1. LDN Low Dose Naltrexone
Michael Gresh
PharmD Candidate 2017
University of Connecticut
Special Thanks to:

2. 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

3. 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

4. Opioid Receptors CNS and PNS Endogenous Opioid Peptides
Naltrexone
Approved by FDA in 1984
Opiate antagonist
Indicated to treat Opiate and Alcohol addiction
Dose: between mg per day
Opioid Receptors CNS and PNS
• Epsilon (Endorphins)
• Delta (Enkephalins)
• Kappa (Dynorphins)
• Mu (Morphine)
• Sigma
Endogenous Opioid Peptides
• Endorphins
• Enkephalins
• Dynorphins

5. Pharmicokinetics Oral Absorption: Metabolism: Excretion: Half Life
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

6. 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
vomiting for hours-can be severe!

7. 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

8. Low Dose Naltrexone aka “LDN”

9. What is LDN and how does it work?
Dose: 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)
Since endogenous endorphins work at opioid receptors to produce analgesic processes, it would seem that LDN would have no benefit.

10. Proposed Indications for LDN
Autoimmune disorders
Cardiac diseases
Dermatologic diseases
Ear, Nose, Sinus & Throat
Endocrine diseases
Gastrointestinal diseases
Hematologic/Blood marrow disorders
Infectious diseases
Malignancies/cancers
Neurologic diseases
Ocular diseases
Psychological disorders
Pulmonary disease
Rheumatologic disorders
Urologic diseases
Vasculitis

11. 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.

12. Mechanism(s) of Action
Cellular Science

13. 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 fold increase in enkephalin levels – J. Smith

14. 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

15. 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
Important information to now explain why we have had tremendous difficulty in treating chronic pain using opioids!!!

16. 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.
Sources
Dalayeun, JF; et al. "Physiology of beta-endorphins. A close-up view and a review of the literature." Biomedicine & Pharmacotherapy. 1993, Vol. 47, issue 8.
Lundbeck Institute. "Neurological Control: Neurotransmitters." (June 1, 2009)
Sailing, Jasmine. "Endorphins: Free Smack!" Morbid Curiosity,
Stoppler, Melissa Conrad, MD. "Endorphins: Natural Pain and Stress Fighters." March 15, (June 1, 2009)
The Merck Manuals Online Medical Library. "Neurotransmission." Nov (June 1, 2009)
The Merck Manuals Online Medical Library. "Principles of Endocrinology." Nov (June 1, 2009)
University of Bonn. "Runners' High Demonstrated: Brain Imaging Shows Release Of Endorphins In Brain." ScienceDaily. Mar. 6, (June 5, 2009)
Wake Forest University Baptist Medical Center. "Small Study Points To Addictive Effects Of Frequent Tanning." ScienceDaily. Mar. 29,
WebMD. "Meditation Boosts Mood, Immune System." Aug. 18, (June 4, 2009)
Zimmerberg, Betty. "Synaptic Transmission: A Four Step Process." Multimedia Neuroscience Education Project, Williams College Neuroscience (June 5, 2009)

17. 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.
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

18. 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 Jan;44(1 Pt 1):92-4.
Enkephalins and endorphins as modifiers of the immune system: present and future.
Wybran J
Sources
Dalayeun, JF; et al. "Physiology of beta-endorphins. A close-up view and a review of the literature." Biomedicine & Pharmacotherapy. 1993, Vol. 47, issue 8.
Lundbeck Institute. "Neurological Control: Neurotransmitters." (June 1, 2009)
Sailing, Jasmine. "Endorphins: Free Smack!" Morbid Curiosity,
Stoppler, Melissa Conrad, MD. "Endorphins: Natural Pain and Stress Fighters." March 15, (June 1, 2009)
The Merck Manuals Online Medical Library. "Neurotransmission." Nov (June 1, 2009)
The Merck Manuals Online Medical Library. "Principles of Endocrinology." Nov (June 1, 2009)
University of Bonn. "Runners' High Demonstrated: Brain Imaging Shows Release Of Endorphins In Brain." ScienceDaily. Mar. 6, (June 5, 2009)
Wake Forest University Baptist Medical Center. "Small Study Points To Addictive Effects Of Frequent Tanning." ScienceDaily. Mar. 29,
WebMD. "Meditation Boosts Mood, Immune System." Aug. 18, (June 4, 2009)
Zimmerberg, Betty. "Synaptic Transmission: A Four Step Process." Multimedia Neuroscience Education Project, Williams College Neuroscience (June 5, 2009)

