Low Dose Naltrexone:

A Novel Approach in Treating Neuroinflammatory

and other Chronic Degenerative Conditions
August 11 , 2018
Nicholas Palermo, DO, MS
Former program Director Eastern CT Family Medicine Residency
program at Manchester Memorial Hospital
Associate Professor of Family Medicine UNECOM
Family Physician and Bioenergetics Therapist

Gene Gresh, R.Ph., FIACP, IFMCP

Research and Compounding Specialist
Fellow International Academy of Compounding Pharmacists
Institute for Functional Medicine Certified Practitioner
PIONEER HEALTH COMPOUNDING PHARMACY, LLC
 Objectives
At the end of this presentation you will be able to :

 Describe the mechanisms of action of LDN

 Explain how LDN reduces inflammation through glial cell down-

regulation

 Clarify how LDN optimizes the opioid system to reduce pain

 List various conditions that LDN has shown success in treating

 Discuss the benefits vs risks in LDN therapy

 Give an overview of a recent unpublished LDN patient survey

 Naltrexone
 Approved by FDA in 1984
 Opiate antagonist
 Indicated to treat Opiate and Alcohol
addiction
 Dose: between 50-300mg per day

http://www.micromedexsolutions.com.ezproxy.lib.uconn.edu
 Pharmicokinetics

 Oral Absorption:
 Almost complete up to 96%
 Peak plasma levels occur within 1 hour
 Metabolism:
 Hepatic: significant first-pass resulting in 5-40% bioavailability
 Active metabolite: 6-beta-naltrexol
 Excretion:
 Renal elimination: 53-79%
 Half Life
 Naltrexone: 4-6 hours
 6-beta-naltrexol: 13 hours
 Special warnings and precautions for use:

 Adverse reaction with opioids – severe – ensure no opioid use!!

 Don’t forget Tramadol and Codeine

 Confirm normal kidney and liver function ??

 Just as in any potential pharmaceutical use

 Also insure blood sugar and thyroid level

 LDN may alter drug requirement
 SAFETY

 No evidence of toxicity in volunteers receiving 800 mg/day for

seven days

 Prolonged use at 50mg is acceptable

 duration of treatment is not limited

Low Dose Naltrexone
aka “LDN”


 What is LDN and how does it
work?
 Typical Dose: 1.5-4.5 mg PO taken once nightly (or in the morning)
 Mechanisms of Action:
Brief period of opioid blockade  adaptive increase in endorphin and enkephalin
production
 Endorphin & Enkephalin
 Work on opioid receptors to produce analgesia
 Increase in endorphins normalizes immune response
 Increased Met (5) aka Opioid Growth Factor regulates cell division in
normal and abnormal cells
 Works directly on various Toll Like Receptors
 This paradoxical effect has not been seen with higher dosages (50mg)
Proposed Indications for LDN
 Autoimmune/Neurodegenerativ
e  Celiac
 Multiple Sclerosis
 Hashimoto’s Thyroiditis
 Parkinson's Disease
 Alzheimer’s
 Rheumatoid Arthritis
 Polymyalgia Rheumatica
 Sjogren’s
 Lupus
 Myasthenia Gravis
 Gastrointestinal Diseases
 Ulcerative Colitis
 Crohn's
 IBS/IBD
 Dermatologic diseases
 Eczema
 Psoriasis
 Infectious diseases
 Lyme’s Disease
Proposed Indications for LDN

 Chronic Pain Syndromes

 Headaches
 Complex Regional Pain
 Peripheral Neuropathy
 Fibromyalgia/Chronic Fatigue
 Restless Leg Syndrome
 Depression/Anxiety
 Cancers
 LDN-History
 In 1985, Bernard Bihari, MD, a physician with a clinical practice in New
York City, discovered the effects of a much smaller dose of naltrexone
(approximately 3mg once a day) on the body's immune system. He found that
this low dose, taken at bedtime, was able to enhance a patient's response to
infection by HIV, the virus that causes AIDS. [Note: Subsequently, the optimal
adult dosage of LDN has been found to be 4.5mg.]

