Post on 18-Feb-2022
Immunology Part-6:
LDN Updates and Dosing
Information
Dr. Paul S. Anderson
1.5 hours Pharmacology CE – April 20, 2021
© PS Anderson and www.ConsultDrA.com 2021
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Abstract
Since the publication of the data regarding cyclic dosing
from St. George’s University by Liu, et. al in 2016 the
question of continuous dosing of LDN versus cyclic dosing
has been posed.
In this presentation Dr. Anderson will discuss the cell and
tumor biology – pharmacology interface where this idea
comes from and develop the concept using new
immunobiology data around LDN. He will share dose
strategies and clinical applications.
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Outline:
I. Introduction
II. What really is “Low Dose” Naltrexone and Why do we use it?
III. MOA: How does it work?
IV. Data Updates – Immunobiology – Condition Data
V. Oncology and Naltrexone
VI. Why is it SO Nonlinear…
VII.Practicalities
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QUESTIONS ABOUT -----? Go here:
https://www.consultdranderson.com/contact/
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If you are reading the slides and not listening to audio:
• A LOT is not on the slides.
• Many questions I get are answered in the audio portion
• So, it’s fine to skim the slides but please do both the “A”
and the “V” parts
• Thank you!
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Note: This is an update:
• Prior LDN webinar is still valid, and I am not repeating
much from that here.
https://www.consultdranderson.com/courses/28-immunology-
part-1-low-dose-naltrexone/
• The point is to update the cell and tumor biology regarding
LDN, new research publications etc. Especially publications
and clinical vignettes of the past three years.
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Excellent review of what we know and MOA data:
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Why an update?
• Confusing dosing strategies
• To cycle or not to cycle?
• Is less better?
• Is more better?
• Or????
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Low Dose???
Where did the “magic” 4.5 mg dose come from?
According to the LDN Research Trust:
In the 1980s, Dr. Ian Zagon and Dr. Patricia McLaughlin (at Penn State) began investigating LDN.
Bernard Bihari, MD, (1931-2010) was the discoverer of the clinical effects of low-dose naltrexone (LDN) in humans. In his groundbreaking clinical trial of patients with HIV/AIDS at Downstate Medical Center in 1985-86.
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Where did the “magic” 4.5 mg dose come from?
At an LDN Research Trust Conference I spoke with a colleague of Dr.
Bihari, regarding where the idea of “What actually is ‘low dose
naltrexone?’”…
“In an interview Dr. Bihari said ‘we know lower doses
work. We know we see the best clinical results
between 1 and 10 mg daily. So, we set the idea of
“low dose” at 4.5 – 5 mg.’ Yes, that is it.”
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We know more about “How it
Works”
Clinician / Patient Experience
LDN Thoughts
• Although rarely an effective mono-therapy:
– I usually see LDN as an excellent adjunct to all the usual
interventions.
– Many people (who do not have initial aggravations – see
below) state that they do not notice a difference BUT
when you withdraw the LDN they do report aggravation
of Sn/Sx
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Other Clinicians:
• Over the years I have interacted with a number of clinicians who report clinical benefits in ”cyclic dosing” of LDN in many patients.
• More and more are following those guidelines for cancer patients
• Most non-oncology indications have been in autoimmune patients
• Some have been in chronic pain patients
• Dr. Bihari does not feel that there is a need for any such breaks from the daily use of LDN, whereas, Dr. Lawrence feels that there might be some sort of accommodation that might occur. He advocates taking a break about every 10 days or so I think (not sure about the schedule because I have never taken an intentional break, I have missed a dose once or twice and never noticed a difference on those days when I did).
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Dr. MR Lawrence and Cycling in AI:
Dr Lawrence liking cycling dose as he has MS (His notes from another blog) This
temporary increase in symptoms may also perhaps be explained when we consider the
manner in which this drug is expected to work. Initially, MS occurs due to a reduction in
the activity of the controlling influence of the suppressor T-cells within the immune
system. During an acute relapse, the overall number of T-cells is reduced, the normal
balance of helper T-cells and suppressor T-cells is disrupted and the damaging helper
(CD-4) T-cells tend to predominate. This is the situation most pronounced during an
acute relapse but occurs similarly, but to a lesser extent, in chronic progressive MS.
