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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:
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 Gastrointestinal Diseases
e Celiac
Multiple Sclerosis Ulcerative Colitis
Hashimoto’s Thyroiditis Crohn's
Parkinson's Disease IBS/IBD
Alzheimer’s Dermatologic diseases
Rheumatoid Arthritis Eczema
Polymyalgia Rheumatica Psoriasis
Sjogren’s Infectious diseases
Lupus Lyme’s Disease
Myasthenia Gravis
Proposed Indications for LDN
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
–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.
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
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
Recently discovered:
Naltrexone HCl is a 50:50 mixture of
both D (dextro) & L (levo) Isomers
http://www.micromedexsolutions.com.ezproxy.lib.uconn.edu
Naltrexone-Mechanism of Action
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
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”
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.
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
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.
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.
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
Sleep Disturbance
Headache
Hashimoto’s
Chronic Pain Syndromes
Fibromyalgia & Chronic Fatigue
Depression & Anxiety
Various Autoimmune Conditions
Various Gastrointestinal conditions
Various Cancers
Most effective dosage range
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?