 In the mid-1990's, Dr. Bihari found that patients in his practice with cancer
(such as lymphoma or pancreatic cancer) could benefit, in some cases
dramatically, from LDN. In addition, people who had an autoimmune disease
(such as lupus) often showed prompt control of disease activity while taking
LDN.
Mechanism(s) of Action
 LDN-Mechanism of Action
 Reversible competitive antagonism of LDN 1.5mg to 4.5mg usually
taken between 9PM and 3AM blocks the opioid receptor transiently

 Briefly and temporarily blocking endorphin receptors at night

normally triggers a rebound stimulation of endorphins the
following day

 • x 3-4 fold increase in Beta Endorphin Levels – B. Bihari

 • x 12-15 fold increase in Enkephalin levels – J. Smith
LDN increases Endorphins & Enkephalins

 –Promote healing
 –Inhibit cell growth
 –Reduce inflammation
 –Positively augment the immune system
 –provide a sense of euphoria- “endorphin rush”
 –Provide a sense of well-being and satisfaction
 –Provide “natural” analgesia
 ENDORPHINS
 Our bodies natural “opioids” that provide pain relief, a sense of
euphoria and a sense of completion.

 Endorphin deficiency may play a role in many psychiatric

conditions.. Depression, OCD, or even self hurting behavior

 Endorphins are quickly broken down by enzymes after binding to

receptors which makes them not addictive---where as Opioid
drugs resist this breakdown and extend the euphoria creating
addictive behavior, dependence and a feedback decrease in
endogenous ENDORPHINS
 ENDORPHINS

 Endorphins are naturally produced in response to pain

and stress, but their production can also be triggered by
various human activities.

 Endorphins may be responsible for the "placebo effect,”

 response of endorphin-release prompted by a tricked
hypothalamus, creating a sense of well-being after
consuming a much-hyped sugar pill, or even after
simply anticipating something pleasurable.
 ENDORPHINS

 In addition to decreased feelings of pain,

secretion of endorphins leads to feelings of
euphoria, modulation of appetite, release of
sex hormones, and enhancement of the
immune response.
 With high endorphin levels, we feel less pain
and fewer negative effect of stress.
 OTHER ENDORPHIN RELEASE

 Exercise -- The "runner's high" really exists, but you'll need to work for it.
Heavy weightlifting or intense aerobic activity that includes periods of
sprinting or increased exertion will trigger the greatest response.
 Meditation or controlled-breathing exercises -- Tai chi, Pilates and yoga are
believed to trigger endorphins.
 Childbirth -- Giving birth to a child is clearly a subcategory of both pain and
stress.
 Alcohol -- Light to moderate drinking stimulates endorphins, but heavy
drinking doesn't. Drugs that block the attachment of endorphins to receptors
have been shown to eliminate cravings in alcoholics.
 OTHER ENDORPHIN RELEASE

 Chili peppers -- Capsaicin, which puts the burn in chilies, also triggers the
body to release some fire-quenching endorphins.
 Bodywork -- Both acupuncture and massage therapy trigger your inner drug
dealer.
 Ultraviolet light -- This may explain why some users of tanning beds achieve
something of a "runner's high," and why others may overuse them at the risk
of their health

http://science.howstuffworks.com/life/endorphins3.htm
 ENKEPHALINS

 It is shown that lymphocytes have surface receptors for

endorphins and enkephalins. Furthermore, endorphins and
enkephalins can influence several immune functions such as
antibody synthesis, lymphocyte proliferation, and natural
killer cytotoxicity. It is thus possible that the receptors play a
functional role

Fed Proc. 1985 Jan;44(1 Pt 1):92-4.