Under the influence of LDN there will be an expected increase in the overall numbers
of T-cells but, because the CD-4, helper T-cells tend to predominate at this time, an
increase in their numbers will expectedly tend to increase MS symptoms. It is only
when the numbers of suppressor T-cells effectively "catch up" that the normal balance
is restored and symptoms once again diminish and improve. Dr. M R Lawrence
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The “Norwegian” Alternative Dosing Strategy
patterned after information from Dr. Tom Gilhooly
Norwegian document notes that “a larger dose of LDN possibly can be used to
reduce or avoid aggravation of symptoms that can occur with the traditional
dose strategy for LDN. It also suggests that this strategy is more suitable for
patients who have constant inflammatory conditions in the body (eg.
fibromyalgia, ME, progressive MS, arthritis, etc).”
• Original Norwegian document translated to English by Brian Haviland and
Steinar Hauge for Facebook group “GotEndorphins LDN”
• https://ldnresearchtrust.org/sites/default/files/Dr%20Tom%20Gilhooly%20LD
N%202013%20Conference.pdf
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Steinar Hauge of the Norwegian LDN site www.ldn.no
At a low dose (1.5 mg) "stimulation and stabilization" is strong and immune suppression is
hardly present. When immune suppression is weak and the immune system is stimulated,
the autoimmune reactions are enhanced and many are experiencing symptom aggravation
until stabilization occurs.
At 3 to 4.5 mg the "stimulation and stabilization" action is at maximum strength and the
immune suppression is weaker. This explains why starting at a 3 mg dose may give a
tough startup sometimes.
At high doses (6 mg) the immune suppression action is strong and "stimulation and
stabilization" is weaker. Therefore symptom aggravation will likely be less but your immune
system will still be gently stimulated and the stabilization of the immune system will be in
place gradually.
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Steinar Hauge of the Norwegian LDN site www.ldn.no
This groups idea comes from the basis that:
“LDN first stimulates and then stabilizes the
immune system as a result of increased endorphin
levels.”
(This idea does match the data I quote below from
McLaughlin 2015).
**NOTE: They do NOT recommend this in cancer.
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Dose reduction from 6 mg (2 x 3 mg) LDN:
1. Try 6 mg for a few days but stop if experiencing severe discomfort. It may take a few
days before any effect happens.
2. If one feels worse after directly starting at 6 mg (3 mg BID) LDN or if one feels worse after a
period of 6 mg LDN then the dose is probably too high and should be lowered down to 4.5
mg.
3. If one has dosed at 6 mg (3 mg BID) LDN for 2 to 3 weeks with good effect, try to decrease
to 4.5 mg. If results are not as good at 4.5 mg, then go back to 6 mg and stay at this dose
even longer before again trying to reduce to 4.5 mg. Attempting to move periodically to 4.5
mg may provide better results. N.B. If reduction does not give better results, you can
continue to use 6mg (3mg BID) as standard dose.
4. Whether to take 3 mg, 4.5 mg or 3mg BID as standard dose is individual and will vary from
person to person. If one has reduced the dose to 4.5 mg and has had good effects then
stay at this dose. If the effects are still poor, but better than the 6 mg, one can try to vary
between 3 and 4.5 mg to see what dose works best. When you have found the dose that
seems to work best (eg. 3mg, 4,5mg or 3mg BID), then stay at this dose.
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Cort Johnson. Weird Dosing, Backward Protocols and Rejections – in ME/CFS and Fibromyalgia
• “Loading Dose” idea then tapering
• Higher doses of 6 mg QD to BID
• Interesting case descriptions
https://www.healthrising.org/blog/2020/03/02/strangeness-low-dose-naltrexone-
chronic-fatigue-fibromyalgia-dosing/
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LDN does appear to have a distribution of effects
through a variety of dose and timing schedules:
• Immune stimulation and balancing / modulation appear to be at doses under
5 mg.
• Doses above 5 – 6 mg (and higher) are more immunosuppressive
• And, just as humans have differing effect from opiate drugs from person to
person, some people may experience these “modulating versus suppressive”
effects at lower doses.
– See also: Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)—Review of
Therapeutic Utilization. Medical Sciences. 2018; 6(4):82.
https://doi.org/10.3390/medsci6040082
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LDN: Suppression even at 7 mg
Animal Experimental Models
PA Note: Of note the LDN dose was too high (eq to 7 mg IV in a human) so the larger suppression is likely exaggerated.