19. 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

20. 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: /ebm
OGF-OGFr axis regulates cell proliferation by altering the G1/S phase of the cell cycle through the p16 and p21 cyclin – dependent inhibitory kinases

21. Endorphin/Enkephalin Stimulation
Immune modifying effect:
Local effects –
Reduces pro-inflammatory cytokines---Interleukin (2,6,12), TNF (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

22. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces, but they have also been implicated in autoimmune and inflammatory disorders. The loss of Th17 cell populations at mucosal surfaces has been linked to chronic inflammation and microbial translocation
The dysregulation of Th17 cells has been associated with autoimmune disorders and inflammation. In the case of autoimmune disorders, Th17 cell over activation can cause an inappropriate amount of inflammation, like in the case of rheumatoid arthritis. Th17 cells have also been shown to be necessary for maintenance of mucosal immunity. In HIV, the loss of Th17 cell populations can contribute to chronic infection

23. 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

24. 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

25. 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

26. 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 mg
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: /bph

27. 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): The 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:  /s PMCID: PMC
Once activated, microglia produce inflammatory and excitatory factors (Substance P, nitric oxide, i.e.) that can cause pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise.
In addition it has been shown to have anti-inflammatory effects in the periphery as seen through suppression of TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages

28. 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
In addition, 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. The potential implications of such glial regulation of pain and opioid actions are vast, suggestive that targeting glia and their proinflammatory products may provide a novel and effective therapy for controlling clinical pain syndromes and increasing the clinical utility of analgesic drugs.

29. 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.

31. STUDIES

32. “Low Dose Naltrexone as a Treatment for Active Crohn’s Disease”
American Journal of Gastroenterology in 2007
Am J Gastroenterol Apr;102(4): 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

33. 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.

34. 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

35. 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”

36. “Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn’s disease”
Digestive Diseases & Sciences in 2011
Dig Dis Sci Jul;56(7): doi: /s 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

37. 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.

38. 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)
88% of naltrexone pts had at least a 70 point decline in CDAI vs 40% of placebo pts (p = 0.009)
78% of naltrexone 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)
33% of naltrexone pts achieved remission (CDEIS < 6) vs 8% of placebo pts.
Fatigue was the only side effect and reported mostly in the placebo arm.
Dig Dis Sci Jul;56(7): doi: /s Epub 2011 Mar 8.

39. 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 Jul;56(7): doi: /s Epub 2011 Mar 8.

40. Study Results: QoL
Quality of life indices improved to a greater extent in subjects treated with naltrexone compared to placebo but was not significant.
Dig Dis Sci Jul;56(7): doi: /s Epub 2011 Mar 8.

41. Extended Open-Label Study
With the extended naltrexone therapy (24-weeks), CDAI scores demonstrated further significant reduction compared to the 12-week naltrexone treatment values. When subjects who had been on placebo for 12 weeks were then treated with naltrexone, a significant decline in CDAI scores also occurred. Columns represent means ± SEM. (Significantly different from corresponding week 12 at **p < 0.01 and ***p < 0.005). b Mucosal healing as determined by endoscopic appearance was maintained when naltrexone was extended beyond the 12-week time point to 24 weeks. Although a decrease by 36% in endoscopic scores was reported in those continued on naltrexone compared to week 12, this difference was not significant. However, the week-24 values were significantly improved (p = 0.005) compared to baseline. Mucosal healing was evident in those who had taken placebo for 12 weeks and then subsequently were treated with naltrexone. **Significantly different from corresponding week 12 level at p < 0.01
Dig Dis Sci Jul;56(7): doi: /s Epub 2011 Mar 8.