Enkephalins and endorphins as modifiers of the immune system: present and future.
Wybran J
 LDN impacts cancer cell division

 Opioid Growth Factor (OGF) also known as Metkephalin (Met5)

 Its an endogenous pentapepide
 OGF activates a specific receptor called Opioid Growth Factor
receptor (OGFr or ζ-opioid receptor).
 OGF and OGFr axis regulates cell growth in normal and abnormal
cells
 LDN-increases production of OGF and OGFr by a positive
biofeedback mechanism
 There is an increase in the number and density of OGF receptors
 LDN and cancer cell growth
 LDN uses the OGF-OGFr pathway to control the cell cycle

 The effects of LDN are dependent on the OGF-OGFr axis. LDN

upregulates OGF-OGFr at the translational level

 Metenkephalin production (OGF) stimulates P16 and P21

inhibitory pathways of cancer cell division

R. N. Donahue, P. J. McLaughlin, I. S. Zagon. Low-dose naltrexone targets the opioid growth factor-opioid
growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model.
Experimental Biology and Medicine, 2011; 236 (9): 1036 DOI: 10.1258/ebm.2011.011121
 Endorphin/Enkephalin Stimulation

Immune modifying effect:

 Local effects –
 Reduces pro-inflammatory cytokines---Interleukin (2,6,12), TNF-a
(Tumor Necrosis Factor alpha), Gamma Interferon and NF-Kb
 Naltrexone influences mu, kappa and delta receptors locally
 Central effects –
 Increases endogenous enkephalins (Metenkephalin) centrally to
heal the bowel.
Smith JP, Stock H, Bigaman S, et al. Low-dose naltrexone therapy improves active Crohn's disease. Am J of Gastroenterol
2007;102:820–8
 LDN-another MOA
 LDN has analgesic, anti-inflammatory, and neuroprotective
properties that are NOT dependent on opioid receptor
antagonism

 Related to microglia activation in the nervous system

 Naltrexone-Mechanism of Action

 Recently discovered:
Naltrexone HCl is a 50:50 mixture of
both D (dextro) & L (levo) Isomers

 Each isomer has a very different

and distinct biologic activities

 The mechanism is dose

dependant!!
Courtesy of the LDN Research Trust 2016 Fact Sheet
 Naltrexone-Mechanism of Action

 Naltrexone HCl (L-isomer) is a pure

opioid antagonist.

 It is a reversible competitive antagonist

at μ(mu), ĸ (kappa) and to a lesser
extentδ(delta) opioid receptors

http://www.micromedexsolutions.com.ezproxy.lib.uconn.edu
 Naltrexone-Mechanism of Action

 Naltrexone HCl (D-isomer) is an antagonist

for certain immune cells such as Toll Like
Receptors (i.e. TLR4 + TLR9)
 This antagonism results in decreased
cytokines, TNF-a, ROS, NF-kB
 reduces inflammation
 Potentially down regulating oncogenes
 NOTE: This immunomodulatory effect
is NOT seen in doses of 50-300mg
Wang, X., Zhang, Y., Peng, Y., Hutchinson, M. R., Rice, K. C., Yin, H., and Watkins, L. R. (2016) Pharmacological characterization of the opioid inactive isomers
(+)-naltrexone and (+)-naloxone as antagonists of toll-like receptor 4. British Journal of Pharmacology, 173: 856–869. doi: 10.1111/bph.13394.4
 LDN-TLR4
 While blocking opioid receptors, LDN simultaneously blocks a non-
opioid receptor called Toll-like receptor 4 (TLR4).
 TLR4 is found on macrophages called microglia.
 Microglia are central nervous system immune cells along with astrocytes
represent 70-80% of all CNS cells (aka Glia) .
 Triggers hit TLR4  activation microglia  production of
inflammatory & excitatory factors
 If microglia are chronically activated it can lead to neurotoxicity.
Watkins, Hutchinson, Ledeboer, Milligan et al Brain Behav Immun 2007 Feb; 21(2): 131-146The use of low-dose naltrexone (LDN) as
a novel anti-inflammatory treatment for chronic pain
Jarred Younger, Luke Parkitny, David McLain
Clin Rheumatol. 2014; 33(4): 451–459. Published online 2014 February 15. doi: 10.1007/s10067-014-2517-2 PMCID: PMC3962576
 Activated Glia=opioid tolerance &
hyperalgesia!!!

