LOW DOSE NALTREXONE THERAPY

WHAT IS LOW DOSE NALTREXONE?

It reduces pain and fights inflammation. It is used to treat cancers, autoimmune diseases, chronic pain and mental health issues, to name a few. Treatment is constantly evolving, with new conditions and methods of treatment being shared regularly.

In 1984 Naltrexone was approved by the FDA in the USA for the treatment of opioid addiction, used at the standard dose of 50mg to 100mg per day. It is a pure antagonist at various opioid receptors, Delta Kappa, Mu, and Opioid Growth Factor (OGF) receptors.

Which Conditions can be treated with Low Dose Naltrexone? The list is pretty extensive.

What is LDN and how does it work? LDN is a competitive opioid receptor antagonist. At the standard dose, naltrexone blocks the effects of both the endogenous opioids, which are in endorphins and pharmaceutical opioids. LDN is a pure antagonist, which is vital to know as a lot of people think it is a controlled medicine, narcotic or an opioid.

LDN is a pure inhibitor, so there is no narcotic effect. The chemical structure is almost identical to endorphins that we make naturally called met-enkephalin, also known as OGF or Opioid Growth Factor.

LDN is an antagonist at the OGF receptors and there are OGF receptors on a wide range of cells in the body.  When we talk about low dose naltrexone we mean doses that are a 10th or less of the standard dose of Naltrexone. Most of the research studies have used 4.5mg per day. Doses range from 0.001mg – 16mg in clinical practice.

Low Dose Naltrexone binds to the endorphin receptors for about 1 – 1/2 hours, and the blockade lasts about 4 – 6 hours. The effects of LDN are analgesia and anti-inflammatory. One of the other effects is that it increases the production of your own endorphins.

Research into the effects of LDN began in the 1980s by Dr. Ian Zagon and Dr. Patricia McLachlan at Penn State. Dr. Bernard Bihari, in New York was the pioneer of using LDN in clinical practice. In the mid-1980s he was using it to treat HIV in his patients. His patients were taking Naltrexone for their opioid addictions and as he weaned them off it he noticed positive side effects with other conditions and symptoms. He was a Harvard trained physician who was a specialist in neurology. He was running the New York State health department, and he was aware of the research that was going on and tried it out for clinical use.

The first published human trial was in 2007 by Dr. Jill Smith, it was a study for Crohn’s disease.

• Naltrexone exists in a racemic mixture of isomers (“left-handedness and right-handedness”)
• Dextro-naltrexone binds toll-like receptors (TLR)
• Levo-naltrexone binds opioid receptors

DEXTRO-NALTREXONE

• Antagonist effect at Toll-like receptors (TLR)
• TLR-4 receptors exist on microglial cells, other macrophages, mast cells
• Activated microglial cells produce proinflammatory cytokines, substance P, nitric oxide
• Inhibition leads to a decreased proinflammatory cascade

LEVO-NALTREXONE

• Antagonist effect at opioid receptors
• Small temporary opioid blockade
• Upregulates endogenous opioid production
• Upregulates opioid receptors
• Increased endorphins favorable to the immune system

Endorphins are your natural peptides produced in many cells that regulate cell growth, including your immune cells. Many patients who have autoimmune disease tend to have low levels of endorphins, Met-enkephalin, aka opioid growth factor (OGF), an important immunomodulatory. Opioid receptors are in the central and the peripheral nervous system, the GI tract, and on lymphocytes. By using LDN you receive a brief blockade, creating a rebound effect giving you more endorphins, including OGF, and increased production of the OGF receptors.

This is a wide range of diseases, and many clinicians will find it difficult to understand how one drug can have a positive effect on all these pathologies.

The first thing to understand is that naltrexone – the drug in LDN – comes in a 50:50 mixture of 2 different shapes (called isomers). It has been recently discovered that one particular shape binds to immune cells, whilst the other shape binds to opioid receptors.

Although consisting of exactly the same components, the two isomers appear to have different biological activity.

