LDN

Low Dose Naltrexone

Special Thanks to: Michael Gresh

PharmD Candidate 2017
University of Connecticut
Katelyn Zachau, DO
Board Certified Family Medicine
Practicing Integrative Medicine & Primary Care
Everwell Integrated Medicine, LLC
Collaborative Natural Health Partners, LLC
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
 Review of Naltrexone

 Introduction to Low Dose Naltrexone (LDN)

 Mechanism of Action of LDN-cellular science

 Studies on LDN

 How to prescribe LDN

 Clinical Experience with LDN

 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!!

 Confirm normal kidney and liver function

 Some elderly patients on 300mg naltrexone develop abnormal liver

function tests
 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?
 Dose: 1.5-4.5 mg PO taken once nightly (or daily)

 MOA:
 Brief period of opioid blockade  adaptive increase in endorphin and
enkephalin production
 Endorphin & Enkaphalin
 Work on opioid receptors to produce analgesia
 Increase in endorphins prolonged upregulation of important elements of
the immune system

 This paradoxical effect has not been seen with higher dosages (50mg)
Proposed Indications for LDN
 Autoimmune disorders  Malignancies/cancers

 Cardiac diseases  Neurologic diseases

 Dermatologic diseases  Ocular diseases

 Ear, Nose, Sinus & Throat  Psychological disorders

 Endocrine diseases  Pulmonary disease

 Gastrointestinal diseases  Rheumatologic disorders

 Hematologic/Blood marrow disorders  Urologic diseases

 Infectious diseases  Vasculitis

 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
Cellular Science
 LDN-Mechanism of Action
 Reversible competitive antagonism of LDN 1.5mg to 4.5mg taken
between 9PM and 3AM blocks the opioid receptor transiently

 Briefly and temporarily blocking endorphin receptors at night

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, emotional instability 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 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.
 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 pentapeptide
 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
 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)
 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!!!

 When activated – glia release a variety of substances (proinflammatory

cytokines, chemokines, etc.) resulting in inflammatory and excitatory
factors that can cause sickness behaviors such as pain sensitivity, fatigue,
cognitive disruption, sleep disorders, mood disorders, and general malaise
 These substances in turn increase the excitability of nearby neurons
 Its expression is up-regulated under neuroinflammatory conditions.
 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
 Opioid antagonists (Naloxone/Naltrexone) block TLR4 signaling
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, inducing the release of proinflammatory products, especially proinflammatory
cytokines.
 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.
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
Dig Dis for 12 weeks
Sci. 2011 Jul;56(7):2088-97. exhibited endoscopic
doi: 10.1007/s10620-011-1653-7. mucosal
Epub 2011 Mar 8. healing
 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.
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.
 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
 “Low dose naltrexone in the treatment of
dissociative symptoms”

Nervenarzt. 2015 Mar;86(3):346-51. doi: 10.1007/s00115-014-4015-9.

[Low dose naltrexone in the treatment of dissociative symptoms].
[Article in German]
Pape W1, Wöller W.


 Study Results
 The low dose treatment with naltrexone proved to be effective
whereby 11 out of 15 patients reported immediate positive effects
and 7 described a lasting helpful effect. The majority of patients
who felt positive effects reported a clearer perception of both their
surroundings and their inner life. Assessment of reality and dealing
with it improved as did the perception of their own body and
affects as well as self-regulation. The treatment was very low in side
effects.
 Authors Conclusion
 Treatment with low-dose naltrexone may be a helpful element in
the treatment of patients with complex posttraumatic stress
disorder. However, it has to be realized that the decrease of
dissociation may lead patients to a not yet resolvable challenge, in
as much as dissociation had previously been a necessary
mechanism of self-protection
 LDN-Female
Reproductive Disorders


 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
 LDN-PMS

 Phil Boyle, MD “Clinical experience in treating PMS is 80%

response”

 • Many say – I have my life back – I am me again!!

The International Institute for Restorative Reproductive Medicine

www.iirrm.org – “We intend to do a clinical trial with LDN 3-4.5mg nightly”

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

medication” New Orleans, August 2013
Current concepts of beta-endorphin physiology
in female reproductive dysfunction
Elevated or high levels of beta-endorphin have been associated
with:
 Exercise associated amenorrhea, stress-associated amenorrhea,
and polycystic ovarian syndrome. …..(consider: High Dose
Naltrexone 25mg BID)
Depressed or low levels of beta-endorphin have been associated
with:
 PMS and menopause, (Endometriosis – Hilgers) ……(LDN 3-
4.5mg nightly) Galway, Ireland
 LDN-PRESCRIBING INFO
 Start with 1.5mg QD HS x 2 weeks
 Side effects (almost never happens 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
 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)

CLINICAL CONSIDERATIONS
 LDN-possible Side Effects
 Vivid Dreams

 Sleep Disturbance

 Nausea (generally will last for about 2 weeks)

 Headache

 Dry Mouth (over 95% acceptable)

 LDN- Drug Interactions
 Opioids (including Tramadol)

 • Safe to combine with steroids

 • Suggest to discontinue LDN 2 days before surgery and resume

after stopping pain relief
 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

 Patients who have had organ transplants and are taking

immunosuppressive medications are cautioned against taking LDN
 Other areas for use of LDN
LDN has been useful in diseases that are triggered by a deficiency in
endorphins such as autoimmune diseases and cancer, as well as diseases
that are accelerated by a deficiency in endorphins such as HIV/AIDS.

● Multiple Sclerosis ● Lymphoma

● Parkinson’s Disease ● Lung Cancer
● Alzheimer’s Disease ● Breast Cancer
● Endometriosis ● Liver Cancer
● Dystonia ● Systemic Lupus
● Psoraisis ● Complex Regional Pain
Syndrome
 LDN Therapy???
 Cancer
 Autoimmune Diseases
 HIV/AIDS
 CNS Disorders
 Anecdotal reports continue to be received concerning beneficial effects of LDN on
the course of Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis
(ALS—Lou Gehrig’s disease), and primary lateral sclerosis. Dr. Jaquelyn
McCandless has found a very positive effect of LDN, in appropriately reduced
dosage and applied as a transdermal cream, in children with autism.
Low-dose naltrexone for disease prevention and quality of life
Norman Brown a,*, Jaak Panksepp b
Medical Hypotheses June 2008

 Accumulating evidence suggests that LDN can promote health supporting

immune-modulation which may reduce various oncogenic and
inflammatory autoimmune processes.
 Since LDN can upregulate endogenous opioid activity, it may also have a
role in promoting stress resilience, exercise, social bonding, and emotional
well-being, as well as amelioration of psychiatric problems such a autism
and depression.
 It is proposed that LDN can be used effectively as a buffer for a large
variety of bodily and mental ailments through its ability to beneficially
modulate both the immune system and the brain neurochemistries that
regulate positive affect.
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.
Questions?