 TLR4  activated glia  excite nearby neurons  incr. glutamate

& decr. GABA  release proinflammatory cytokines &
chemokines  IL-6, TNF-a, NFkB, ROS  switch from
neuroprotective to neurodestructive
 Opioids cause glial cell activation by acting on the
TLR4 receptors leading to a cascade of pro-
inflammatory cytokines –this may help explain Opioid
Tolerance & Opioid induced hyperalgesia
Glia as the “bad guys”: Implications for improving clinical pain control and
the clinical utility of opioids
Linda R. Watkins a,¤,1, Mark R. Hutchinson a, Annemarie Ledeboer a,b, Julie Wieseler-Frank a, Erin D. Milligan a, Steven F. Maier
Brain, Behavior, and Immunity 21 (2007) 131–146

 “two recently recognized roles of glia (microglia and

astrocytes) in: (a) creating and maintaining enhanced
pain states such as neuropathic pain, and (b)
compromising the efficacy of morphine and other
opioids for pain control”
 While glia have little-to-no role in pain under basal
conditions, pain is amplified when glia become
activated,
Glia as the “bad guys”: Implications for improving clinical pain control and
the clinical utility of opioids
Linda R. Watkins a,¤,1, Mark R. Hutchinson a, Annemarie Ledeboer a,b, Julie Wieseler-Frank a, Erin D. Milligan a, Steven F. Maier
Brain, Behavior, and Immunity 21 (2007) 131–146

 glia become increasingly activated in response to repeated

administration of opioids. Products of activated glia increase neuronal
excitability via numerous mechanisms, including direct receptor-
mediated actions, upregulation of excitatory amino acid receptor
function, downregulation of GABA receptor function, and so on.
These downstream effects of glial activation amplify pain, suppress
acute opioid analgesia, contribute to the apparent loss of opioid
analgesia upon repeated opioid administration (tolerance), and
contribute to the development of opioid dependence.
 Naltrexone-Mechanism of Action
 A 2017 proof-of-concept trial revealed that LDN may be beneficial in
improving outcomes in Major Depressive Disorder

 LDN may exert antidepressant effects by enhancing dopaminergic

signaling.
 http://www.sciencedirect.com/science/article/pii/S0165032716304499

Corrigendum to “Randomized, proof-of-concept trial of low dose naltrexone for patients with
breakthrough symptoms of major depressive disorder on antidepressants” [J. Affect. Disord. 208
(2017, Jan. 15) 6-14, doi: 10.1016/ j.jad.2016.08.029, Epub 2016 Oct. 1]
D. Mischoulon, L. Hylek, A.S. Yeung, A.J. Clain, L. Baer, C. Cusin, D.F. Ionescu, J.E. Alpert, D.P.
Soskin, M. Fava
 Summary of Mechanisms of Action
Brief period of opioid blockade  adaptive increase in
endorphin and enkephalin production
 Endorphin & Enkephalin
 Work on opioid receptors to produce analgesia
 Increase in endorphins normalizes immune response
 Increased Met (5) aka Opioid Growth Factor regulates cell
division in normal and abnormal cells
 Works directly on various Toll Like Receptors
 These MOA’s are specifically related to doses 4.5mg and lower
STUDIES
 “Low Dose Naltrexone
as a Treatment for Active
Crohn’s Disease”
American Journal of Gastroenterology in 2007

Am J Gastroenterol. 2007 Apr;102(4):820-8. Epub 2007 Jan 11.

Low-dose naltrexone therapy improves active Crohn's disease.