SUMMARY OF MECHANISM OF ACTION

The summary of 10 years of research is that LDN works because:

• Levo-Naltrexone is an antagonist for the opiate/endorphin receptors
• This causes increased endorphin release
• Increased endorphins modulate the immune response
• This reduces the speed of unwanted cells growing. Dextro-Naltrexone is an antagonist for at least one, if not more immune cells
• Antagonises “TLR,” suppressing cytokine modulated immune system
• Antagonises TLR-mediated production of NF-kB – reducing inflammation, potentially downregulating oncogenes

Taking Naltrexone in larger doses of 50-300mg seems to negate the immunomodulatory effect by overwhelming the receptors, so for the effect to work, the dose must be in the range of 0.5-10mg, usually maxing at 4.5mg in clinical experience.

The Use of Low-dose Naltrexone, and the Occurrence of Side Effects

Many patients who start LDN do not experience any severe side effects.

As mentioned earlier, your symptoms may become worse – in MS, this can be characterized by increased fatigue or increased spasticity. In CFS/ME, this can be the onset of apparent flu-like symptoms. LDN can cause sleep disturbances if taken at nighttime – this is most likely because of the increase in endorphin release. These disturbances can take the form of vivid dreams or insomnia.

In various studies (and anecdotal accounts), the number of T-Lymphocytes has been shown to dramatically increase when a patient starts on LDN. This may account for some of the benefits patients feel when they are being treated for an autoimmune disease or cancer. This has not been directly evidenced in multiple sclerosis.

Clinical experience shows that in less than ten percent of cases treated, increased introductory symptoms may be more severe or more prolonged than usual, lasting sometimes for several weeks. Rarely, symptoms may persist for two or three months before the appropriate beneficial response is achieved.

If side effects are troublesome, try reducing your dose by 50% for 7 days, before increasing it again.

Some patients very rarely experience gastrointestinal side effects, such as nausea and or constipation/diarrhea. The reason for this is currently unknown, but may be due to the presence of large numbers of delta-opiate receptors in the intestines.

Patients experiencing this side effect can request LDN Sublingual Drops, which transfer the LDN directly into the bloodstream – avoiding the GI tract.

Patients who do have these side effects should increase their dose by no more than 0.5mg per week and should consult with their GP or pharmacist for appropriate treatment for the stomach upset, if necessary. (eg Omeprazole, Ranitidine, Gaviscon, Fybogel, Mucogel and Pepto Bismol are ok – but not Kaolin & Morphine or Loperamide/Imodium.)

USE OF LDN IN CHRONIC PAIN

LDN has been tested experimentally in a small number of chronic pain conditions. One such condition is fibromyalgia (FM). FM is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation as well as profound fatigue, cognitive disruption, and sleep difficulty. Although FM does not respond to common anti-inflammatories and does not seem to be an inflammatory disorder in the classic sense, inflammatory processes may still be involved. We have shown in two separate, small clinical trials that LDN may be an effective treatment for FM. In both trials, LDN was administered at 4.5 mg daily, once at night before bedtime. In the first crossover trial, published in 2009, LDN reduced fibromyalgia pain significantly greater than placebo in 6 out of the 10 women. While the pilot study was encouraging, it had limitations such as a single-blind design. To help validate the findings, a second study in 30 women with fibromyalgia was conducted. In that double-blind, crossover, counterbalanced study, 57 % of the participants were observed to exhibit a significant (1/3) reduction of pain during LDN. At the end of the LDN treatment, half of the participants reported feeling “much improved” or “very much improved” from LDN. Together, these two studies suggest that LDN is superior to placebo in reducing the pain associated with fibromyalgia.

EVIDENCE FOR A NOVEL CENTRAL ANTI-INFLAMMATORY ACTION OF NALTREXONE

While preliminary evidence exists for the efficacy of LDN, it is critical that we better understand the mechanism of clinical action. This information would allow researchers to develop even more effective treatments for fibromyalgia and other pain disorders. We now present three pieces of evidence to support the argument that LDN may be a useful therapeutic agent in pain conditions that involve ongoing inflammation. First, we will discuss in vivo and in vitro basic scientific evidence of naltrexone’s anti-inflammatory effects. Second, we will identify a relationship between LDN and baseline inflammation. Third, we will mention other inflammatory conditions in which LDN has demonstrated clinical efficacy.

WHY A LOW DOSAGE?

