters the strength of the synaptic connections between the neurons in the spinal cord.
• Low threshold neurons activated by light touch of the skin begin to activate neurons in the CNS that normally respond to noxious stimulus.
• Hence a simple touch of the skin feels painful.
• Although the pain feels as if it originates in the periphery, it actually is a result of abnormal sensory processing in the CNS.
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Pradeep Chopra, MD
GLIA The final frontier in understanding
disease
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Glia 1
• Glia constitute 70% to 80% of all cells in
the CNS
• Perform immune surveillance under basal
conditions
• Glia when activated release pro-
inflammatory cytokines
24
Watkins, Hutchinson, Ledeboer, Milligan et al Brain Behav
Immun 2007 Feb; 21(2): 131-146
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Glia – Activated
• Create and maintain neuropathic pain
• Compromise the efficacy of opioids
25
Watkins, Hutchinson, Ledeboer, Milligan et al Brain Behav Immun
2007 Feb; 21(2): 131-146
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Activated Glia and Neuropathic Pain
• When activated – glia release a variety of substances (proinflammatory cytokines, chemokines, etc.)
• These substances in turn cause neuroinflammation
• This is a shift in our understanding of chronic pain from neural signalling to a cellular mechanism
26
Watkins, Hutchinson, Ledeboer, Milligan et al Brain
Behav Immun 2007 Feb; 21(2): 131-146
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Pradeep Chopra, MD
Glia and nerves under normal conditions
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Pradeep Chopra, MD
Activated Glia
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Pradeep Chopra, MD
Chemicals released by activated Glia
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Pradeep Chopra, MD
Nerve inflammation - Central Sensitization
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Pradeep Chopra, MD
The problem is no longer in the nerves. Its in the cells (Glia
cells)
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Pradeep Chopra, MD
Toll like receptors TLR4
• TLR4 is predominantly expressed by microglia • Its expression is upregulated under
neuroinflammatory conditions. • TLR4 have been shown to be a key glial
activation receptor in initiation and maintenance of neuropathic pain
• Opioids cause glial cell activation by acting on the TLR4 receptors leading to a cascade of pro-inflammatory cytokines
• Opioid antagonists (naloxone, naltrexone) block TLR4 signalling
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Opioids
•Activate glia
•Increased
Central
Sensitization
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Pradeep Chopra, MD
Opioids 2
• Repeated exposure to opioids leads to
enhanced pro-inflammatory cytokine
release from glia (Johnston et al)
• Blocking such opioid induced glial
activation enhances acute opioid analgesia
and suppresses the development of opioid
tolerance. (Hutchinson, Johnson)
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Pradeep Chopra, MD
Low Dose Naltrexone
LDN
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Pradeep Chopra, MD
Low Dose Naltrexone (LDN) 2
• Reduction of pro-inflammatory cytokines can
be achieved with low doses of naltrexone (Liu et
al, Greeneltch et al, Tsai et al)
• Effect not mediated by opioid receptor activity
• Potentially mediated by activity on Toll Like
Receptors 4 (TLR4)
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Pradeep Chopra, MD
Low Dose Naltrexone (LDN) 2
• There are several theories as to how LDN may work.
1. Transiently blocks opioid receptor leading to positive feedback production of endorphins (Zagnon)
2. LDN increases production of OGF (opioid growth factor) as well as number of and density of OGF receptors by intermittently blocking the opiate receptor. Increased in OGF repairs tissue and healing.
3. Effect not mediated by opioid receptor activity. Potentially mediated by activity on Toll Like Receptors 4 (TLR4)
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LDN and CRPS
41 Chopra, Li, Unpublished data from retrospective review, 2013 – under review
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Pradeep Chopra, MD
Case of RSD treated with LDN
44
RSD with dystonia
before LDN RSD after LDN
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Pradeep Chopra, MD
Severe RSD with skin lesions
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Pradeep Chopra, MD
CRPS treated with LDN
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Ehlers Danlos
Syndrome (EDS) Connective tissue disorders
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Pradeep Chopra, MD
Incidence of Ehlers Danlos
Syndrome
• Incidence of EDS is 1%
• Number of cases of EDS in the USA is
3.1 million
• Entire population of Iowa or Mississippi or
Kansas
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50 Pradeep Chopra, MD
Ehlers Danlos Syndrome 1
•EDS is a group of inherited disorders
•Affects connective tissue (‘connects’)
•Connective tissue is found in skin, joints and
blood vessels
•Very flexible, unstable joints (‘Double
jointed’), stretchy skin and many other
symptoms
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51 Pradeep Chopra, MD
EDS1
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57 Pradeep Chopra, MD
Pain in EDS1
•Recurrent dislocations of joints
•Muscle pain – weak muscles, muscle spasms
•Ligament tear and injury
•Neuropathic pain, Complex Regional Pain
Syndrome (CRPS)
•Unstable spine
•Tethered cord syndrome
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58 Pradeep Chopra, MD
Ehlers Danlos Syndrome and LDN 1
•LDN in EDS patients helps in two ways:
•Helps lower pain, tolerate pain
•It also helps with stability of the connective
tissue
•Patients report feeling ‘more put together’
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Fibromyalgia Centrally Sensitized pain
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Pradeep Chopra, MD
Fibromyalgia
• Chronic widespread pain
• Allodynia (pain to normal touch)
• Fatigue, poor sleep, joint stiffness
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Other Pain Disorders = 6 Total # Patients = 67
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Average Dose:
Standard Deviation:
Most Common Dose:
Minimum Dose:
Maximum Dose:
(mg/day)
4.5
1
6
Prescribing LDN
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Average change in pain score = 5.15 points (SD = 1.32)
Pain Scores for All Patients
Chopra, P, Li T: unpublished data under review
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Opioid Use
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# Patients who discontinued LDN before 1st follow-up: 3/67
# Patients who discontinued LDN after 1st follow-up: 1/67
Reason for discontinuation: No pain relief
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Pradeep Chopra, MD
Acknowledgements
• Linda Elsegood
• LDN Research Trust
• My patients who have put up with my crazy
notion of treating their pain with an opioid
antagonist
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