“The OGF-OGFr pathway regulates proliferation of peripheral immune cells following stimulation by MOG35–55 antigen. Exogenous OGF or endogenous OGF following LDN treatment inhibited CD4+ and CD8+ T and B cell replication within the spleen and draining inguinal nodes within the first week of immune-related response, and in spinal cord tissue on day 15 following antigen stimulation. These data support that modulation of the OGF-OGFr pathway is an effective therapeutic paradigm for MS.”McLaughlin PJ, McHugh DP, Magister MJ, Zagon IS. Endogenous opioid inhibition of proliferation of T and B cell subpopulations in response to immunization for experimental autoimmune encephalomyelitis. BMC Immunol. 2015;16:24. Published 2015 Apr 24. doi:10.1186/s12865-015-0093-0
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Suppressive dose (animal model) at 10 mg/kg:
N. Xu, et al. Naltrexone (NTX) relieves inflammation in the collagen-induced- arthritis CIA) rat models
through regulating TLR4/NFκB signaling pathway. International Immunopharmacology 79 (2020) 106056
NTX could relieve the severity of arthritis in CIA rat models, and10 mg/kg is the optimal
dose. NTX could regulate T lymphocyte subsets: CD4+/CD8+T cells, Th1/Th2 cells and
Th17/Treg cells, decrease the expression of the proinflammatory cytokines TNF-α, IL-
6, IL-12 alpha and IL-17, increase the expression of the anti-inflammatory cytokine IL-
10, and regulate immune responses to reconstruct the immune balance to alleviate
inflammation. NTX could interact with MOR and DOR in the spleen, inhibit the
TLR4/NF-κB signaling pathway and regulate systemic immune responses to alleviate
inflammation. In addition, NTX could interact with KOR and DOR in synovial tissues
inhibiting the TLR4/RANKL/NF-κB pathway to decrease the erosion of articular
cartilage and bone tissue in joints by inhibiting osteoclast differentiation. Therefore,
NTX could provide RA patients with a new alternative therapy, especially for those who
may not have obvious therapeutic effects from traditional control drugs and biological
agents, with broad application prospects and great clinical feasibility.
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Immunology
Clin Rheumatol (2014) 33:451–459
Double blind crossover FMS study at 4.5 mg QHS:
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Luke Parkitny and Jarred Younger. Reduced Pro-Inflammatory Cytokines after Eight
Weeks of Low-Dose Naltrexone for Fibromyalgia. Biomedicines 2017, 5, 16;
doi:10.3390/biomedicines5020016
10-week, single-blind, crossover investigation of the immune effects of LDN in
women with FM. Each participant first took part in a two-week baseline phase
that was immediately followed by an eight-week LDN administration phase.
While participants were told they could receive the placebo at any time during
the protocol, no placebo capsules were actually administered
Rx: During the medication administration phase, each participant self-
administered LDN at a 4.5 mg oral dose, taken in capsule form, at least one
hour before going to bed at night. A change to a lower dose of 3.0 mg was
made available to the participant if they experienced unpleasant adverse
effects at the standard dose.
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Luke Parkitny and Jarred Younger. Reduced Pro-Inflammatory Cytokines after Eight
Weeks of Low-Dose Naltrexone for Fibromyalgia. Biomedicines 2017, 5, 16;
doi:10.3390/biomedicines5020016
Cytokines: In our primary analyses, we found the following inflammatory
plasma markers to be significantly reduced at Drug compared to BL
(baseline): IL-1, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL12p40, IL-12p70,IL-15, IL-
17A, IL-27, IFN-, TGF-, TGF-, TNF-, and G-CSF
We found that the cytokines most suppressed by LDN are known to
promote nociception, allodynia, and hyperalgesia, including TNF-α, IL-1β,
IL-2, IL-6, IL-15, and IL-17
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Bolton MJ, Chapman BP, Van Marwijk H. BMJ Case Rep 2020;13:e232502.
doi:10.1136/bcr-2019-232502
This series of three case reports compiled by people with
long-term ill-health due to chronic fatigue syndrome shows
the range of responses they observed when taking LDN,
from life changing to a reduction in some symptoms only.
Treatment doses ranged from 4 to 12 mg.