42. LDN in Chronic Pain

43. “Low Dose Naltrexone for the treatment of Fibromyalgia”
Arthritis and Rheumatism in 2013
Arthritis Rheum Feb;65(2): doi: /art 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.

44. 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): doi: /art

45. 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.

46. “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:  /s
PMCID: PMC
The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain
Jarred Younger, Luke Parkitny, and David McLain

47. 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.”

48. “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
First online: 02 April 2013
Treatment of Complex Regional Pain Syndrome (CRPS) Using Low Dose Naltrexone (LDN)
Pradeep Chopra , Mark S. Cooper
/s y

49. 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.

50. 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

51. “Low dose naltrexone in the treatment of dissociative symptoms”
Nervenarzt Mar;86(3): doi: /s
[Low dose naltrexone in the treatment of dissociative symptoms].
[Article in German]
Pape W1, Wöller W.

52. 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.

53. 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

54. LDN-Female Reproductive Disorders

55. 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

56. 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
– “We intend to do a clinical trial with LDN 3-4.5mg nightly”
Phil Boyle uses BioIdentical progesterone as well to achieve these results..
Courtesy of: Phil Boyle, MD “Novel uses for a licensed medication” New Orleans, August 2013

57. 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
Fertility and Sterility Seifer DB et al, Yale University School of Medicine

59. LDN-PRESCRIBING INFO Start with 1.5mg QD HS x 2 weeks 3mg QD 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
No effect..Increase dose to 4.5mg QD HS x 2 weeks
Usual Maintenance Dose: 4.5mg HS

60. 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)

61. CLINICAL CONSIDERATIONS

62. LDN-possible Side Effects
Vivid Dreams
Sleep Disturbance
Nausea (generally will last for about 2 weeks)
Headache
Dry Mouth (over 95% acceptable)

63. 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

64. LDN-Cautions
LDN is an opioid antagonist- may need to wean patients currently on long term opioids over 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

65. Naltrexone Clinical Considerations
Warn patient against non-prescribed or illicit opioid use, as the very high amount of opioid required to overcome the antagonist effect of naltrexone hydrochloride may result in life-threatening or fatal overdose.
Instruct patient of the risk for accidental opioid overdose after detoxification is completed or temporarily interrupted, including use of lower doses or previously tolerated doses
Advise patient to carry identification to alert medical care providers of current detoxification therapy
This drug may cause nausea, loss of appetite, diarrhea, constipation, or an opioid withdrawal-like symptom complex (eg, tearfulness, abdominal cramps, restlessness, bone or joint pain, myalgia, nasal symptoms)
Advise patient to immediately report symptoms of opioid withdrawal (eg, confusion, somnolence, visual hallucinations, vomiting, diarrhea). Withdrawal symptoms may occur within 5 minutes of ingestion and may last up to 48 hours
Instruct patient to report signs or symptoms of depression, worsening depression, or suicidal ideation
Advise patient to report signs/symptoms of acute hepatitis or other hepatic dysfunction

66. 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
Parkinson’s Disease
Alzheimer’s Disease
Endometriosis
Dystonia
Psoraisis
Lymphoma
Lung Cancer
Breast Cancer
Liver Cancer
Systemic Lupus
Complex Regional Pain Syndrome

67. 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.

68. 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.

69. Low-Dose Naltrexone in Diseases’ Treatment: Global Review Research Inventy: International Journal of Engineering And Science Vol.6, Issue 2 (February 2016), PP Issn (e): , Issn (p): ,
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.

71. Questions?