Smith JP1, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS
 Trial Design
Dr. Jill Smith from Penn State led the open
label trial.
Objective: safety and efficacy of LDN was
tested in patients with active Crohn’s disease.
Trial Results
 89% of pts showed a significant response to
therapy ( > 70 point decrease in CDAI, p <
0.001)
 67% achieved remission (CDAI < 150)
 Pts remained statistically lower than baseline
4 wks after completion of therapy
 Pts reported improvements in QOL
 After just 4 wks of therapy the ulcerated and
inflamed mucosa of one patient’s rectum was
healed.
 Pts with open fistulas had closure after
treatment
 Conclusion
 Dr. Smith concluded that LDN was effective and safe in the
treatment of CD.
 The only side effect seen was sleep disturbances (7 pts).
 The compelling results allowed Dr. Smith to receive a grant from
the NIH to run a phase 2 randomized double blind placebo
controlled trial called “Therapy with the Opioid Antagonist Naltrexone
Promotes Mucosal Healing in Active Crohn’s Disease: A Randomized
Placebo-Controlled Trial”
 “Therapy with the opioid antagonist
naltrexone promotes mucosal healing
in active Crohn’s disease”

Digestive Diseases & Sciences in 2011

Dig Dis Sci. 2011 Jul;56(7):2088-97. doi: 10.1007/s10620-011-1653-7. Epub 2011 Mar 8.
Therapy with the opioid antagonist naltrexone promotes mucosal healing in active
Crohn's disease: a randomized placebo-controlled trial.
Smith JP1, Bingaman SI, Ruggiero F, Mauger DT, Mukherjee A, McGovern CO, Zagon IS

 Trial Overview
 40 pts with CD were randomized to receive either
4.5 mg naltrexone daily or placebo for 12 wks.

 Primary outcome was a 70 point decline in CDAI.

 Secondary outcome was mucosal healing based

upon colonoscopy and appearance and histology.
Study Results

 88% of LDN pts had at least a 70 point

decline in CDAI vs 40% of placebo pts
(p = 0.009)
 78% of LDN pts had an endoscopic
response ( 5 point reduction in Crohn's
disease endoscopy index severity score
(CDEIS) from baseline) vs 28% in
placebo pts (p = 0.008)

Dig Dis Sci. 2011 Jul;56(7):2088-97. doi: 10.1007/s10620-011-1653-7. Epub 2011 Mar 8.
 Study Results

 Naltrexone promotes mucosal healing in Crohn’s disease. The endoscopic appearance of representative patients’ colonic
mucosa is shown at baseline (a, c) demonstrating erythema, edema, ulceration, and loss of vascularity. Corresponding H &
E histologic sections obtained from the same areas demonstrate marked inflammation and ulceration with crypt distortion
at baseline (a1 and c1). No change was found in the endoscopic appearance (b) or the histological score (b1) in subjects
randomized to placebo for 12 weeks. In contrast, the subjects treated with naltrexone for 12 weeks exhibited endoscopic
mucosal healing (d) and histologic examination showed decreased inflammatory cells with restoration of crypt architecture
(d1) Dig Dis Sci. 2011 Jul;56(7):2088-97. doi: 10.1007/s10620-011-1653-7. Epub 2011 Mar 8.
 Study Results: QoL

Dig Dis Sci. 2011 Jul;56(7):2088-97. doi: 10.1007/s10620-011-1653-7. Epub 2011 Mar 8.
Extended Open-Label
Study

Dig Dis Sci. 2011 Jul;56(7):2088-97. doi: 10.1007/s10620-011-1653-7. Epub 2011 Mar 8.
Extended Open-Label
Study

Dig Dis Sci. 2011 Jul;56(7):2088-97. doi: 10.1007/s10620-011-1653-7. Epub 2011 Mar 8.
LDN in Chronic Pain


 “Low Dose Naltrexone
for the treatment of
Fibromyalgia”
Arthritis and Rheumatism in 2013

Arthritis Rheum. 2013 Feb;65(2):529-38. doi: 10.1002/art.37734.

Low-dose naltrexone for the treatment of fibromyalgia: findings of a small,
randomized, double-blind, placebo-controlled, counterbalanced, crossover trial


assessing daily pain levels.
Younger J1, Noor N, McCue R, Mackey S.
 Trial Overview
 In a randomized double blind placebo-
controlled, counterbalanced, crossover
trial 31 women were given 4.5 mg of
naltrexone.
 57% of pts receiving LDN had a
significant (30%) reduction in pain.
 ½ of the participants reported feeling
either “much improved” or “very much
improved” after the trial.