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Olli Polo, Pia Pesonen & Essi Tuominen (2019) Low-dose naltrexone in the
treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fatigue: Biomedicine,
Health & Behavior, 7:4, 207-217, DOI: 10.1080/21641846.2019.1692770
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Olli Polo, Pia Pesonen & Essi Tuominen (2019) Low-dose naltrexone in the
treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fatigue: Biomedicine,
Health & Behavior, 7:4, 207-217, DOI: 10.1080/21641846.2019.1692770
A low dose (3.0–4.5 mg/day, low-dose naltrexone, LDN) appears to
have an opposite effect [to high dose naltrexone], enhancing the
endorphin effect [5].
This is thought to have relevance in illnesses such as ME/CFS,
where insufficient secretion of opioid peptides affects immune
response or pain control [6,7], or the release of pro-
inflammatory cytokines [8,9].
Recently, LDN was shown to restore the impaired transient
receptor potential melastatin 3 ion channel function in natural
killer cells of ME/CFS patients [10].
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Olli Polo, Pia Pesonen & Essi Tuominen (2019) Low-dose naltrexone in the
treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fatigue: Biomedicine,
Health & Behavior, 7:4, 207-217, DOI: 10.1080/21641846.2019.1692770
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Olli Polo, Pia Pesonen & Essi Tuominen (2019) Low-dose naltrexone in the
treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fatigue: Biomedicine,
Health & Behavior, 7:4, 207-217, DOI: 10.1080/21641846.2019.1692770
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Olli Polo, Pia Pesonen & Essi Tuominen (2019) Low-dose naltrexone in the
treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fatigue: Biomedicine,
Health & Behavior, 7:4, 207-217, DOI: 10.1080/21641846.2019.1692770
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Olli Polo, Pia Pesonen & Essi Tuominen (2019) Low-dose naltrexone in the
treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fatigue: Biomedicine,
Health & Behavior, 7:4, 207-217, DOI: 10.1080/21641846.2019.1692770
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Olli Polo, Pia Pesonen & Essi Tuominen (2019) Low-dose naltrexone in the
treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Fatigue: Biomedicine,
Health & Behavior, 7:4, 207-217, DOI: 10.1080/21641846.2019.1692770
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MS
These observations have been optimized to work in favor of therapeutic treatment of MS. Thus, LDN has become a widespread therapeutic used to safely inhibit inflammatory processes by inhibiting proliferation of T-lymphocytes and B-lymphocytes following a peripheral autoimmune trigger, and to inhibit T-cell infiltration into the CNS (17).
From: Multiple Sclerosis: Perspectives in Treatment and Pathogenesis. Ian S. Zagon and Patricia J. McLaughlin (Editors), Codon Publications, Brisbane, Australia. ISBN: 978-0-9944381-3-3; Doi: http://dx.doi.org/10.15586/codon.multiplesclerosis.2017.ch8
Quoting [17]. McLaughlin PJ, Zagon IS. Duration of opioid receptor blockade determines clinical response. Biochem Pharmacol. 2015;97:236–246. http://dx.doi.org/10.1016/j.bcp.2015.06.016
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Citation: Cant R, Dalgleish AG and Allen RL (2017) Naltrexone Inhibits IL-6 and TNFαProduction in Human Immune Cell Subsets following Stimulation with Ligands for
Intracellular Toll-Like Receptors. Front. Immunol. 8:809. doi: 10.3389/fimmu.2017.00809
Endometriosis?
O. V. Golianovskyi, et.al. Prospective of low dose
naltrexone use in treatment of autoimmune pathology
and endometriosis. Reproductive Endocrinology No. 55
(2020) / Gynecology 11-2020
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I’d download the next paper before the authors are
all killed mysteriously…
Or me…
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Choubey - 2020
LDN stimulates the release of b-endorphins by acting on the opioid receptor (Gold et al., 1982; The Uses of Low- Dose Naltrexone in Clinical Practice, 2020). LDN acts as a TLR4 antagonist, in a human pilot study (4.5mg of LDN daily) significantly reduced serum pro-inflammatory cytokines (IL)-1, IL-2, IL-12, IL-18, etc (Parkitny and Younger, 2017). Importantly, low cost, low side effects, no reports of LDN interactions with other medications, and oral availability make LDN as a lucrative option to be used as an immunomodulatory agent and may be considered for use in combination with antiviral drugs or hydroxychloroquine for the treatment of severe or critical cases of COVID-19.
Our data provide a proof-of-concept for the potential feasibility of repurposing of FDA approved non-peptide opioid antagonist; naltrexone as host-targeted broad-spectrum antiviral therapies to combat COVID-19 infections. The next step will be to confirm data in COVID-19 patients. LDN alone or as an adjuvant therapy with hydroxychloroquine or an antiviral agent may give physicians more time to provide supportive treatment for patients with COVID-19.