Successful treatment of chronic pain with naltrexone may require low dosages. Theoretically, a complete blockade of endogenous opioid systems would not be a desirable outcome with a chronic pain patient. Basic science evidence supports that concept by showing that low- and high-dose opioid antagonists have quite different impacts on the physiologic system.

It may initially seem strange that a medication can have an opposite effect when given at a low dosage. However, there is a strong precedent for this concept—and with opioid-related drugs in particular. A paradoxical hyperalgesic effect of low-dose morphine was first widely reported in 1987. Morphine was administered via the IV route to rats after arthritis was induced using Freund’s adjuvant. A dose of 100 μg/kg produced clear analgesia, 50 μg/kg produced less significant analgesia, and 30 μg/kg showed no difference from saline. At around 10 μg/kg, however, the researchers saw the development of morphine hyperalgesia, which became most pronounced at 6 μg/kg. This finding, which has been replicated several times, suggests that there is a small window at which opioid analgesics produce the opposite effects than those typically expected. The dosage of morphine that appears to cause paradoxical hyperalgesia is approximately 1/10th of the dosage typically used to produce analgesia. We note that the dosage of naltrexone that is used to reduce pain is also approximately 1/10th of the dosage used for substance abuse treatment.

ADVANTAGES OF LDN

Because LDN is still an experimental therapy for chronic pain, there must be significant promise to justify recommending its use. LDN carries several advantages that may make it an attractive treatment option, which are reviewed below.

LOW COST

As a generic medication, naltrexone HCl is inexpensive. While pricing can vary considerably by region and pharmacy, the monthly cost of LDN appears to average US$35 per month. That cost includes compounding and assumes no insurance coverage. The price is lower than what would be paid for current on-patent medications for fibromyalgia, which can cost over US$100 per month.

LOW SIDE EFFECTS

One of the most exciting aspects of LDN is the low reported incidence of adverse side effects. We have not seen incidences of ulcers, renal insufficiency, interference with warfarin and other common medications, increased heart attack or clotting risk, or other problems that can be seen with nonsteroidal anti-inflammatory drugs. We have observed no cases of severe adverse events in our research, and none have been reported from other laboratories. We have observed no withdrawal symptoms when LDN treatment is stopped, and withdrawal is not a known effect of treatment discontinuance [46]. However, the complete sample size of all LDN trials combined is still quite small and thus clinically useful data and experience are limited.

Side effects of LDN treatment are mild. In our research, participants have rated LDN as slightly more tolerable than placebo (91.0 versus 89.5 %, not significant). The most common side effect we have observed is the reporting of more vivid dreams, which is seen in approximately 37 % of the participants. In a minority of cases, patients report nightmares. As a side effect, vivid dreams develop rapidly (as soon as the first dosing) and decrease over time. It is unclear what mechanism may drive increased vividness of dreams. Individuals generally self-report increased effectiveness of sleep, so it is unlikely that the vivid dreams represent an adverse disruption of normal sleep patterns. It is important to note that increase vividness of dreams is also the most commonly reported side effect during placebo administration, so some cases may be driven by expectancy.

The frequency of headaches when taking LDN was slightly higher than during placebo administration, though more participants will need to be assessed in order to determine the statistical significance of the difference. Spontaneous headaches are common in individuals with fibromyalgia and frequently appeared in all stages of the clinical trials.

While not observed in research studies, some physicians have anecdotally reported anxiety and tachycardia as adverse reactions to LDN. As anxiety is a known symptom of opioid withdrawal, it is possible that some individuals would experience anxiety due to blockade of endogenous opioids. Further observation will need to be carried out to determine how common this adverse event is and how to best manage it.

For individuals without severe hepatic disease, there does not appear to be any need to frequently monitor hepatic function. Even at much larger dosages, naltrexone does not significantly change hepatic enzyme activity. We have not observed any toxicity issues with chronic use.

NO KNOWN ABUSE POTENTIAL

As an opioid antagonist, naltrexone is used as a treatment for substance abuse. LDN does not exert any euphoric or reinforcing effects, and we have observed no cases of LDN misuse or abuse. Furthermore, we have not seen the development of dependence and tolerance with the medication. In our studies, the cessation of LDN is generally followed by a slow return of symptoms to baseline levels.