Arthritis Rheum. 2013 Feb;65(2):529-38. doi: 10.1002/art.37734.

 Authors Conclusion
 The preliminary evidence continues to show that low-dose
naltrexone has a specific and clinically beneficial impact on
fibromyalgia pain. The medication is widely available, inexpensive,
safe, and well-tolerated.
“The use of low-dose Naltrexone (LDN) as
a novel anti-inflammatory treatment for
chronic pain”
Clinical Rheumatology in 2014

Clin Rheumatol. 2014; 33(4): 451–459.

Published online 2014 Feb 15. doi: 10.1007/s10067-014-2517-2
PMCID: PMC3962576
The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
Jarred Younger, Luke Parkitny, and David McLain

 Authors Conclusion
 “The totality of the basic and clinical research to date suggests that
LDN is a promising treatment approach for chronic pain conditions
thought to involve inflammatory processes..”
 “LDN may emerge as the first of many glial cell modulators that
could be used to treat chronic conditions”
 “As conventional anti-inflammatories have poor blood brain-barrier
permeability, we expect centrally active immune modulators to be
an area of interest in the future.”
 “Treatment of Complex Regional Pain
Syndrome (CRPS) Using Low Dose
Naltrexone (LDN)”
Journal of Neuroimmune Pharmacology in 2013

Journal of Neuroimmune Pharmacology

June 2013, Volume 8, Issue 3, pp 470-476
First online: 02 April 2013
Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN)
Pradeep Chopra , Mark S. Cooper
10.1007/s11481-013-9451-y

 Study Abstract

 Complex Regional Pain Syndrome (CRPS) is a neuropathic pain

syndrome, which involves glial activation and central sensitization in
the central nervous system. Here, we describe positive outcomes of
two CRPS patients, after they were treated with low-dose naltrexone
(a glial attenuator), in combination with other CRPS therapies.
Prominent CRPS symptoms remitted in these two patients, including
dystonic spasms and fixed dystonia (respectively), following treatment
with low-dose naltrexone (LDN). LDN, which is known to
antagonize the Toll-like Receptor 4 pathway and attenuate activated
microglia, was utilized in these patients after conventional CRPS
pharmacotherapy failed to suppress their recalcitrant CRPS
symptoms.
 CRPS

LEFT: Advanced CRPS

symptoms in Case 1. 4-5
years after onset of the
disorder, a Allodynia and
pronounced vasomotor
dysfunction are present in
the lower right extremity.
RIGHT: Post treatment
 Authors Conclusion
 Our use of LDN treatment for CRPS patients was motivated by a
presumed neuroinflammatory etiology for long-standing CRPS
symptoms. The remission of pain and dystonic spasms in Case 1, as
well a remission of all CRPS symptoms (including fixed dystonia) in
Case 2, provide evidence that a multi-modal interventional approach,
which includes low-dose naltrexone (a known glial attenuator), should be
considered as a treatment option for the treatment of CRPS patients,
particularly those patients with dystonic movement disorders
 “Letter to the Editor: Off-Label, Low-Dose Naltrexone for
Refractory Painful Diabetic Neuropathy.”

 Received Amitriptyline, Pregabalin, Duloxetine, Lamotrigine, and nonsteroidal anti-

inflammatory drugs (NSAIDs) at least 1 – 2 months on each therapy.

 Injectable vitamin B complex and vitamin-D

 Titrated LDN from 1mg to 4mg (2 weeks)

 Pain Before: 90% (0–100 points) VAS, 8 - McGill pain questionnaire, and 8-Likert pain
scale. Neuropathy symptom 9/9

 After: 5% (0–100 points) VAS, 2 - McGill pain questionnaire, and 1-Likert pain scale.
Sleep was good. Sensory loss still present.

Pain Med. 2016 Apr;17(4):790-1. Hota D, Srinivasan A, Dutta P, Bhansali A, Chakrabarti A.