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Oncology
1983 Observations:
Dichotomous biological responses following different dosages of naltrexone and
thus different durations of opioid receptor blockade were first reported in 1983 (18).
Low dosages (0.1 mg/kg) of naltrexone inhibited the growth of the neuroblastoma
tumors, but higher dosages (10 mg/kg) of naltrexone were not more inhibitory and, in
fact, resulted in enhanced tumor growth. This was the first indication that the action
of receptor blockade did not directly correlate with antagonist dosage (18).
*** Note this is 7 mg versus 70 mg Naltrexone***
From: Multiple Sclerosis: Perspectives in Treatment and Pathogenesis. Ian S. Zagon and
Patricia J. McLaughlin (Editors), Codon Publications, Brisbane, Australia. ISBN: 978-0-
9944381-3-3; Doi: http://dx.doi.org/10.15586/codon.multiplesclerosis.2017.ch8
Quoting [18]: 18. Zagon IS, McLaughlin PJ. Naltrexone modulates tumor response in
mice with neuroblastoma. Science 1983;221:671–673.
http://dx.doi.org/10.1126/science.6867737
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https://ldnresearchtrust.org/rof-angus-dalgleish-md-role-ldn-
cancer-management-low-dose-naltrexone
LDN 03-11-2020
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LDN + Chemosensitization
• All three showed positive cell line sensitization when
dosed on a cyclic basis (next slide):
1. Gemcytabine
2. Oxaliplatin
3. Cyclophosphamide
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LDN High versus Low dose:
• The following slide depicts the effect of two variables:
– Low versus High dose of LDN
– Continuous versus punctuated LDN dosing
– Both assessed via cell number and percent viability.
• The dose as well as dosing strategy both affected these
criteria.
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LDN HDN LDN HDN
No break - Break - No break - Break No break - Break - No break - Break
https://ldnresearchtrust.org/sites/default/files/202
0-04/Dosing-Info-a4_0.pdf
Protocol guideline from the LDN website for cancer:
1.5mg daily for 7 days increasing by 1.5mg weekly until
on 4.5mg for 7 days. Once stable on dose of 4.5mg for 7
days – start alternating 3 days on 3 days off if indicated.
** Of note, for simplicity and patient compliance I use 4
days on and 3 days off so they are on a weekly cycle.
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Oncology Dosing
Starting doses can be anywhere from 0.5 mg to 1.5 mg and is increased up to
4.5 mg; which is the maximum dose for Low Dose Naltrexone. Specifically for
cancer patients, the dose should be a goal daily for at least 7 days before
starting an "on/off cycle"
● An "on/off cycle" consists of 4 days on and 3 days off LDN
● The 3 days off should fall directly before chemotherapy treatment.
Although there are no known contraindications with chemotherapy, it is
recommended to avoid use together until further research is completed
It has been seen in some cancer patients, that taking a CBD product on the 3
days off increases the anti-tumor effect of LDN
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Case
Comments – Why?:
• “I find LDN works best when Vitamin D levels are
optimized.”
• “I never start LDN early in an AI case or they flare.”
• “All my LDN patients seem to flare.”
• And so on…
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Brief case pair:
• I will verbally describe two autoimmune cases that
had different responses to LDN with a standard 1.5
/ 3.0 / 4.5 dose taper.
• Both had remitting and relapsing MS with
complaints of transient neuropathy, transient
aphasia and fatigue.
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Brief case pair:
• Case-1 aggravated with all doses and
required an increase to 3 mg BID for a month
then a reverse taper to 4.5 mg which
ultimately was cycled 4 days on and 3 days
off.
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Brief case pair:
• Case-2 had no aggravation and had
symptomatic lessening at the 3-week mark on
her 4.5 mg dose.
• She was stable at 4 weeks and then went to a
4 day on / 3 day off cycle and stayed stable.
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The difference?
• The underlying parts of the case and how well they were
being addressed:
– GI function and health
– Environmental toxicity
– Nutrient absorption and sufficiency
– Endocrine balance
– Physical factors (Movement, physical medicine etc.)
