LDN refers to doses of 1.5 mg to 4.5 mg, a usual dose range. Now people start as low as 0.5 mg; Dr. Kim starts at 0.1 mg, the ULDN, and literature research shows even lower doses are used in the laboratory. A challenge is finding a compounding pharmacy that can compound microdose ULDN, for example, 1 microgram – it is hard to find a laboratory that will assay and verify that they created that microdose of ULDN.
Another challenge is the interaction between LDN and opioid medications. If you take LDN while on an opioid, it can precipitate withdrawal and symptoms that can include heightened anxiety, nausea, vomiting, and abdominal pain. An example is a medication Embeda, a morphine + LDN capsule where if you swallow it whole, the morphine is effective and the LDN is not released. If it is crushed, as for snorting, then withdrawal has been reported. <Editor’s note: Embeda production ceased in 2019>
Dr. Kim thinks ULDN can be useful on patients taking opioids, based on observations that antagonists at lower settings appear to be weak agonists. Essentially, using 1 microgram of naltrexone, or ULDN, may offer improved pain control while lessening side effects. There are two ways to think about this. One is hormesis.
Hormesis is talking about a nonlinear effect where something acts as an inhibitor at high concentrations, but as a stimulator at lower concentrations. Originally this was referred to as the Arndt–Schulz rule, where a weak poison enhanced life processes, while strong concentrations inhibited these processes, and even terminated them. Although the rule fell out of favor because of limited reliability, it is the likely basis for homeopathy.
Another way to think about it is as a receptor-antagonist interaction, where at first the inhibitors inhibit receptor-ligand interaction – for example, if you take naltrexone it will inhibit the receptor where opioid medications usually bind. In response to lowered stimulation, either the body produces and deploys more detectors or receptors to the cell membrane. Over time this means you need a greater amount of inhibitor to produce the same effect, known as overcoming the inhibition over time.
That also works in scenarios of effect in the opposite way: antagonist versus agonist. Naltrexone is an antagonist, whereas opioids and endorphins are agonists. They both bind to the receptor. After binding, an agonist activates the receptor, so for the opioid receptor, that person would experience pain relief. With naltrexone, the antagonist, it binds to the receptor, but then the usual action of the receptor does not happen. The FDA-approved regular dose of naltrexone is 50 – 150 mg, and at this dose it is a competitive inhibitor. It blocks opioid binding through antagonistic action - nothing happens; and it out-competes opioids for binding to the opiate receptor.
LDN at 1.5 to 4.5 mg given to opioid-naïve patients can partially block endorphin reactions, and multiple possibilities may happen.
· One is increased production of endorphin negative feedback, meaning that the body can sense that endorphin stimulation is below a certain level, a negative feedback mechanism is triggered, and more endorphin is produced.
· Opioid receptor resetting resulting in increased sensitivity to endorphins. The antagonist, or by blocking the opioid receptor, allows the opioid receptor to go back to the original configuration of being off. An overstimulated receptor results in the receptors being stuck at quasi-on mode, which is one way it’s thought that tolerance, or requiring a higher dose of medication to get the same effect is thought to occur.
· Opioid upregulation, where more receptors are produced and deployed to the cell membrane. Lower stimulation from endorphins results in increased sensitivity to endorphins
· LDN is thought to be a CNS anti-inflammatory agent, by regulation or blocking glial cell activation. Micro-dose ULDN at 1 microgram binds to the opioid receptors, but this low dose is not likely to overwhelm the opioid medication, so some receptors will be occupied by the opioid, and some at a lower percentage, would be occupied by naltrexone. So at the varying concentrations, based on dosing, opioid receptors appear to be re-set, which results in sensitization. Normally, opioid medications are unopposed and the receptor results in down-regulation, meaning fewer receptors will be produced and deployed to the cell membrane
· Some authors theorize that unopposed opioid stimulation of receptors results in a tolerance effect. <see illustration> This is an illustration of new opioid receptor and ligand viewed from the side and the top – ligand in this case would mean medication.
Oxytrex is an investigational medication combining oxycodone and 1 microgram of naltrexone. Dr. Kim spoke on two trials showing that using Oxytrex for pain can provide similar pain relief with fewer side effects (Chindalore, 2005, chronic osteoarthritis hip, 39% greater pain reduction in the Oxytrex group); (Wester 2006, chronic back pain, 55% less physical dependence and less constipation and somnolence). As Oxytrex is not available commercially, a pharmacy capable of compounding ULDN is needed.
Dr. Kim’s personal experience after more than 10 yrs prescribing LDN is that ULDN is very helpful in an endorphin-depleted sub-population. To estimate endorphin reserves he asks questions to gauge their energy levels, quality of restorative sleep, and resilience: how long they have had the illness, how they sleep, then a resiliency question.
Dr. Kim’s use of ULDN includes a neuroanatomical or pharmacological approach to pain. First, explore if pain can be reduced through neuroanatomical acupuncture or other techniques not involving pharmaceuticals. Second is starting or increasing ULDN. The third, if pain continues, is to trial decreasing pain medication.
· Microdosing naltrexone 1-2 micrograms/day along with opioids decreases the side effects of opioids and increases pain control
· Combining ULDN with non-pharmacological pain management is clinically significant
· For non-opioid-dependent patients, ULDN is useful for endorphin-depleted patients
· Given the opioid crisis in the US, ULDN should be explored in depth. We can reduce side effects and ensure about the same analgesia.
Summary from Dr. John Kim’s presentation at the 2018 LDN Research trust Conference. Listen to the video for the show.
Keywords: LDN, low dose naltrexone, ultra-low dose naltrexone, microdose, ULDN, opioid, pain, agonist, receptor-antagonist interaction, hormesis, endorphin, opioid receptor, upregulation, Embeda, Oxytrex, neuroanatomical