 Conditions Possibly Related to
Endorphin Deficiency
 1. PMS
 2. Polycystic ovaries or Endometriosis
 3. TEBB (Tail End Brown Bleeding)
 4. Fatigue
 5. Low Mood
 6. Anxiety
 7. Sleep
 8. Family History of Autoimmunity
 9. Infertility

Courtesy of: Phil Boyle, MD “Novel uses for a licensed

medication” New Orleans, August 2013
Prescribing LDN


 Dose Titration
 Start with 1.5mg QD HS x 2 weeks
 Side effects (infrequently occur at this dose)
 Beneficial effect- continue at current dose
 No effect..Increase dose to 3mg QD HS x 2 weeks
 3mg QD x 2 weeks
 Side effects- decrease dose for 7 days
 Beneficial effect- continue at current dose
 No effect..Increase dose to 4.5mg QD HS x 2 weeks
 Usual Maintenance Dose: 4.5mg HS
 Side effects- decrease dose for 7 days or change time of dose
 Autoimmune Link
 Gluteomorphins (from gluten) and caseomorphins (from casein) act as
exogenous opioids that suppress immune function. Hence an autoimmune
diet needs to be free of gluten and dairy

 “LDN is most effective when combined with an autoimmune diet, free

of gluten and dairy, rich in fresh and fermented vegetables, with low to
modest amounts of high-quality protein”
 Dr. Thomas Cowan----

NOTE: Consider other food related sensitivities

 LDN-Compounding
 • Needs to be specially compounded as a Rapid Release* preparation
 (just means NOT a SLOW release formulation)

 – DO NOT use lactose or calcium carbonate as a filler

 – Preferably microcrystalline filler (avicel)

 Other dosage forms: Liquid, Transdermal

CLINICAL CONSIDERATIONS
 LDN-possible Side Effects
 Vivid Dreams

 Sleep Disturbance

 Nausea (generally will last for about 2 weeks)

 Headache

 Dry Mouth (over 95% acceptable)

 Patient Education
 Many prescribers are not properly educating patients on LDN use

 If side effects occur---WHAT DO YOU DO?

 Change time of day
 Change dosage—can lower dose significantly
 Suggest to be taken with food
 Exacerbation of allergies…

 Educate patients to “stick with it”--- up to a year in some cases

 Other remedies to be used with LDN

 Fish Oil, Quercetin, 5HTP, Probiotics, Vitamin D, Iodine, Vitamin A etc

 Certain conditions a pulsed therapy.. i.e. Cancer

 LDN- Drug Interactions
 Opioids (including Tramadol)

 Anti-rejection Immune suppressants

 Safe to combine with steroids

 Suggest to discontinue LDN 2 days before surgery and resume

after stopping opioid pain relief
 May use in combination with Gabapentin or Lyrica
 LDN-Cautions
 LDN is an opioid antagonist- may need to wean patients currently on long
term opioids over 10-14 days before starting LDN

 Hashimoto’s Thyroiditis patients on Thyroid replacement may need to

start at 1.5mg HS and monitor for a decrease in Thyroid dose as the LDN
may lead to a prompt decrease in the condition requiring a decrease in
Thyroid hormone replacement… also consider with Diabetic treatment

 Patients who have had organ transplants and are taking

immunosuppressive medications are cautioned against taking LDN
Low-Dose Naltrexone in Diseases’ Treatment: Global Review
Research Inventy: International Journal of Engineering And Science Vol.6, Issue 2 (February 2016), PP -01-04 Issn (e): 2278-4721, Issn
(p):2319-6483, www.researchinventy.com

Authors Conclusion: In reviewing the

published literature on LDN we conclude that
3 to 4.5mg per day in humans is effective for
idiopathic diseases with alterations in immune
system, as well as those ones with
inflammatory and tumor characteristics.
 Prescriber Feedback
 Best response so far has been chronic fatigue syndrome/fibromyalgia -
several patients with great pain relief and increased energy. Also one
Grave’s patient who has reduction in her methimazole dose with
ultimate plans to wean off methimazole and maintain on naltrexone.
It's been a nice therapy so far for me to use in my practice.