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Alternative dose forms:
● Sublingual drops
o Drops are placed under the tongue from a dropper bottle
● Creams: 0.5 mg/mL
o Useful for children who you have difficulty administering the other
formulations, or those who are allergic to additives in other formulations of LDN
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Practicalities
To dose at night or morning:
• May be better at night
• Likely not a huge issue (especially with sleep disruption
and nightmares)
• Try in the PM first and switch to AM as needed for the
case
• It is better to use it sometime than not…
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After a great deal of research and many thousands of
doses in multiple medical indications:
• As with everything in medicine, nobody knows
everything.
• Humans and their immune systems are not all the
same.
• We of course want “one answer / one protocol” to
use – which is not reasonable when interacting with
the human immune system.
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After a great deal of research and many thousands of
doses in multiple medical indications:
• There are known outliers in LDN response, and
sometimes very low or ultra low dose schedules
work when “typical” doses do not.
• Similarly, sometimes higher doses work (especially
in FMS / CFS-ME) when typical doses do not.
• So, this has led me to the following clinical
conclusions:
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After a great deal of research and many thousands of
doses in multiple medical indications:
• In cancer I generally ramp up to 4.5 mg in 1.5 mg
increments for 1-2 weeks then cycle 4.5 mg 4 days
on and 3 days off.
• In very sensitive cancer patients I will ramp the
dose up 0.5 mg at a time (and still cycle the dose 4
days on and 3 off).
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After a great deal of research and many thousands of
doses in multiple medical indications:
• In autoimmunity I either use a 0.5 mg slow taper or a 1.5 mg taper, and then when an effective dose is found (usually between 1.5 and 4.5 mg assessed over 4 weeks on a 7 day a week dose) I then (if tolerated) cycle that 4 days on and 3 off as well. If cycling isn’t tolerated, then do 7 days a week.
• If the patient is sensitive and aggravates (especially in CFS-ME / FMS or uncontrolled autoimmunity) Then the idea of suppressive doses first (such as 3 mg BID for 2-4 weeks; then a ramp down) are worth trying.
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After a great deal of research and many thousands of
doses in multiple medical indications:
• In some patients regardless of the use of more “standard” dosing they will still not be able to tolerate the standard dose ranges.
• These are times where a “Very-low” or “Ultra-low” dose strategy may be required.– Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)—
Review of Therapeutic Utilization. Medical Sciences. 2018; 6(4):82. https://doi.org/10.3390/medsci6040082
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VLDN - ULDN
In a dosing range at less than 1 mcg per day, oral naltrexone or intravenous
naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding
protein involved in mu-opioid receptor signaling. This dose is termed ultra low-
dose naltrexone/naloxone (ULDN). It has been of use in postoperative control
of analgesia by reducing the need for the total amount of opioids following
surgery, as well as ameliorating certain side-effects of opioid-related treatment.
A dosing range between 1 mcg and 1 mg comprises very low-dose
naltrexone (VLDN), which has primarily been used as an experimental adjunct
treatment for boosting tolerability of opioid-weaning methadone taper.
Med. Sci. 2018, 6, 82; doi:10.3390/medsci6040082
(*A super bad ass lit review of the relevant data.)
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VLDN
To investigate the feasibility of administering antagonists with opiates without
intense withdrawal during detoxification, 5 methadone maintained patients were
evaluated while tapering methadone and receiving at the same time very low
(0.125 mg), then increasing daily doses of naltrexone in the course of a 6-day,
day hospital treatment. Reduced quantities of adjunctive medications were
administered, as compared to the standard protocols, the treatment was
completed without incidents or particular discomfort and all patients were easily
induced to naltrexone maintenance by the day of discharge.
Mannelli P, Gottheil E, Buonanno A, De Risio S. Use of very low-dose
naltrexone during opiate detoxification. J Addict Dis. 2003;22(2):63-70.
doi: 10.1300/J069v22n02_05. PMID: 12703669.
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ULDN J Pain and Symptom Management – Vol25 No6, 2003http://rsds.org/wp-content/uploads/2014/12/ultra-low-dose-oral-naltrexone.pdf
• We present a patient with painful diabetic peripheral neuropathy who experienced significant improvement after the addition of an “ultra-low” dose of oral naltrexone (1microgram twice daily) to his opioid regimen. This observation suggests that an “ultra-low” dose of oral naltrexone can be utilized safely and may be another strategy to increase the potency of an opioid agonist.
• “ultra-low” doses, caused prolongation of the action potential duration (APD).6 This excitatory opioid effect was blocked by “ultra low” doses of naltrexone or naloxone.
• A compounding pharmacy prepared a solution of 1 mg of naltrexone (from powder) in 1 liter of sterile water. A total of 100 cc of the solution was stored in a caramel container, delivered to the patient, and kept out of the light in the refrigerator. We instructed the patient to take 1 cc twice daily
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Jackson D, Singh S, Zhang-James Y, Faraone S and Johnson B (2021) The Effects
of Low Dose Naltrexone on Opioid Induced Hyperalgesia and Fibromyalgia.
Front. Psychiatry 12:593842. doi: 10.3389/fpsyt.2021.593842
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LDN Prescribing
LDN Dosing in Oncology
• DOSING:
– In the oncology setting (and patient not on opiates) I will
ramp the dose faster:
• Often 2.5 then 4.5 mg
• Alternatively (if I feel a slower ramp is needed) 1.5 then 3.0
then 4.5 mg ramped up every 2-4 weeks.
• CYCLE: 4 days “on” and 3 days “off”
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LDN and Opiates
• DOSING:
– Offer ULDN FIRST!
– If the patient is on opiates and CONSENTS to a trial of LDN I tend
to go slower:
• 0.5 mg X 2 weeks
• 1 mg X 2 weeks
• 1.5 – 2.5 mg X 1 month
• 3.5 – 4.5 mg terminal dose
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LDN and Opiates
• In Opiate using patients there are many factors which can make LDN either not
interfere or cause interference and breakthrough pain.
– If patient is on OPIATES:
• 10-20% will have cross reactivity / Breakthrough pain
– Decrease in opiate effect
– Must disclose this and monitor
• 80-90% will not
• Slower ramping up of dose is needed to assess
• You may find a dose at which there is no opiate inhibition and then one in
which there is as you ramp up. – So STOP at the one with no breakthrough!
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LDN Dosing in Autoimmunity / Infections etc.
• DOSING:
– In the auto-inflammatory setting (Patient with more stable case) I
tend to dose:
• 1 mg X 1 month
• 1.5 – 2.5 mg X 1 month
• 3.5 – 4.5 mg terminal dose
• (An alternate strategy is 1.5 mg X 2 weeks, 3 mg X 2 weeks then
4.5 mg)
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Always consider the stability of the case:
At a low dose (1.5 mg) "stimulation and stabilization" is strong and immune suppression is
hardly present. When immune suppression is weak and the immune system is stimulated,
the autoimmune reactions are enhanced and many are experiencing symptom aggravation
until stabilization occurs.
At 3 to 4.5 mg the "stimulation and stabilization" action is at maximum strength and the
immune suppression is weaker. This explains why starting at a 3 mg dose may give a
tough startup sometimes.
At high doses (6 mg) the immune suppression action is strong and "stimulation and
stabilization" is weaker. Therefore symptom aggravation will likely be less but your immune
system will still be gently stimulated and the stabilization of the immune system will be in
place gradually.
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Higher dose to “calm” then try to taper
1. Try 6 mg for a few days but stop if experiencing severe discomfort. It may
take a few days before any effect happens.
2. If one feels worse after directly starting at 6 mg (3 mg BID) LDN or if one
feels worse after a period of 6 mg LDN then the dose is probably too high and
should be lowered down to 4.5 mg.
3. If one has dosed at 6 mg (3 mg BID) LDN for 2 to 3 weeks with good effect,
try to decrease to 4.5 mg. If results are not as good at 4.5 mg, then go back to 6
mg and stay at this dose even longer before again trying to reduce to 4.5 mg.
Attempting to move periodically to 4.5 mg may provide better results. N.B. If
reduction does not give better results, you can continue to use 6mg (3mg BID)
as standard dose.
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Higher dose to “calm” then try to taper
4. Whether to take 3 mg, 4.5 mg or 3mg BID as standard dose is individual and
will vary from person to person. If one has reduced the dose to 4.5 mg and has
had good effects then stay at this dose. If the effects are still poor, but better
than the 6 mg, one can try to vary between 3 and 4.5 mg to see what dose
works best. When you have found the dose that seems to work best (eg. 3mg,
4,5mg or 3mg BID), then stay at this dose.