 I have another woman today whose rheumatoid arthritis symptoms

dissipated on your LDN (3 mg/day)! Very exciting indeed!

Timothy Petersen, MD, ECNU

Endocrinologist
 Recent unpublished LDN patient survey

 420 patient surveys sent

 126 (30%) patient responses

 Of the 126 patients:

 99/126 (78.6%) reported positive results
 27/126 (21.4%) discontinued use mostly due to side effects
 Most common: Sleep disturbance, Nausea and Headaches

 NOTE: Colleague reported response rates in the range of 60-80%

 Major conditions reported for LDN
therapy with positive outcomes

 Hashimoto’s
 Chronic Pain Syndromes
 Fibromyalgia & Chronic Fatigue
 Depression & Anxiety
 Various Autoimmune Conditions
 Various Gastrointestinal conditions
 Various Cancers
 Most effective dosage range

 10-15% responded at 1.5mg

 10-15% responded at 3mg

 30-35% responded at 4.5mg

 Time to response

 Most patients reported a positive response between 3 and 6

months of therapy

 Interestingly, in some autoimmune situations (i.e. MS and

Alzheimer’s) it took up to 12 months before a positive
response was noted
 Positive effects reported

 30% greater sense of well being

 25% increased energy

 20-25% decreased anxiety and depression

 20% had better sleep

 5% increased libido
 Ultra Low Dose Naltrexone
ULDN
 Dose: 1 to 4 micrograms (0.001 to 0.004mg) Taken with Opioids
 STUDY
 Analgesic effect at a significantly lower oxycodone dose
 Improved safety significant reduction in number of moderate to severe events
 Constipation by 44%
 Somnolence by 33%
 Pruritis by 51%
 oxytrex is the first opioid analgesic to demonstrate reduced physical
dependence after prolonged opioid therapy in a large well controlled study
The Journal of Pain Volume 7, Issue 12, December 2006, Pages 937–946
Oxytrex Minimizes Physical Dependence While Providing Effective Analgesia: A Randomized Controlled Trial
in Low Back Pain
Lynn R. Webster⁎, Peter G. Butera†, Lauren V. Moran†, , , Nancy Wu†, Lindsay H. Burns†, Nadav Friedmann†
 Opioid
tolerance/dependance
stems from a switch in
signaling

Published in: Lynn R Webster; Expert Opinion on Investigational Drugs 2007, 16, 1277-1283.
DOI: 10.1517/13543784.16.8.1277
Copyright © 2007 Informa UK Ltd
 ULDN: ultra-low-dose opioid
antagonist/agonist formulation, may
improve several worrisome side
effects of chronic opioid therapy. Its
desired clinical benefits include
slowing the development of physical
dependence and analgesic
tolerance and enhancing analgesia.
The specific mechanism seems to
be the blocking of a switch in G-
protein coupling that occurs with
prolonged opioid use.

Published in: Lynn R Webster; Expert Opinion on Investigational Drugs 2007, 16, 1277-1283.
DOI: 10.1517/13543784.16.8.1277
Copyright © 2007 Informa UK Ltd
 Very Low Dose Naltrexone
VLDN
 Dose: 125 to 250 micrograms (0.125 to 0.25mg)
 Use to mitigate opioid withdrawl
 At the end of treatment, there were more subjects rated ‘much’ or ‘very much’
improved compared with baseline in the NTX groups (χ2 = 29.49 (2);
P = 0.001). In particular, 30.8% of patients receiving methadone and placebo
NTX either were doing worse than at admission, or showed minimal or no
improvement by discharge, compared with <11% in each VLNTX group.
 There was an overall 37% decrease in opiate craving scores across treatment
condition between days 1 and 6
Mannelli, P., Patkar, A. A., Peindl, K., Gorelick, D. A., Wu, L.-T. and Gottheil, E. (2009), CLINICAL
STUDY: Very low dose naltrexone addition in opioid detoxification: a randomized, controlled trial.
Addiction Biology, 14: 204–213. doi:10.1111/j.1369-1600.2008.00119.x
Questions?