5. Most of these cases WOULD NOT be amenable to cyclic dosing for a while…
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PEDIATRIC DOSE CALCULATIONS
• General Rules:
• It is very important to maintain precision when using these rules to determine the correct dose of medication
for the pediatric patient. Therefore, it is suggested to use the following rounding rules:
• Weight Doses (mg)
• When calculating doses in weights, medications that are less than 1 mg should be rounded two decimal places
(hundredths place).
• Doses that are 1mg - 10 mg should be rounded to one decimal place (tenths place).
• Doses greater than 10 mg should be rounded to the whole number.
• Volume Doses (mL)
• Doses that are less than 1 milliliter should be rounded to two decimal places (hundredths place).
• Doses greater than 1 milliliter should be rounded to one decimal place (tenths place).
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PEDIATRIC DOSE CALCULATIONS
* As a general rule in practice over the past decades we
have found that the application of “Clark’s Rule” has yielded
great safety and efficacy in calculating pediatric doses for
both IV and Oral medications. The other methods are listed
for technical accuracy.
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PEDIATRIC DOSE CALCULATIONS
1. Clark's Rule is a medical term referring to a procedure used to calculate the amount of medicine to give to a child aged 2-17. The procedure is to take the child's weight in pounds, divide by 150lbs, and multiply the fractional result by the adult dose to find the equivalent child dosage.
• Pediatric dose = [child’s weight (lb) / 150 (lb)] x Adult dose
• For example: If an adult dose of medication calls for 30mg and the child weighs 30lbs. Divide the weight by 150 (30/150) to get 1/5. Multiply 1/5 times 30mg to get 6mg. (Or convert the fraction to a decimal and multiply – 0.20 in this case).
Common IV example:
• Adult goal dose is 100 grams IV Vitamin C
• Child weighs 25 pounds
• [25 lb / 150 lb] x 100 grams
• 1/6 x 100 grams [convert to a decimal]
• 0.167 x 100 grams = 16.7 gram dose max
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PEDIATRIC DOSE CALCULATIONS
2. Young’s Rule: utilizes similar concepts as Fried’s Rule except it is based on the child’s age in years. When given
the adult dose of a medication it is possible to use this formula to find the correct pediatric dose.
Pediatric dose = [child's age in years / child's age in years + 12 years] x Adult Dose
3. Fried's Rule is a method used to calculate the correct dose of medication for the pediatric patient when given
only the adult dose. This method should not be considered as accurate as the nomogram method because it is
based on the assumption that the child is of average size and utilizes age rather than weight. It is important to note
that because age does not necessarily indicate the patient's weight, medication adjustments may be necessary once
the patient's response is determined.
• Fried's rule is a method of estimating the dose of medication for a child by dividing the child's age in months by
150 and multiplying the result by the adult dose.
Pediatric dose = child's age in months / 150 x Adult Dose
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PEDIATRIC DOSE CALCULATIONS
3. The Nomogram method is utilized to determine the correct pediatric medication dosage based specifically on
the patient's size. The patient's size is identified as body surface area (BSA) in meters squared (M2). The average
adult client (weighing 150 - 154 lbs) will have a BSA of 1.73M2. The nomogram chart can be used to identify the
patient's BSA based on their height and weight (in. and lbs. or cm and kg).
• The surface area is determined where a straight line connecting the patient's height and weight crosses over the
BSA column.
• Once the BSA of the patient is determined the following formula can be used to calculate the correct pediatric
dosage:
Pediatric dose = Child's BSA in M2 / 1.73M2 x Adult Dosage
Some data derived from the pharmacology databank at: http://www.austincc.edu/rxsucces/ped2.html
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Select Resources:
• LDN Research Trust: https://ldnresearchtrust.org/
• Pain, Opiates and ULDN https://vimeo.com/358998952
• ULDN-Opioids: https://www.khemcorp.com/ultra-low-dose-
naltrexone-for-lower-opiate-tolerance-research-summary/
• Cancer and LDN https://vimeo.com/168562089 (The one I’m in....)
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QUESTIONS ABOUT (CE Cert, etc.) -----? Go here:
https://www.consultdranderson.com/contact/
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AAMP Conferences – 18 Cat-1 CME
• Spring - May 21, 22 & 23
– CHRONIC INFECTION CASES
– https://aampconferences.com/aamp-spring-conference-2021/
• Fall – September 24, 25 & 26
– ONCOLOGY
– https://aampconferences.com/aamp-fall-conference-2021/
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89
Thank You – Questions?
(c) PS Anderson - www.ConsultDrA.com 2021